Convenient synthesis of 2,3-disubstituted quinazolin-4(3H)-ones and 2-styryl-3-substituted quinazolin-4(3H)-ones: Applications towards the synthesis of drugs

Article abstract of DOI:10.1039/c5ra03888j

Simple, convenient, and green synthetic protocols have been developed for the one pot synthesis of 2,3-disubstituted quinazolin-4(3H)-ones and 2-styryl-3-substituted quinazolin-4(3H)-ones under catalyst and solvent free conditions. The multicomponent reaction (3-MCR) involving isatoic anhydride, an amine, and orthoester afforded the 2,3-disubstituted quinazolin-4(3H)-ones in excellent yields under classical heating at 120 °C for 5 h or under microwave irradiation at 140°C for 20-30 min. The use of ammonium acetate instead of the amine provides the 2-substituted quinazolin-4(3H)-ones. The reactions are compatible with various substituted isatoic anhydrides, aryl/heteroaryl/alkyl/cycloalkyl amines, and orthoesters. The strategies are extended to the one pot tandem condensation involving isatoic anhydride, an amine, orthoester, and aldehyde to afford highly functionalized (E)-3-aryl/heteroaryl-2-styrylquinazolin/(2-(heteroaryl)vinyl)quinazolin-4(3H)-ones. The applications of the methodologies are demonstrated through the synthesis of various drugs which act on the central nervous system such as methaqualone, mebroqualone, mecloqualone, piriquialone, and diproqualone.

Full text of DOI:10.1039/c5ra03888j

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ARTICLE TYPE
Convenient synthesis of 2,3-disubstituted quinazolin-4(3H)-ones and 2-
styryl-3-substituted quinazolin-4(3H)-ones: Applications towards the
synthesis of drugs
Dinesh Kumar, Pradeep S. Jadhavar, Manesh Nautiyal, Himanshu Sharma, Prahlad K. Meena, Legesse
Adane, Sahaj Pancholia and Asit K. Chakraborti*a
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Simple, convenient, and green synthetic protocols have been developed for one pot synthesis of 2,3ꢀ
disubstituted quinazolinꢀ4(3H)ꢀones and 2ꢀstyrylꢀ3ꢀsubstituted quinazolinꢀ4(3H)ꢀones under catalyst and
10 solvent free condition. The multicomponent reaction (3ꢀMCR) involving isatoic anhydride, an amine,
and orthoester afforded the 2,3ꢀdisubstituted quinazolinꢀ4(3H)ꢀones in excellent yields under classical
heating at 120 °C for 5 h or under microwave irradiation at 140 °C for 20ꢀ30 min. The use of ammonium
acetate instead of the amine provides the 2ꢀsubstituted quinazolinꢀ4(3H)ꢀones. The reactions are
compatible with various substituted isatoic anhydrides, aryl/heteroaryl/alkyl/cycloalkyl amines, and
15 orthoesters. The strategies are extended to the one pot tandem condensation involving isatoic anhydride,
an amine, orthoester, and aldehyde to afford highly functionalized (E)ꢀ3ꢀaryl/heteroarylꢀ2ꢀ
styrylquinazolin/(2ꢀ(heteroaryl)vinyl)quinazolinꢀ4(3H)ꢀones. The applications of the methodologies are
demonstrated through the synthesis of various drugs acting on the central nervous system such as
methaqualone, mebroqualone, mecloqualone, piriquialone, and diproqualone.
with acetaldehyde followed by benzylic oxidation and
20 Introduction
35 oxidative dehydrogenation using potassium iodideꢀtertꢀbutyl
hydroperoxide2 (Route A), (ii) domino coupling/condensation
cyclization process involving 2ꢀhalo benzamide with amidine
catalyzed by CuI3 (Route B), (iii) acid catalyzed
rearrangement of 4ꢀiminoꢀ4Hꢀ3,1ꢀbenzoxazine4 (Route C),
40 (iv) reaction of Nꢀacetyl anthranilic acid acetic anhydride
followed by the acid catalysed reaction of the intermediate
formed 4Hꢀ3,1ꢀbenzoxazine with amine5 (Route D), (v)
reaction of 2ꢀnitro benzoyl chloride with amine followed by
nitro reduction and its subsequent reaction with orthoester1k
45 (Route E), (vi) reaction of anthranilic acid, amine and acetic
acid6 (Route F), (vii) reaction of isatoic anhydride, amine and
orthoester7 (Route G) and, (viii) reaction of 2ꢀmethylꢀ4Hꢀ
Functionalised quinazolinones are highly sought for targets to
synthetic medicinal/organic chemists due to the broad
spectrum of biological activities exihibited by compounds
bearing this scaffold (Fig 1).1
benzo[1,3]oxazinꢀ4ꢀone with amine (Route H).8
O
NHAr1
NH2
CH3
NAr1
O
+
I
HN
Ar1
+
N
H
H2N
MeCHO
O
Route B
25
N
CH3
Route A
Route C
Route D
O
N
Ar1
N
COOH
Figure 1. Some pharmaceutically important quinazolinones.
Route H
O
Ar1-NH
Ar1-NH
2
+
+
2
N
NHAc
CH3
This spurred interest to develop synthetic methodologies
for this privileged pharmacophore for generation of new
30 therapeutic leads. The various synthetic strategies (Scheme 1)
adopted for the generation of 2ꢀmethylꢀ3ꢀsubstituted
quinazolieꢀ4(3H)ꢀones can be classified in the following
routes: (i) reaction of Nꢀ(2ꢀaminobenzyl)substituted amines
O
Route E
O
Route F
Route G
O
Ar1-NH2
Cl
+
Ar1-NH
+
(OEt) CMe
+
2
3
N
O
COOH
+ Ar1-NH2
H
NO2
(OR)3CMe
R = Me, Et
MeCO H
+
2
NH2
50 Scheme 1. Strategies for synthesis of 2ꢀmethyl–substituted quinazolinꢀ
4(3H)ꢀones
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On the other hand, the available methodologies for the
preparation of 2ꢀstyryl quinazolinꢀ4(3H)ꢀones (Scheme 2) are
limited to the: (i) reaction of anthranilic acid with styryl
increase of yield at higher temperature (entry 7, table 1). The
best result was obtained in performing the reaction at 120 °C
for 4 h (entry 9, table 1) as lesser yield was obtained in
carboxylic acid followed by amine insertion9 (Route A) and 50 lowering the reaction time to 2ꢀ3 h (entries 10 and 11, table
5
(ii) Knoevenagel condensation of 2ꢀmethylꢀ3ꢀsubstituted
quinazolinꢀ4(3H)ꢀone with aromatic aldehyde in the presence
of LDA1b or in refluxing glacial acetic acid10 (Route B), and
(iii) reaction of double lithiated 2ꢀmethyl quinazolinꢀ4(3H)ꢀ
1). To evaluate any beneficial/detrimental effect of solvents
on the formation of 4, the reactions were performed in
hydrocarbon, halogenated hydrocarbon, protic polar, and
aprotic polar solvents under reflux but the yields were inferior
one with aldehyde followed by TFA mediated dehydration11 55 compared to the solvent free condition. However, among the
10 (Route C).
different solvents used, the best result was obtained in case of
toluene (72%) followed by EtOH (56%).†
Table 1. The 3ꢀMCR of 1, 2, and 3 under various conditions to form 4.a
60 Entry
Temperature
(°C)
Time
(h)
Yield
(%)b
1
2
3
4
5
6
7
8
9
rt (25ꢀ30)
40
60
6
6
6
6
6
6
6
5
4
3
2
nil
trace
22
56
68
85
85
85
85
66
54
65
70
80
Scheme 2. General strategies for the synthesis of 2ꢀstyryl quinazolinꢀ
100
120
150
120
120
120
120
4(3H)ꢀones.
The adverse effect of the manufacturing processes of drugs
15 and pharmaceuticals on the environment urges for sustainable
development.12 The major drive towards this initiative is the
replacement of the use of volatile organic solvents (VOSs) by
solvent free reaction condition as VOSs are major contributors
to the environmental pollution due to their abundant use (more
20 than 85% of the total mass utilization of a chemical process)
and incomplete recovery efficiency (50 ꢀ 80%).13 Further, the
use of costly, explosive, toxic and carcinogenic chemicals
(catalyst/reagents) do not qualify them under sustainability
metrics as they augment the ecosystem toxicity resulting in
25 socioꢀeconomic burden. Thus, the development of ecoꢀ
friendly/green approaches to chemical synthesis is an ongoing
demand. In view of the role of the Nꢀbased heterocycles as
versatile pharmacophore there has been significant interest for
the development of sustainable synthesis.14 In this context,
30 solventꢀfree and catalyst free protocol for organic synthesis is
highly desirable to comply with the tripple bottomline
philosophy of green chemistry,15 to meet the demand of the
timely supply of the designed molecules for biological
evaluation,16 and for enrichment of the medicinal chemists’
35 tool box.17
10
11
aThe mixture of 1 (1 mmol), 2 (1 mmol, 1 equiv), and 3 (1 mmol, 1 equiv)
was treated under different condition. b Isolated yield of 4.
75
The requirement of longer time (4 h) led to search for an
alternative mode in performing the reaction to minimise the
reaction time. The microwaveꢀassisted synthesis offers means
towards green and rapid synthesis18 and has been used in this
laboratory for various organic reactions including the
80 synthesis of heterocycles.19 Therefore, the model reaction of
1, 2 and 3 was performed under microwave heating with
variation of the temperature and reaction time. The best
reaction condition was found to be the use of 150 W input
power at 140 °C for 20 min affording 4 in 90% yield†.
Thus, two methods for solvent and catalystꢀfree synthesis
of 2ꢀmethylsubstituted quinazolinones adopting the 3ꢀMCR
strategy are developed by the treatment of isatoic anhydride,
amine, and orthoacetate under: (i) conventional heating at 120
°C (oilꢀbath) for 4 h (Method A) and (ii) microwave heating at
85
90 140 °C for 20 min (Method B).
The versatility of these two methodologies can be
demonstrated through the reaction involving varieties of
isatoic anhydrides, amines, and orthoesters under
conventional (Method A, table 2) and microwave (Method B,
95 table 2) heating. Various aryl/heteroaryl/alkyl amines react
smoothly with isatoic anhydrides and orthoesters to form the
corresponding 2,3ꢀdisubstituted quinazolinꢀ4(3H)ꢀones in
excellent yields. However, inferior yields were obtained from
amines having electron withdrawing substituents (entry 17 &
100 18, table 2) compared to the amines bearing electron donating
substituents (entry 10 & 11, table 2). The reaction conditions
are compatible with heterocyclic (entry 19ꢀ21, table 2),
arylalkyl (entry 22ꢀ25, table 2), alicyclic (entry 26, table 2),
Results and Discussions
In order to develop
a
convenient synthesis of 2ꢀ
methylsubstituted quinazolinones, the model reaction
involving equimolar mixture of isatoic anhydride 1, aniline 2
40 and triethyl orthoacetate 3 was performed under solvent and
catalyst free condition at different temperature (table 1) to
form 2ꢀmethylꢀ3ꢀphenylquinazolinꢀ4(3H)ꢀone 4. No product
formation was observed at rt (25ꢀ30 °C) (entry 1, table 1) after
6 h. However, the yield of 4 increased with the increase of the
45 reaction temperature (entry 2ꢀ5, table 1). The optimal result
was obtained at 120 °C (entry 6, table 1) with no further
2
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and allyl (entry 27, table 2) amines.
With respect to the orthoesters, the reactions were
performed with commercially available orthoesters and
excellent yields were obtained in each case. The reaction
works well with substituted isatoic anhydrides (entries 28ꢀ34,
table 2).
31
32
Me
Me
R1 = H
R1 = 4ꢀSCH3
80
74
81
77
5
Table 2. The 3ꢀMCR for oneꢀpot synthesis of 2,3ꢀdisubstituted
quinazolinꢀ4(3H)ꢀones.a.
50 33
Me
R1 = H
80
82
34
Me
R1 = H
78
84
aMethod A: Isatoic anhydride (2.5 mmol) was treated with the
amine/NH4OAc (2.5 mmol, 1 equiv) and orthoester (2.5 mmol, 1 equiv)
55 under neat condition at 120 °C for the 5 h. Method B: Isatoic anhydride
(2.5 mmol) was treated with the amine/NH4OAc (2.5 mmol, 1 equiv) and
orthoester (2.5 mmol, 1 equiv) under neat condition at 140 °C (150 W) for
20ꢀ30 min. b Isolated yield of the desired quinazolinone.
10 Entry Isatoic
anhydride
R
H
Amine/
NH4OAc
Yield (%)b
Method B
Method A
The 2ꢀmethylꢀ3ꢀsubstituted quinazolinones serve as the
60 starting materials for the preparation of 2ꢀstyrylꢀ3ꢀsubstituted
quinazolinones during the condensation with aldehydes which
however requires the use of strong base such as LDA1b,11 or
reflux in HOAc for prolonged period (12 h). The
multicomponent reactions (MCRs)20 have been recognised as
65 new green synthetic tools to rapidly generate the synthetic
targets in convergent and atomꢀeconomical fashion.
Therefore, the tandem one pot reaction (Route D, Scheme 3)21
of 1, 2, 3, and benzaldehyde 5 to form the 2ꢀstyrylꢀ3ꢀphenyl
quinazolinone 6 was planned that would involve a 3ꢀMCR
70 process involving 1, 2, 3 followed by condensation of 5 with
the in situ generated 4 in tandem. The only report for the
preparation of 2ꢀstyryl quinazolinones following this strategy
requires the use of 50 mol% of the protic ionic liquid
[Hmim]TFA as the promoter.21a
1
2
3
4
5
NH4OAc
91
91
90
83
78
92
90
91
90
86
Me NH4OAc
Et NH4OAc
nBu NH4OAc
Ph NH4OAc
15
6
H
R1 = H
Me R1 = H
90
85
90
86
92
88
85
85
82
81
82
72
70
92
88
90
87
91
90
86
88
85
82
81
80
79
20
7
8
9
10
11
25 12
13
14
15
16
30 17
18
H
R1 = 4ꢀMe
Me R1 = 4ꢀMe
H
R1 = 4ꢀOMe
Me R1 = 4ꢀOMe
H
H
R1 = 2ꢀCl
R1 = 4ꢀCl
Me R1 = 4ꢀCl
Me R1 = 4ꢀBr
Me R1 = 4ꢀF
H
R1 = 4ꢀCF3
Me R1 = 4ꢀCF3
75
Scheme 3. The oneꢀpot tandem synthesis of 3ꢀphenylꢀ2ꢀstyrylquinazolinꢀ
4(3H)ꢀone.
19
20
H
H
78
81
To test the feasibility, the model reaction was performed
using optimized reaction conditions (conventional and
80 microwave heating) for the condensation of 1, 2, 3, to form 4
followed by the addition of benzaldehyde 5 (1 equiv) and
stirring the reaction mixture for further 5 h. This one pot
process proved to be effective under both conventional and
microwave heating (entry 1, table 3). Thus, it was realized
85 that these two steps can be effectively carried out in oneꢀpot
to afford varieties of 2ꢀstyryl quinazolinones. The different
combinations of amines and aldehydes were opted to get
diversified synthesis of 2ꢀstyrylꢀ4(3H)ꢀquinazolinones (table
3). The aromatic aldehydes having different functional groups
90 as well as heteroꢀaromatic aldehydes worked adequately under
the optimized condition giving highly functionlized 2ꢀstyrylꢀ
4(3H)ꢀquinazolinones.
70
72
21
35 22
23
Me
H
68
72
70
71
75
72
Me
24
25
H
76
72
76
75
Me
26
H
70
78
73
82
40 27
Me
28
Me
R1 = H
82
85
Table 3. Oneꢀpot synthesis of (E)ꢀ3ꢀaryl/heteroarylꢀ2ꢀstyrylquinazolinꢀ
4(3H)ꢀone.a
O
O
Ar1
29
45 30
Me
Me
R1 = H
R1 = 4ꢀCH3
69
67
73
70
1. Neat, 120 °C, 5 h
O
N
Ar1-NH2
+
O
+ CH3CH(OHEt)3
2. Ar2-CHO, 120 °C, 5 h
N
H
N
Ar2
95
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Yield (%)b____
Method A Method B
R1
O
Entry Product
NH2
O
R1
O
N
+
+
CH3C(OEt)3
N
CH3
Method A Method B
N
H
O
1
: R1 = CH3
: R1 = Br
2a
2b
4a
: Methaqualone 68 %
4b: Mebroqualone 70 %
4c: Mecloqualone 72 %
74 %
76 %
75 %
1
2
3
4
5
6
7
8
9
Ar1 = H; Ar2 = Ph
79
75
74
72
75
78
70
70
75
76
74
77
75
71
81
76
78
75
74
80
72
75
76
79
76
76
75
77
2c: R1 = Cl
5
Ar1 = H; Ar2 = 4ꢀOMeꢀC6H4
Ar1 = Ph; Ar2 = Ph
Scheme 4. Synthesis of the sedative and hypnotic drugs 4aꢀc following
Ar1 = Ph; Ar2 = 4ꢀMeꢀC6H4
Ar1 = Ph; Ar2 = 4ꢀBrꢀC6H4
Ar1 = Ph; Ar2 = 4ꢀCF3ꢀC6H4
Ar1 = Ph; Ar2 = 4ꢀOMeꢀC6H4
Ar1 = Ph; Ar2 = 4ꢀOCH2PhꢀC6H4
Ar1 = 4ꢀMeꢀC6H4; Ar2 = 4ꢀClꢀC6H4
45
the 3ꢀMCR procedures.
The tandem one pot procedure for the synthesis of 2ꢀ
styrylquinazolinone was extended for the preparation of
piriquialone 6a following the sequential addition of 1, oꢀ
10
10 Ar1 = 4ꢀOMeꢀC6H4; Ar2 = 4ꢀOMeꢀC6H4
11 Ar1 = 4ꢀSMeꢀC6H4; Ar2 = 4ꢀOMeꢀC6H4
toludine 2a, 3 and pyridineꢀ2ꢀcarboxaldehyde 5a (Scheme 5).
H C
O3
O
NH2
15 12 Ar1 = 4ꢀSMeꢀC6H4; Ar2 = 4ꢀNMe2ꢀC6H4
13 Ar1 = 4ꢀSMeꢀC6H4; Ar2 = 4ꢀClꢀC6H4
14 Ar1 = 4ꢀFꢀC6H4; Ar2 = 4ꢀClꢀC6H4
CH3
N
1.
O
neat, 120 °C, 5 h
CH3C(OEt)3
+
+
O
N
2. ArCHO, 120 °C, 5 h
N
N
H
3
2a
1
ArCHO =
6a: Piriquialone
A
B
N
5a
CHO Method
60 %
Method
65 %
50
Scheme 5. The tandem process for the synthesis of the sedative and
hypnotic drug 6a.
15
16
70
76
72
78
The synthesis of the sedative and hypnotic drug
diproqualone 8 would involve the epoxide aminolysis22 of
55 glycidol with the 2ꢀmethylquinazolinone 7. The requisite
starting material 7 was synthesesd in 90ꢀ92% yields by the
newly developed 3ꢀMCR of 1, 3, and NH4OAc. The treatment
of 7 with glycidol in the presence of Zn(ClO4)2·6H2O (2
mol%)22b at room temperature under neat condition afforded 8
60 in 81% yield (Scheme 6).
20 17
18
72
75
75
76
O
O
O
CH3C(OEt)3
OH
3
+
O
NH
O
N
OH
72
71
•
OH
Zn(ClO4)2 6 H2O
Neat, rt, 1 h
N
N
H
O
N
NH4OAc
1
7
8
Diproqualone (81%)
Method A Method B
90% 92%
Scheme 6. Synthesis of the sedative and hypnotic drug 8.
19
Conclusions
The present work reports a simple and convenient synthesis
65 of 2,3ꢀdisubstituted quinazolinꢀ4(3H)ꢀones under catalyst and
solvent free conditions following 3MCR strategies. The
reactions are performed under classical heating at 120 °C for 5
h or under microwave dielectric heating under controlled
input power, temperature, and pressure for 20ꢀ30 min. The
70 reactions were compatible with different variations of isatoic
anhydride, amine and orthoester to generate functionalized
2,3ꢀdisubstituted quinazolinꢀ4(3H)ꢀones. This has been further
extended for the oneꢀpot synthesis of functionalized (E)ꢀ3ꢀ
aryl/heteroarylꢀ2ꢀstyrylquinazolin/(2ꢀ
75 (heteroaryl)vinyl)quinazolinꢀ4(3H)ꢀones without the necessity
of acid/base in the final condensation step. The catalyst and
solvent free condition along with operational simplicity
(recrystllisation using EtOH) offers a green process for the
synthesis of quinazolinꢀ4(3H)ꢀones. The synthetic utility was
80 demonstared through the synthesis of several CNS depressants
such as methaqualone, mebroqualone, mecloqualone,
piriquialone, and diproqualone in good to excellent yields.
20
71
76
aMethod A: The mixture of isatoic anhydride (2.5 mmol),
25 amine/NH4OAc (2.5 mmol) and triethyl orthoacetate (2.5 mmol) was
heated under neat condition at 120 ºC for 5 h followed by addition of
aldehyde (2.5 mmol, 1 equiv) and continued stirring for further 5 h.
Method B: The mixture of isatoic anhydride (2.5 mmol), amine/NH4OAc
(2.5 mmol) and triethyl orthoacetate (2.5 mmol) was heated under neat
30 condition at 140 °C (150 W) for 20 min followed by addition of aldehyde
(2.5 mmol, 1 equiv) and continued for further 20ꢀ30 min. b Isolated yield
of the corresponding 2ꢀstyrylquinazolinone.
The ultimate utility of any synthetic potocol is judged on
the basis of its use for the synthesis of target molecules. The
35 wide applications of 4(3H)ꢀquinazolinones and its 2ꢀstyryl
derivatives as CNS depressant prompted us to test these new
methodologies for the synthesis of a few CNS depressants.
Thus the sedative and hypnotic drugs methaqualone 4a,
mebroqualone 4b, and mecloqualone 4c were synthesized
40 through the 3ꢀMCR process involving isatoic anhydride,
appropriate amine and triethyl orthoacetate following the
Method A and Method B in very good yields (Scheme 4).
Acknowledgement
DK thanks CSIR, New Delhi for award of Research
85 Associateship. LA thanks FICCI, New Delhi for award of C V
4
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Typical experimental procedure for the synthesis of methaqualone 4a
70 (Scheme 3):
Raman Fellowship 2012 for African researchers.
2-Methyl-3-o-tolylquinazolin-4(3H)-one 4a: The equimolar mixture of
isatoic anhydride 1 (0.41 g, 2.5 mmol), triethyl orthoacetate 3 (0.41 g, 2.5
mmol) and 2ꢀmethyl aniline (0.21 g, 2.5 mmol) was stirred magnetically
at 120 °C (oil bath temp). After completion of reaction (TLC, 4 h), the
75 crude reaction mixture was recrystallized from EtOH to obtain
Notes and references
aDepartment of Medicinal Chemistry, National Institute of
Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S.
Nagar 160 062, Punjab, India. E-mail: akchakraborti@niper.ac.in
† Electronic Supplementary Information (ESI) available: Typical
experimental procedure, spectral data of all compounds, scanned spectra
of unknown compounds. See DOI: 10.1039/b000000x/
5
analytically pure 4a (0.43 g, 68 %) as white solid; mp = 118ꢀ119 °C (lit1b
ꢀ1
114ꢀ115 °C); IR (KBr)
= 3008, 1683, 1600, 1471, 1274 cm 1H
max
;
NMR (400 MHz, CDCl3) δ: 8.29 (d, J = 7.9 Hz, 1H), 7.78 (t, J = 7.6 Hz,
1H), 7.69 (d, J = 8.2 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.41ꢀ7.36 (m, 3H),
80 7.16 (d, J = 7.3 Hz, 1H), 2.19 (s, 3H), 2.13 (s, 3H); MS(APCI) m/z 251.41
(M+H)+.
Typical experimental procedure for the synthesis of mebroqualone 4b
(Scheme 3):
‡ General Information: The glasswares were thoroughly washed and
10 dried in an oven. Chemicals and all solvents were commercially available
(Aldrich Chemical, Merck AG, Fluka and SꢀD Fine Chemicals) and used
without further purification. The 1H/13C NMR spectra were recorded on a
Bruker Avance 400/100 MHz NMR spectrometer in CDCl3 with residual
undeuterated solvent (CDCl3: 7.26/77.0) using TMS as an internal
15 standard. Chemical shifts (δ) are given in ppm and J values are given in
Hz. 13C NMR spectra were fully decoupled and were referenced to the
middle peak of the solvent CDCl3 at 77.0 ppm. Splitting pattern were
designated as s, singlet; bs, broad singlet; d, doublet; dd, doublet of
doublet; t, triplet; m, multiplet. Mass spectra were recorded on a Finnigan
20 MATꢀLCQ [for APCI] mass spectrometer. Infraꢀred (IR) spectra were
recorded on Perkin Elmer FTꢀIR spectrometer in the range 4000ꢀ600 cmꢀ1
either as neat samples for liquids or using KBr for preparing pellets for
solid samples. Compounds were routinely checked for their purity on the
silica gel GFꢀ254 and visualized under UV at wavelength 254 nm.
25 Melting points were measured with Gupta scientific melting point
apparatus and were uncorrected. The microwaveꢀassisted reactions were
performed using CEM Discover model no 908010 equipment.
Evaporation of solvents was performed at reduced pressure, using a rotary
evaporator.
Synthesis of 3-(2-Bromophenyl)-2-methylquinazolin-4(3H)-one 4b:
85 The equimolar mixture of isatoic anhydride 1 (0.41 g, 2.5 mmol), triethyl
orthoacetate 3 (0.41 g, 2.5 mmol) and 2ꢀbromo aniline (0.28 g, 2.5 mmol)
was stirred magnetically at 120 °C (oil bath temp). After completion of
reaction (TLC, 4 h), the crude reaction mixture was recrystallized from
EtOH to obtain analytically pure 4b (0.54 g, 70 %) as white solid; mp =
90 143ꢀ145 °C (lit1b 143ꢀ144 °C); IR (KBr) max = 2923, 1687, 1607, 1471,
1281 cm ꢀ1 1H NMR (400 MHz, CDCl3) δ: 8.28 (d, J = 7.9 Hz, 1H), 7.79ꢀ
;
7.76 (m, 2H), 7.70 (d, J = 7.5 Hz, 1H), 7.51ꢀ7.47 (m, 2H), 7.50ꢀ7.46 (m,
3H), 7.40ꢀ7.36 (m, 2H), 2.22 (s, 3H); MS(APCI) m/z 271.24 (M+H)+
Typical experimental procedure for the synthesis of mecloqualone 4c
95 (Scheme 3):
Synthesis of 3-(2-chlorophenyl)-2-methylquinazolin-4(3H)-one 4c:
The equimolar mixture of isatoic anhydride 1 (0.41 g, 2.5 mmol), triethyl
orthoacetate 3 (0.41 g, 2.5 mmol) and 2ꢀChloro aniline (0.32 g, 2.5 mmol)
was stirred magnetically at 120 °C (oil bath temp). After completion of
100 reaction (TLC, 4 h), the crude reaction mixture was recrystallized from
EtOH to obtain analytically pure 4c (0.48 g, 72 %) as brown solid; mp =
126ꢀ128 °C (lit1b 126ꢀ127 °C); IR (KBr) max = 2925, 1688, 1608, 1471,
30 Typical experimental procedure for the synthesis of 2,3-disubstituted
quinazolin-4(3H)-ones (Entry 7, Table 3):
Method A: The equimolar mixture of isatoic anhydride 1 (0.41 g, 2.5
mmol), aniline 2 (0.23 g, 2.5 mmol) and triethyl orthoacetate 3 (0.41 g,
2.5 mmol) was stirred magnetically at 120 °C (oil bath temp). After
35 completion of the reaction (TLC, 4 h), the crude reaction mixture was
recrystallized from EtOH to obtain analytically pure 4 (0.50 g, 85 %) as
white solid; mp = 144ꢀ145 °C (lit18c 144ꢀ146 °C); IR (KBr) νmax : 2968,
1281 cm ꢀ1 1H NMR (400 MHz, CDCl3) δ: 8.28 (d, J = 6.8 Hz, 1H), 7.78
;
(t, J = 8.2 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.62ꢀ7.60 (m, 1H), 7.50ꢀ7.46
105 (m, 3H), 7.36ꢀ7.33 (m, 1H), 2.23 (s, 3H); MS(APCI) m/z 271.24 (M+H)+
Typical experimental procedure for the synthesis of piriquilone 6a
(Scheme 4):
1
Synthesis of (E)-2-(2-(pyridin-2-yl)vinyl)-3-(o-tolyl)quinazolin-4(3H)-
one (piriquialone) 6a: The equimolar mixture of isatoic anhydride 1
110 (0.41 g, 2.5 mmol), triethyl orthoacetate 3 (0.41g, 2.5 mmol) and
NH4OAc (0.23 g, 3 mmol) was stirred magnetically at 120 °C (oil bath
temp) for 5 h followed by addition of pyridineꢀ2ꢀcarboxaldehyde 5a (0.27
g, 2.5 mmol) and the stirring was continued for another 4 h (TLC). The
crude reaction mixture was recrystallized from EtOH to obtain
1648, 1602 cmꢀ1; H NMR (400 MHz, CDCl3): δ = 8.27 (d, J = 7.5 Hz,
1H), 7.76 (d, J = 7.2 Hz 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.51 (m, 4H), 7.27
40 (d, J = 6.0 Hz, 2 H ), 2.24 (s, 3H); 13C NMR (100 MHz, CDCl3): δ =
162.3, 154.2, 147.5, 137.8, 134.6, 130.0, 129.3, 128.0, 127.0, 126.8,
126.6, 120.8, 24.4; MS(APCI) m/z: 237.33 (M+H)+.
Method B: The equimolar mixture of isatoic anhydride 1 (0.41 g, 2.5
mmol), aniline 2 (0.23 g, 2.5 mmol) and triethyl orthoacetate 3 (0.41g, 2.5
45 mmol) was subjected to microwave irradition (150W/140 °C) for 20 min.
After completion of reaction, the crude reaction mixture was
recrystallized from EtOH to obtain analytically pure 4 (0.52 g, 88 %) as
white solid.
115 analytically pure 6a (0.50 g, 60%) as white solid; mp = 195ꢀ196 °C (lit21
1
195 °C); IR (KBr)
= 3326, 1645, 1525, 1126, 1023 cmꢀ1; H NMR
max
(CDCl3, 400 MHz): δ = 8.50 (d, J = 3.9 Hz, 1 H), 8.31ꢀ8.34 (m, 1 H),
8.00 (d, J = 15.0 Hz, 1 H), 7.80ꢀ7.82 (m, 2 H), 7.61ꢀ7.63 (m, 1 H), 7.48ꢀ
7.52 (m, 1 H), 7.40ꢀ7.46 (m, 3 H), 7.30 (d, J = 7.8 Hz, 1 H), 7.22 (d, J =
120 7.6 Hz, 1 H), 7.14ꢀ7.18 (m, 1 H), 6.92 (d, J = 15.0 Hz, 1 H); MS (APCI)
m/z: 340.42 (M + H)+.
Typical experimental procedure for the synthesis of 2-styryl
50 quinazolin-4(3H)-ones (Entry 3, Table 4)
Method A: The equimolar mixture of isatoic anhydride 1 (0.41 g, 2.5
mmol), aniline 2 (0.23 g, 2.5 mmol) and triethyl orthoacetate 3 (0.41 g,
2.5 mmol) was stirred magnetically at 120 °C (oil bath temp) for 4 h
followed by addition of benzaldehyde 5 (0.26 g, 2.5 mmol) and the
55 stirring was continued for another 4 h (TLC). The crude reaction mixture
was recrystallized from EtOH to obtain analytically pure 6 (0.64 g, 79%)
as white solid; mp = 196ꢀ197 °C (lit21 196 °C); IR (KBr) νmax : 3442,
1676, 1545, 1472, 1258, 1132 cmꢀ1; 1H NMR (CDCl3, 400 MHz): δ =
8.30 (d, J = 7.9 Hz, 1H), 7.97 (d, J = 15.5 Hz, 1H), 7.79 (d, J = 3.4 Hz,
60 2H) 7.53ꢀ 7.61 (m, 3H), 7.47ꢀ7.50 (m, 1H), 7.28ꢀ7.34 (m, 7H), 6.39 (d, J
= 15.5 Hz, 1H); MS (APCI) m/z: 325.21 (M + H)+.
Method B: (Entry 3, Table 4): The equimolar mixture of isatoic
anhydride 1 (0.41 g, 2.5 mmol), aniline 2 (0.23 g, 2.5 mmol) and triethyl
orthoacetate 3 (0.41g, 2.5 mmol) was subjected to microwave irradition
65 (150W/140 °C) for 20 min followed by addition of benzaldehyde 5 (0.26
g, 2.5 mmol) and continued the reaction for another 20 min. The crude
reaction mixture was recrystallized using EtOH to obtain analytically pure
6 (0.66 g, 81%) as white solid.
Typical experimental procedure for the synthesis of diproqualone 8
(Scheme 5):
Step-1 Synthesis of 2-methylquinazolin-4(1H)-one 7: The mixture of
125 isatoic anhydride 1 (0.41 g, 2.5 mmol), triethyl orthoacetate 3 (0.41 g, 2.5
mmol) and NH4OAc (0.23 g, 3 mmol, 1.2 equiv) was stirred magnetically
at 120 °C (oil bath temp). After completion of the reaction (TLC, 4 h), the
crude reaction mixture was recrystallized from EtOH to obtain
analytically pure 2ꢀmethylquinazolinꢀ4(3H)ꢀone 7 (0.36 g, 90 %) as white
130 solid; mp = 230ꢀ232 °C (lit7c 229ꢀ230 °C); IR (KBr) νmax : 1675, 1462,
1258, 750 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ = 12.07 (s, 1 H), 8.29 (d,
J = 7.9 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.47 (t,
J = 7.1 Hz, 1H), 2.60 (s, 3 H); MS(APCI) m/z: 161.28 (M+H)+.
Step-2 Ring opening of glycidol with 2-methylquinazolin-4(1H)-one:
135 To a magentiaclly stirred mixture of 2ꢀmethylquinazolinꢀ4(3H)ꢀone 7
(0.16 g, 1 mmol) and oxiranꢀ2ꢀylmethanol (0.07 g, 1 mmol) was added
Zn(ClO4)2·6H2O (2 mol%) under neat condition at rt and the stirring was
continued for 30 min. The crude reaction mixture was purified by flash
column chromatography to obtain analytically pure 8 (0.18 g, 78 %) as
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DOI: 10.1039/C5RA03888J
white solid; mp = 142ꢀ145 °C (lit34 142ꢀ145 °C); IR (KBr) νmax : 3132,
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1
1632, 1613, 1543, 1390 cmꢀ1; H NMR (400 MHz, CDCl3): δ = 8.10 (dd,
J = 8.0 Hz & 1.2 Hz, 1H),7.76ꢀ7.80 (m, 1H), 7.58 (d, J = 7.7 Hz, 1H),
7.45ꢀ7.49 (m, 1H), 5.08 (d, J = 4.6 Hz, 1H), 4.79 (t, J = 5.7 Hz, 1H), 4.27ꢀ
4.30 (m, 1H), 3.82ꢀ3.87 (m, 2H), 2.65 (s, 3H); MS(APCI) m/z: 235.32
(M+H)+.
75
5
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| Journal Name, [year], [vol], 00–00
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View Article Online
DOI: 10.1039/C5RA03888J
Convenient synthesis of 2,3-disubstituted quinazolin-
4(3H)-ones and 2-styryl-3-substituted quinazolin-4(3H)-
ones: Applications towards the synthesis of drugs.
Dinesh Kumar, Pradeep S. Jadhavar, Manesh Nautiyal, Himanshu Sharma,
Prahlad K. Meena, Legesse Adane, Sahaj Pancholia and Asit K. Chakraborti*a
Department of Medicinal Chemistry, National Institute of Pharamaceutical Education and
Research (NIPER), Sector 67, S. A. S. Nagar 160 062, Punjab, India.
E. mail: akchakraborti@niper.ac.in; akchakraborti@rediffmail.com
O
Catalyst and Solvent free
O
O
N
O
X
N
H
O
R1
R1
R
R2-CHO
(R = Me)
N
N
R1NH2
+
X
R2
X
N
RC(OEt)3
X = H
X = H, NO2, Cl, Br; R = H, Me, Et, n-Bu; R1 = Aryl or Hetroaryl or alkyl; R2 = Aryl or Hetroaryl