Efficient and practical one-pot route to synthesise quinazolin4(3H)-ones using trifluoromethanesulfonic anhydride and 2-chloropyridine

Article abstract of DOI:10.3184/174751915X14229898818046

An effective, novel and rapid one-pot three-component route to quinazolin-4(3H)-ones from commercially available starting materials is described. Isatoic anhydride reacts with acyl chlorides and different amines using a combination of trifluoromethanesulf

Full text of DOI:10.3184/174751915X14229898818046

120 RESEARCH PAPER
VOL. 39 FEBRUARY, 120–122
JOURNAL OF CHEMICAL RESEARCH 2015
Efficient and practical one-pot route to synthesise quinazolin4(3H)-ones
using trifluoromethanesulfonic anhydride and 2-chloropyridine
Mohsen Dadgar* and Nasim Milani Kalkhorani
Department of Applied Chemistry, Faculty of Science, Islamic Azad University, South Tehran Branch, Tehran, Iran
An effective, novel and rapid one-pot three-component route to quinazolin-4(3H)-ones from commercially available
starting materials is described. Isatoic anhydride reacts with acyl chlorides and different amines using a combination of
trifluoromethanesulfonic anhydride (Tf2O) and 2-chloropyridine (2-ClPy) to produce the corresponding quinazolinone derivatives
in good to excellent yields.
Keywords: amines, isatoic anhydride, 4(3H)-quinazolinones, multicomponent reactions, trifluoromethanesulfonic anhydride,
2-chloropyridine
Quinazolinone derivatives are essential units in a wide range
of relevant pharmacophores with a broad spectrum of abilities.1
Due to their wide range of pharmacological and therapeutic
activities including anticonvulsant,2 anti-inflammatory,3
hypolipidemic,4 anticancer5 and anti-ulcer,6 the synthesis
of quinazolinone moieties as a privileged class of fused
heterocyclic compounds7 has attracted researchers’ attention.
In recent years, several synthetic routes have been introduced
for the preparation of 4(3H)-quinazolinone derivatives in which
the condensation of a 2-aminobenzoic acid or its derivatives
with amides has been mentioned as the most common
synthetic approach. Various procedures which have been
recently reported involve the cyclocondensation reaction using
different substrates such as benzyl halides, amines and isatoic
anhydride,8 multi-step reactions under microwave irradiation9
or in ionic liquids,10 and also there are some reports on metal-
catalysed examples.11 Meanwhile, a method has been reported
for the one-pot synthesis of 4(3H)-quinazolinone derivatives
using isatoic anhydride–anthranilic acid, orthoesters and
amines.12 To our knowledge, there have been few reports on
the one-pot synthesis of quinazolin-4(3H)-ones using acyl
halides as starting materials.13 There are a few methods using
an orthoester in place of the acid chloride that have been
reported,14–16 but these pathways have some drawbacks such as
low yields, long reaction times, high temperatures and harsh
reaction conditions, difficult and time consuming work-up,
and use of expensive reagents and catalysts. Therefore, the
development of a novel and efficient methodology for the
synthesis of quinazolin-4(3H)-ones is timely. Focusing on the
pharmacological importance of 4(3H)-quinazolinones and as a
continuation of our research on the development of new routes
for the synthesis of different heterocyclic scaffolds, we wish
to introduce a convenient protocol to prepare 2,3-disubstituted
quinazolinones by a one-pot three-component condensation
reaction between isatoic anhydride, acyl chlorides, and amines
in the presence of trifluoromethanesulfonic anhydride (Tf2O)
and 2-chloropyridine (2-ClPy).
Results and discussion
Amides are attractive starting materials because they are easily
available, but amides themselves are rarely used as precursors in
organic synthesis due to their stability. Due to this low reactivity
of amides, there are several reports on the activation of the
amide moiety. The combination of trifluoromethanesulfonic
anhydride (Tf2O) and pyridine or 2-chloropyridine (2-ClPy) is
the most attractive and feasible example.16–18
We believed that the combination of trifluoromethanesulfonic
anhydride (Tf2O) and 2-chloropyridine (2-ClPy) would
be useful for our purpose. The three component one-pot
condensation of isatoic anhydride 1, benzoyl chloride 2a,
and aniline 3a was selected as a model reaction. The reaction
condition including the solvent, the amount of Tf2O and
2-ClPy, reaction time and required temperature are optimised.
As shown in Table 1, among three different conditions, CH2Cl2,
Table 1 Optimisation of reaction conditionsa
Entry
Solvent
Temperature/°C
Time/h
(Tf2O/2-ClPy)/equiv.
Yield/%
1
2
3
4
5
6
7
8
9
DMF
DMF
DMF
DMF
–
DCM
DCM
DCM
DCM
110
110
r.t.
r.t.
110
r.t.
40
24
2
2
2
2
2
2
2
4
–
20
90
45
57
90b
35
89
92
46
0.5/0.5
0.5/0.5
1 /1
0.5/0.5
0.5/0.5
0.5/0.5
1 /1
40
40
0.25/0.25
aIsatoic anhydride (1) (1.0 mmol), amine (3a) (1.1 mmol), acyl chloride, (2a) (1.1 mmol).
bReaction under solvent-free conditions.
* Correspondent. E-mail: mdadgar@azad.ac.ir

JOURNAL OF CHEMICAL RESEARCH 2015 121
O
O
O
R'
Tf2O, 2-ClPy
O
Cl
NH2
N
+
R'
+
CH2Cl2
40oC
N
H
O
N
R
R
1
2a–e
3a–d
4a–h
Scheme 1 One-pot synthesis of 2,3-disubstituted quinazolin-4-(3H)-one derivatives.
amine (3a–d) (2.2 mmol), acyl chloride (2a–e) (2.2 mmol), and
2-ClPy (1 mmol, 50 mol%) in DCM (2 mL) under an inert atmosphere
at –78 °C. After 15 min, the reaction mixture was then warmed to
40 °C and stirred until completion for 2 h. In all cases, the progress of
the reaction was monitored by TLC. After 2 h, the reaction mixture
was diluted with water. The organic layer was washed with the
saturated aqueous Cu2SO4 solution (5 mL), brine (5 mL×2), and water
(10 mL). The organic layer was dried over anhydrous Na2SO4 and
filtered. The filtrate was concentrated under reduced pressure and
the residue was recrystallised from EtOH to give 2,3-disubstituted
quinazolin-4-(3H)-one derivatives in high yield. The observed and
literature melting points are shown in Table 2.
40 °C and 0.5 equiv. of Tf2O and 2-ClPy led to the best results.
No quinazolinone 4a was formed in the absence of Tf2O and
2-ClPy, and also using the higher amounts of Tf2O and 2-ClPy
showed no significant improvement in this reaction.
Then, a wide range of structurally diverse acyl chlorides
2, amines 3, and isatoic anhydrides 1 were reacted under the
optimum conditions (Scheme 1) and the results are summarised
in Table 2. In all cases, the three component reaction proceeded
smoothly to afford the corresponding quinazolin-4(3H)-
one derivatives in good to excellent yields. The results also
showed that aromatic amines reacted to give the corresponding
quinazolinones in good yields. Also it was found that amines
or acyl halides having an electron-donating or electron
withdrawing group tolerated the cyclisation reaction to give
the corresponding quinazolinone in satisfactory yields. It is
concluded that this procedure is an efficient method for the
preparation of quinazolin-4(3H)-one derivatives from isatoic
anhydride, acyl halides and amines under mild conditions.
1
2,3-Diphenylquinazolin-4(3H)-one (4a): H NMR (400 MHz, CDCl3,
ppm) δ 7.13–7.16 (m, 2H) 7.20–7.24 (m, 2H), 7.27–7.34 (m, 6H),
7.50–7.53 (m, 1H), 7.81–7.85 (m, 2H), 8.22 (d, J=8.0 Hz,1H), 13C NMR
(100 MHz, CDCl3, ppm) δ 122.1, 128.3, 128.4, 128.9, 129.1, 129.5,
130.1, 130.3, 130.5, 135.8, 136.2, 138.9, 148.6, 154.3, 163.5.
2-Phenyl-3-(p-tolyl)quinazoline-4(3H)-one (4b): 1H NMR (400 MHz,
CDCl3, ppm) δ 2.18 (s, 3H), 7.02–7.05 (m, 2H), 7.11–7.15 (m, 2H),
7.21–7.25 (m, 3H), 7.33–7.38 (m, 2H), 7.50–7.53 (m, 1H), 7.73 (s, 2H),
8.31(d, J=7.5 Hz, 1H), 13C NMR (100 MHz, CDCl3, ppm) δ 20.1, 120.3,
126.1, 127.5, 127.7, 128.4, 128.6, 129.0, 129.2, 129.5, 134.5, 135.4,
135.9, 138.1, 146.2, 154.2, 161.8.
2-(p-Tolyl)-3-phenylquinazoline-4(3H)-one (4c): 1H NMR (400 MHz,
CDCl3, ppm) δ 2.25 (s, 3H), 7.11 (d, J=7.5 Hz, 2H), 7.18 (d, J=8 Hz,
2H), 7.25 (d, J=8 Hz, 2H), 7.32–7.38 (m, 3H), 7.55 (s, 1H), 7.88 (s,
2H), 8.39 (d, J=7.5 Hz, 1H), 13C NMR (100 MHz, CDCl3, ppm) δ 20.5,
122.2, 126.4, 126.8, 127.5, 128.4, 128.8, 129.0, 129.3, 133.8, 134.6,
136.7, 140.5, 146.8, 156.5, 162.1.
2-(4-Chlorophenyl)-phenylquinazoline-4(3H)-one (4d): 1H NMR
(400 MHz, CDCl3, ppm) δ 7.15–7.22 (m, 4H), 7.29–7.36 (m, 4H),
7.53–7.58 (m, 2H), 7.80 (s, 1H), 8.35 (d, J=7.5 Hz, 2H), 13C NMR
(100 MHz, CDCl3, ppm) δ 122.0, 127.4, 127.6, 127.9, 128.5, 128.8,
129.3, 129.7, 130.8, 134.1, 134.5, 135.7, 137.8, 147.8, 154.5, 162.5.
3-(4-Chlorophenyl)-2-phenylquinazoline-4(3H)-one (4e): 1H NMR
(400 MHz, CDCl3, ppm) δ 7.08–7.11 (m, 2H), 7.27–7.34 (m, 7H), 7.55
(t, J=7.6 Hz, 1H), 7.74 (t, J=7.3 Hz, 1H), 7.92–7.96 (m, 1H), 8.36 (d,
J=7.5 Hz, 1H), 13C NMR (100 MHz, CDCl3, ppm) δ 121.4, 126.2,
126.3, 127.2, 128.5, 129.2, 129.3, 129.8, 130.6, 133.5, 134.4, 135.2,
137.3, 145.4, 155.5, 161.3. (The characterisation of this novel product is
not formally complete but is well supported by the data given and the
formation of the other products.)
Conclusions
In conclusion, we have developed a convenient one-pot
approach for the synthesis of quinazolin-4(3H)-one derivatives
from isatoic anhydride, different amines and acyl chlorides
by the electrophilic activation of amides using the catalytic
combination of trifluoromethanesulfonic anhydride (TF2O)
and 2-chloropyridine (2-ClPy). The present method is highly
efficient and also the substrates are readily available. The
efficiency, mild conditions, short reaction time, easy isolation
of the products, simplicity and high yields are some of the
remarkable synthetic advantages of this protocol.
Experimental
Melting points were taken on a Kofler hot stage apparatus and are
1
uncorrected. H and 13C NMR spectra were recorded on a Bruker
FT-500 instrument, using TMS as an internal standard. Elemental
analysis was performed with an Elementar Analysensystem GmbH
VarioEL CHNS mode. All reagents and solvents were purchased from
Aldrich or Merck and used without any purification.
Synthesis of quinazolin-4(3H)-ones; general procedure
A solution of Tf2O (1 mmol, 50 mol%) in DCM (1 mL) was added
dropwise by a syringe to a mixture of isatoic anhydride (1) (2.0 mmol),
Table 2 Synthesis of quinazolin-4-(3H)-one derivativesa
M.p./°C
Product
R
R′
C6H5
4-MeC6H4
C6H5
C6H5
C6H5
4-ClC6H4
4-MeOC6H4
C6H5
Yield /%
Observed
ReportedRef
15820
4a
4b
4c
4d
4e
4f
H
H
89
76
78
82
85
86
83
88
159–160
178–179
173–175
172–174
196–199
196–199
198–200
155–157
180–18121
171–1728
177–1788
–
190–1918
199–2008
154–15522
4-Me
4-Cl
2-Cl
H
4g
4h
H
4-MeO
aIsatoic anhydride (2.0 mmol), amine (2.2 mmol), acyl chloride (2.2 mmol), 2-ClPy (1 mmol,
50 mol%) Tf2O (1 mmol, 50 mol%) in DCM, 40 °C, 2 h.

122 JOURNAL OF CHEMICAL RESEARCH 2015
1
3
4
5
6
7
O. Kenichi, Y. Yoshihisa, O. Toyonari, I. Toru and I. Yoshio, J. Med.
Chem., 1985, 28, 568.
Y. Kurogi, Y. Inoue, K. Tsutsumi, S. Nakamura, K. Nagao, H. Yohsitsugu
and Y. Tsuda, J. Med. Chem., 1996, 39, 1433.
S.L. Cao, Y.P. Feng, Y.Y. Jiang, S.Y. Liu, G.Y. Ding and R.T. Li, Bioorg.
Med. Chem. Lett., 2005, 15, 1915.
K. Tereshima, H. Shimamura, A. Kawase, Y. Tanaka, T. Tanimura, T.
Kamisaki, Y. Ishizuka and M. Sato, Chem. Pharm. Bull., 1995, 43, 2021.
W.L.F. Armarego, Fused pyrimidines. Part 1: quinazolines, D.J. Brown,
ed. Interscience, New York, 1967, p. 5.
3-(4-Methoxyphenyl)-2-phenylquinazolin-4(3H)-one (4f): H NMR
(400 MHz, CDCl3, ppm) δ 3.85 (s, 3H), 6.80–6.85 (m, 2H), 7.01–7.05
(m, 2H), 7.27 (s, 3H), 7.33–7.37 (m, 2H), 7.52 (t, J=7.2 Hz, 1H),
7.80–7.84 (m, 2H), 8.21 (d, J=7.5 Hz, 1H), 13C NMR (100 MHz,
CDCl3, ppm) δ 3.42, 118.3, 122.7, 126.4, 126.9, 127.2, 128.2, 128.7,
129.4, 130.2, 130.7, 133.2, 134.2, 145.2, 153.2, 160.1,, 163.4.
1
2-(4-Methoxyphenyl)-3-phenylquinazolin-4(3H)-one (4g): H NMR
(400 MHz, CDCl3, ppm) δ 3.84 (s, 3H), 6.84 (d, J=8.0 Hz, 2H), 7.21 (d,
J=8.0 Hz, 2H), 7.30–7.36 (m, 5H), 7.51 (s, 1H), 7.71–7.77 (m, 2H), 8.30
(d, J=8.0 Hz, 1H), 13C NMR (100 MHz, CDCl3, ppm) δ 54.5, 113.4,
121.8, 126.0, 126.3, 126.6, 127.4, 128.2, 129.1, 129.3, 131.4, 135.6,
139.1, 146.5, 155.7, 161.2, 162.8.
8
9
M. Adib, E. Sheikhi and H.R. Bijanzadeh, Synlett, 2012, 23, 85.
M. Dabiri, P. Salehi, M.S. Khajavi and A.A. Mohammadi, Heterocycles,
2004, 63, 1417.
1
2-Phenyl-3-o-tolylquinazolin--4(3H)-one (4h): H NMR (400 MHz,
10 J. Chen, W. Su, H. Wu, M. Liu and C. Jin, Green Chem., 2007, 9, 972.
11 H. Hikawa, Y. Ino, H. Suzuki and Y. Yokoyama, J. Org. Chem., 2012, 77,
7046.
12 M. Dabiri, M. Baghbanzadeh and A.S. Delbari, J. Comb. Chem., 2008, 10,
700.
13 G.W. Wang, C.B. Miao and H. Kang, Bull. Chem. Soc. Jpn., 2006, 79, 1426.
14 M. Dabiri, P. Salehi, A.A. Mohammadi and M. Baghbanzadeh, Synth.
Commun., 2005, 35, 279.
15 P. Salehi, M. Dabiri, M.A. Zolfigol and M. Baghbanzadeh, Tetrahedron
Lett., 2005, 46, 7051.
CDCl3, ppm) δ 2.15 (s, 3H), 7.04–7.08 (m, 1H), 7.15–7.21 (m, 6H),
7.30–7.35 (m, 2H) 7.60 (t, J=7.2 Hz, 1H), 7.73–7.78 (m, 2H), 8.20 (d,
J=8.0 Hz, 1H), 13C NMR (100 MHz, CDCl3, ppm) δ 18.2, 122.4, 125.3,
126.3, 127.5, 127.7, 127.8, 128.3, 128.4, 129.3, 129.8, 130.2, 133.8,
134.2, 135.2, 143.1, 154.6, 155.0, 162.3.
Support of this investigation by the Islamic Azad University
Tehran South Branch through
acknowledged.
a grant is gratefully
16 B.V. Lingaiaha, G. Ezikiela, T. Yakaiaha, G.V. Reddyb and P.S. Rao,
Synlett, 2006, 2507.
Received 27 November 2014; accepted 2 February 2015
Paper 1402834 doi: 10.3184/174751915X14229898818046
Published online: 13 February 2015
17 A.B. Charette, M. Grenon, A. Lemire, M. Pourashraf and J. Martel, J. Am.
Chem. Soc., 2001, 123, 11829.
18 K. Rad-Moghadam, M. Mamghani and L. Samavi, Synth. Commun., 2006,
36, 2245.
19 Z. Zheng and H. Alper, Org. Lett., 2008, 10, 829.
20 J.F. Liu, J. Lee, A.M. Dalton, G. Bi, L. Yu, C.M. Baldino, E. McElory and
M. Brown, Tetrahedron Lett., 2005, 46, 1241.
21 P.R. Levy and H. Stephen, J. Chem. Soc., 1956, 985.
22 K. Na Yeun and C. Cheol-Hong, Tetrahedron Lett., 2014, 55, 2340.
References
1
D.A. Patil, P.O. Patil, P.K. Deshmukh, G.B. Patil, B.D. Shewale, D.D. Patil
and S.G. Gattani, Res. J. Pharm. Tech., 2010, 3, 979.
J.F. Wolfe, T.L. Rathman, M.C. Sleevi, J.A. Campbell and T.D. Greenwood,
J. Med. Chem., 1990, 33, 161.
2

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and
its content may not be copied or emailed to multiple sites or posted to a listserv without the
copyright holder's express written permission. However, users may print, download, or email
articles for individual use.