Synthesis of quinazolin-4(3H)-ones via the reaction of isatoic anhydride with benzyl azides in the presence of potassium tert-butoxide in DMSO

Article abstract of DOI:10.1007/s10593-019-02563-w

[Figure not available: see fulltext.] In this paper, a novel method is described for the synthesis of quinazolin-4(3H)-one derivatives via the reaction of isatoic anhydride with benzyl azides in the presence of potassium tert-butoxide in DMSO. The reactio

Full text of DOI:10.1007/s10593-019-02563-w

DOI 10.1007/s10593-019-02563-w
Chemistry of Heterocyclic Compounds 2019, 55(10), 964–967
Synthesis of quinazolin-4(3H)-ones via
the reaction of isatoic anhydride with benzyl azides
in the presence of potassium tert-butoxide in DMSO
1
2
Mohammad Hosein Sayahi *, Saeed Bahadorikhalili ,
3
1
Mohammad Mahdavi , Laleh Baghshirin
1
Department of Chemistry, Payame Noor University,
P. O. Box 19395-3697, Tehran, Iran; е-mail: sayahymh@pnu.ac.ir
2
3
School of Chemistry, College of Science, University of Tehran,
Tehran, Iran; е-mail: saeed.bahadorikhalili@khayam.ut.ac.ir
Endocrinology and Metabolism Research Center,
Endocrinology and Metabolism Clinical Sciences Institute,
Tehran University of Medical Sciences,
Tehran, Iran; e-mail: momahdavi@sina.tums.ac.ir
Submitted April 29, 2019
Accepted June 5, 2019
Published in Khimiya Geterotsiklicheskikh Soedinenii,
019, 55(10), 964–967
2
In this paper, a novel method is described for the synthesis of quinazolin-4(3H)-one derivatives via the reaction of isatoic anhydride with
benzyl azides in the presence of potassium tert-butoxide in DMSO. The reaction is completed after 4 h at 100°C to produce the title
products in good yields.
Keywords: benzyl azides, isatoic anhydride, potassium tert-butoxide, quinazolin-4(3H)-ones.
Quinazolin-4(3H)-ones are significant group of hetero-
of aldehydes and anthranilamide or its derivatives in the
18
cyclic compounds possessing a broad range of therapeutic
presence of CuCl
2
,
condensation of aldehydes and
1
2
6
and pharmacological activities, such as anticonvulsant,
anthranilamide in the presence of Cu–β-cyclodextrin-
3
4
5
19
anticancer, hypolipidemic, antiulcer, anti-inflammatory,
modified nanoparticles, condensation of o-bromobenzoic
7
antimicrobial, and cytotoxic activities. In addition, some
quinazolinone derivatives have been reported as active
antimycobacterial agents against the strains of
M. tuberculosis, M. avium, M. fortuitum, M. kansasii, and
esters with isothiocyanates and azides in the presence of
CuBr,20 condensation of benzylacetamide and anthranil-
amide in the presence of a Cu(II)–polyethyleneimine-
modified graphene oxide,21 condensation of aldehydes and
anthranilamide or isatoic anhydride in the presence of a
nanoparticle-supported Pd catalyst,22 amine-induced thermal
8
M. intracellulare. The bioactive natural products febrifugine
and isofebrifugine are examples of clinically important
quinazolinone derivatives with antimalarial activity.9
Due to this wide range of activities, many synthetic
routes have been reported for the preparation of quinazolin-
–11
23
rearrangement of iminobenzoxazines,2 phosphine-catalyzed
intramolecular aza-Wittig reaction, 4 oxidative reaction
between benzyl halides, isatoic anhydride, and primary
12
25
4
(3H)-ones, such as reaction of nitriles with lithiated
amines,
Pd-catalyzed carbonylative cyclization of
1
3
26
anthranilamides,
microwave-assisted condensation of
o-bromoanilines, trimethyl orthoformate, and amines, and
CuI-catalyzed reaction between anthranilamide, terminal
alkynes, and azides.27 Isatoic anhydride is an interesting
starting material for the synthesis of quinazolinone and is
widely used for such synthesis.
However, some of the starting materials of previously
listed routes have to be synthesized and purified first,
1
4
anthranilic acids, carboxylic acids, and amines, carboxy-
lation of ortho C–H bonds in anilides leading to N-acyl-
anthranilic acids and then treatment with anilines in the
presence of PCl
anthranilic acids,
reaction of isocyanide with anthranilamide, condensation
1
5
28
3
,
condensation of imidates with
Pd-catalyzed oxidative insertion
1
6
1
7
0
009-3122/19/55(10)-0964©2019 Springer Science+Business Media, LLC
964

Chemistry of Heterocyclic Compounds 2019, 55(10), 964–967
therefore, these methods are time-consuming. The
Scheme 1
multistep procedures have also notable drawbacks, such as
long reaction times, harsh reaction conditions, difficult
workup, and low yields of the products. In addition, some
of these protocols proceeded using expensive and
environmentally toxic catalysts or reagents. Therefore, the
development of simple and efficient methods for the synthesis
of quinazolin-4(3H)-ones is still desirable.
Herein, we wish to report an efficient synthesis of
quinazolin-4(3H)-one derivatives via the reaction of isatoic
anhydride (1) with benzyl azides in basic medium.
Therefore, a model reaction using benzyl azide (2a), was
investigated under various reaction conditions.
At first, the reaction was studied in the presence of KOt-Bu
in various solvents. DMSO was found to be the best solvent
removal of a nitrogen molecule to form anion 6. Con-
currently, isatoic anhydride (1) forms decarboxylated
intermediate 7 via heating of the reaction mixture. The
[4+2] addition of intermediates 6 and 7 leads to formation
of compound 8. This intermediate is protonated to give
2,3-dihydroquinazolin-4(1H)-one 9 which could undergo
oxidation under the reaction conditions to produce the
desired quinazolin-4(3H)-one 3.
(
Table 1, entries 3, 4). The mole ratio of benzyl azide (2a)
to isatoic anhydride (1) was 1:1 in all experiments, and the
reactions were performed in 4 ml of solvent. Then a variety
of bases such as K
[
Scheme 2
2
CO
3
, Cs
2
CO , and 1,8-diazabicyclo-
3
5.4.0]undec-7-ene (DBU) were studied for this reaction in
DMSO. However, the reaction did not proceed in the
presence of these bases (Table 1, entries 5–7). It was found
that the best yield of 2-phenyl-2,3-dihydroquinazolin-4(1H)-
one (3a) was obtained at 100°C in the presence of KOt-Bu
in DMSO after 4 h, when 1 equiv of KOt-Bu was applied
(
Table 1, entry 3). Therefore these conditions were selected
as optimal.
To study the generality of the new protocol, we
examined the reaction between isatoic anhydride (1) and
various benzyl azides 2a–h under optimal conditions to
produce the corresponding quinazolin-4(3H)-one deriva-
tives 3a–h (Scheme 1). All the reactions were complete
1
13
within 4 h. H and C NMR analysis of the reaction
mixtures clearly indicated formation of quinazolin-4(3H)-one
derivatives 3a–h in good yields.
Formation of quinazolin-4(3H)-one derivatives 3 could
be rationalized via a plausible mechanism provided in
Scheme 2. Treatment of benzyl azide 2 with KOt-Bu leads
to the generation of anionic intermediates 4 and 5 and
In conclusion, we have developed an efficient protocol
for the synthesis of quinazolin-4(3H)-one derivatives. The
desired products were obtained in good yields. Use of
commercially available materials and simple procedure are
advantages of our protocol.
Experimental
IR spectra were obtained on a Bruker Tensor 27 spectro-
Table 1. Optimization of 2-phenyl-2,3-dihydroquinazolin-
1
13
meter in KBr pellets. H and C NMR spectra were
recorded on a Brucker 500 series NMR spectrometer
4
(1H)-one (3a) synthesis*
(
500 and 125 MHz, respectively) in DMSO-d , using TMS
6
as internal standard. Elemental analysis was performed on
a Thermo Finnigan FlashEA 1112 series instrument.
Melting points were determined in a capillary tube on a
Buchi apparatus. The progress of reaction was followed
by TLC (eluent hexane–EtOAc, 4:1) using Merck 60 F254
silica gel plates.
Entry
Base (equiv)
Solvent
Temperature, °C Yield, %
1
2
3
4
5
6
7
KOt-Bu (1)
KOt-Bu (1)
KOt-Bu (1)
KOt-Bu (2)
THF
Reflux
100
15
51
75
70
0
All chemicals were purchased from Merck and Fluka
companies. All products are known compounds and were
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
100
1
13
identified by comparing the IR, H and C NMR spectro-
scopic data, as well as melting points with the literature
data.
100
K
2
CO
CO
3
(2)
(2)
100
Cs
2
3
100
0
Synthesis of quinazolin-4(3H)-ones 3a–h (General
method). A mixture of benzyl azide 2a–h (1 mmol), isatoic
anhydride (1) (0.163 g, 1 mmol), and KOt-Bu (1 mmol) in
DMSO (4 ml) was stirred at 100°C for 4 h. Upon
DBU (2)
100
0
*
3
Isatoic anhydride (1) (1 mmol), BnN (2a) (1 mmol), solvent (4.0 ml),
reaction time 4 h.
9
65

Chemistry of Heterocyclic Compounds 2019, 55(10), 964–967
completion, the reaction mixture was cooled to room
temperature and H O (4 ml) was added. The stirring was
continued for 1 h at ambient temperature. Next, the organic
phase was extracted with CH Cl (2×4 ml), and the
combined organic layers were dried over Mg SO . The
solvent was evaporated, and the residue was purified by
column chromatography using n-hexane–EtOAc, 3:1, as
eluent.
H Ar); 8.26 (2H, dd, J = 8.5, J = 5.5, H Ar); 12.53 (1H, s,
13
2
NH). C NMR spectrum, δ, ppm (J, Hz): 115.4 (d,
2
J
CF = 22.6); 120.8; 125.7; 126.4; 127.3; 129.2; 130.3 (d,
3
1
2
2
J
CF = 8.8); 134.4; 148.5; 151.3; 162.5 (d, JCF = 104.3);
2
4
164.9. Found, %: C 70.02; H 3.84; N 11.71. C14
Calculated, %: C 69.99; H 3.78; N 11.66.
H
9
FN O.
2
2-(2-Chlorophenyl)quinazolin-4(3H)-one (3f). Yield
0.179 g (70%). White solid. Mp 196–197°C (mp 200–
31
–1
2
-Phenylquinazolin-4(3H)-one (3a). Yield 0.156 g
202°C ). IR spectrum, ν, cm : 3317 (NH), 1656 (C=O).
30
1
(
75%). White solid. Mp 234–236°C (mp 230–232°C ).
H NMR spectrum, δ, ppm (J, Hz): 7.50 (1H, t, J = 8.5,
–
1
1
IR spectrum, ν, cm : 3315 (NH), 1661 (C=O). H NMR
spectrum, δ, ppm (J, Hz): 7.51–7.61 (4H, m, H Ar); 7.75
H Ar); 7.62–7.75 (3H, m, H Ar); 7.67 (1H, d, J = 8.0,
H Ar); 7.71 (1H, d, J = 8.5, H Ar); 7.85 (1H, t, J = 8.5,
H Ar); 8.19 (1H, d, J = 8.5, H Ar); 12.58 (1H, s, NH).
(
(
(
1H, d, J = 8.5, H Ar); 7.84 (1H, t, J = 8.5, H Ar); 8.16
1H, d, J = 8.5, H Ar); 8.20 (2H, d, J = 7.5, H Ar); 12.50
1H, s, NH). 13C NMR spectrum, δ, ppm: 120.7; 125.9;
1
3
C NMR spectrum, δ, ppm: 121.2; 125.6 (2C); 127.0;
126.9; 127.3; 129.7; 130.5; 131.6; 133.8; 134.2; 148.4;
1
1
26.5; 127.6; 127.8; 128.4; 130.9; 132.8; 134.2; 148.8;
52.0; 161.9. Found, %: C 75.69; H 4.49; N 12.67.
151.9; 161.2. Found, %: C 65.59; H 3.49; N 10.97.
C
14
H
9
ClN O. Calculated, %: C 65.51; H 3.53; N 10.91.
2
C
14
2
H
10
N
2
O. Calculated, %: C 75.66; H 4.54; N 12.60.
2-(2-Nitrophenyl)quinazolin-4(3H)-one (3g). Yield
-(2-Methoxyphenyl)quinazolin-4(3H)-one (3b). Yield
0.182 g (68%). Yellow solid. Mp 221–323°C (mp 224–
29 –1
0
.181 g (72%). White solid. Mp 202–204°C (mp 200–
02°C ). IR spectrum, ν, cm : 3324 (NH), 1661 (C=O).
226°C (EtOAc) ). IR spectrum, ν, cm : 3317 (NH), 1655
30
–1
1
2
(C=O). H NMR spectrum, δ, ppm (J, Hz): 7.57 (1H, t, J = 8.0,
1
H NMR spectrum, δ, ppm (J, Hz): 3.88 (3H, s, OCH
3
);
.08 (1H, t, J = 7.5, H Ar); 7.19 (1H, d, J = 8.0, H Ar); 7.50–
.55 (2H, m, H Ar); 7.70 (1H, d, J = 7.5, H Ar); 7.49 (1H,
H Ar); 7.66 (1H, d, J = 8.0, H Ar); 7.81–7.93 (4H, m,
7
7
H Ar); 8.18–8.22 (2H, m, H Ar); 12.79 (1H, s, H Ar).
13
C NMR spectrum, δ, ppm: 121.1; 124.4; 125.8; 127.0;
d, J = 7.5, H Ar); 7.82 (1H, t, J = 7.5, H Ar); 8.16 (1H, d,
127.2; 129.1; 131.3; 131.4; 133.8; 134.5; 147.4; 148.4;
151.6; 161.4. Found, %: C 63.03; H 3.43; N 15.75.
C
1
3
J = 7.5, H Ar); 12.00 (1H, s, NH). C NMR spectrum,
δ, ppm: 55.7; 112.0; 120.1; 121.1; 122.4; 125.8; 126.2;
14
H
9
N
3
O . Calculated, %: C 62.92; H 3.39; N 15.72.
3
1
27.4; 130.1; 131.9; 134.0; 149.0; 152.3; 156.9; 160.8.
2-(3-Nitrophenyl)quinazolin-4(3H)-one (3h). Yield
Found, %: C 71.45; H 4.83; N 11.06. C15
lated, %: C 71.42; H 4.79; N 11.10.
12
H N
2
O
2
. Calcu-
0.187 g (70%). Yellow solid. Mp 350–352°C (mp >300°C
29 –1
(EtOAc) ). IR spectrum, ν, cm : 3317 (NH), 1658 (C=O).
1
2
-(3-Methoxyphenyl)quinazolin-4(3H)-one (3c). Yield
H NMR spectrum, δ, ppm (J, Hz): 7.57 (1H, t, J = 8.0,
0
.184 g (73%). White solid. Mp 180–182°C (mp 180–
H Ar); 7.79–7.86 (3H, m, H Ar); 8.17 (1H, d, J = 7.5,
H Ar); 8.41 (1H, d, J = 7.5, H Ar); 8.61 (1H, d, J = 7.5,
30
–1
1
82°C ). IR spectrum, ν, cm : 3324 (NH), 1667 (C=O).
1
13
H NMR spectrum, δ, ppm (J, Hz): 3.87 (3H, s, OCH
.14 (1H, d, J = 7.5, H Ar); 7.45 (1H, t, J = 8.0, H Ar); 7.52
3
);
H Ar); 9.02 (1H, s, H Ar); 12.82 (1H, s, NH). C NMR
7
spectrum, δ, ppm: 122.6; 125.6; 125.8; 127.0; 127.5; 130.2;
(
1H, t, J = 8.0, H Ar); 7.73–7.85 (4H, m, H Ar); 8.16 (1H,
133.9 (2C); 134.3; 134.6; 147.9; 149.2; 154.9; 162.1.
1
3
t, J = 8.5, H Ar); 12.45 (1H, s, NH). C NMR spectrum,
δ, ppm: 55.2; 112.6; 117.2; 119.8; 121.1; 125.6; 126.2;
Found, %: C 62.85; H 3.29; N 15.69. C14
Calculated, %: C 62.92; H 3.39; N 15.72.
H
9
N
3
3
O .
1
27.3; 129.7; 134.0; 134.5; 148.4; 152.0; 159.6; 162.4.
Supplementary information file containing H and 13C
NMR spectra of compounds 3a–h is available at the journal
website at http://link.springer.com/journal/10593.
1
Found, %: C 71.40; H 4.82; N 11.14. C15
lated, %: C 71.42; H 4.79; N 11.10.
12
H N
2
O
2
. Calcu-
2
-(4-Methoxyphenyl)quinazolin-4(3H)-one (3d). Yield
0
(
(
.184 g (73%). White solid. Mp 247–248°C (mp 244–245°C
29 –1
DMF–H
2
O) ). IR spectrum, ν, cm : 3313 (NH), 1667
This research was supported by grants from the Payame
Noor University.
1
C=O). H NMR spectrum, δ, ppm (J, Hz): 3.85 (3H, s,
CH
3
); 7.08 (2H, d, J = 8.0, H Ar); 7.48 (1H, t, J = 7.0,
References
H Ar); 7.70 (1H, d, J = 7.0, H Ar); 7.80 (1H, t, J = 7.0,
H Ar); 8.14 (1H, d, J = 7.0, H Ar); 8.20 (2H, d, J = 8.0,
1
. Hameed, A.; Al-Rashida, M.; Uroos, M.; Ali, S. A.; Arshia;
Ishtiaq, M.; Khan, K. M. Expert Opin. Ther. Pat. 2018, 28,
1
3
H Ar); 12.33 (1H, s, NH). C NMR spectrum, δ, ppm:
281.
5
1
5.4; 114.0; 120.4; 124.6; 125.8; 126.1; 126.9; 129.4;
34.2; 148.7; 152.0; 161.6; 162.3. Found, %: C 71.45;
2. Aly, M. M.; Mohamed, Y. A.; El-Bayouki, K. A.;
Basyouni, W. M.; Abbas, S. Y. Eur. J. Med. Chem. 2010, 45,
3365.
H 4.83; N 11.07. C15
H 4.79; N 11.10.
H
12
N
2
O . Calculated, %: C 71.42;
2
3
. Cao, S. L.; Feng, Y. P.; Jiang, Y. Y.; Liu, S. Y.; Ding, G. Y.;
Li, R. T. Bioorg. Med. Chem. Lett. 2005, 15, 1915.
2
-(4-Fluorophenyl)quinazolin-4(3H)-one (3e). Yield
4
. Kurogi, Y.; Inoue, Y.; Tsutsumi, K.; Nakamura, S.;
Nagao, K.; Yohsitsugu, H.; Tsuda, Y. J. Med. Chem. 1996,
0
.158 g (66%). Yellow solid. Mp 289–291°C (mp 284–
30 –1
2
86°C ). IR spectrum, ν, cm : 3315 (NH), 1666 (C=O).
3
9, 1433.
1
H NMR spectrum, δ, ppm (J, Hz): 7.38 (2H, t, J = 8.5,
H Ar); 7.52 (1H, t, J = 7.0, H Ar); 7.73 (1H, d, J = 7.0,
H Ar); 7.83 (1H, t, J = 7.0, H Ar); 8.15 (1H, d, J = 7.0,
5
. Tereshima, K.; Shimamura, H.; Kawase, A.; Tanaka, Y.;
Tanimura, T.; Kamisaki, T.; Ishizuka, Y.; Sato, M. Chem.
Pharm. Bull. 1995, 43, 2021.
9
66

Chemistry of Heterocyclic Compounds 2019, 55(10), 964–967
. Laddha, S. S.; Wadodkar, S. G.; Meghal, S. K. ARKIVOC
6
7
8
9
1
1
19. Bahadorikhalili, S.; Ashtari, A.; Ma'mani, L.; Ranjbar, P. R.;
2
006, (xi), 1.
Mahdavi, M. Appl. Organomet. Chem. 2018, 32, e4212. DOI:
10.1002/aoc.4212.
. Jafari, E.; Khajouei, M. R.; Hassanzadeh, F.; Hakimelahi, G. H.;
Khodarahmi, G. A. Res. Pharm. Sci. 2016, 11, 1.
. Kuneš, J.; Bažant, J.; Pour, M.; Waisser, K.; Šlosárek, M.;
Janota, J. Farmaco 2000, 55, 725.
20. Sayahi, M. H.; Saghanezhad, S. J.; Bahadorikhalili, S.;
Mahdavi, M. Appl. Organomet. Chem. 2019, 33, e4635. DOI:
10.1002/aoc.4635.
21. Sayahi, M. H.; Bahadorikhalili, S.; Saghanezhad, S. J.;
Mahdavi, M. Res. Chem. Intermed. 2018, 44, 5241.
22. Bahadorikhalili, S.; Mahdavi, M.; Ma'mani, L.; Shafiee, A.;
Mahdavi, H.; Akbarzadeh, T. New J. Chem. 2018, 42, 5499.
23. Snider, B. B.; Zeng, H. Heterocycles 2003, 61, 173.
24. Wang, L.; Wang, Y.; Chen, M.; Ding, M. W. Adv. Synth.
Catal. 2014, 356, 1098
. Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H. Tetrahedron
Lett. 1999, 40, 2175.
0. Takeuchi, Y.; Azuma, K.; Takakura, K.; Abe, H.; Kim, H. S.;
Wataya, Y.; Harayama, T. Tetrahedron 2001, 57, 1213.
1. Kikuchi, H.; Tasaka, H.; Hirai, S.; Takaya, Y.; Iwabuchi, Y.;
Ooi, H.; Hatakeyama, S.; Kim, H. S.; Wataya, Y.; Oshima, Y.
J. Med. Chem. 2002, 45, 2563.
1
1
1
1
2. Connolly, D. J.; Cusack, D.; O'Sullivan, T. P.; Guiry, P. J.
Tetrahedron 2005, 61, 10153.
25. Adib, M.; Sheikhi, E.; Bijanzadeh, H. R. Synlett 2012, 85.
26. He, L.; Li, H.; Neumann, H.; Beller, M.; Wu, X. F. Angew.
Chem., Int. Ed. 2014, 53, 1420.
3. Couture, A.; Cornet, H.; Grandclaudon, P. Synthesis 1991,
1009.
27. Srishylam, V.; Devanna, N.; Basaveswara Rao, M. V.;
Mulakayala, N. Tetrahedron Lett. 2017, 58, 2889.
28. Abbas, S. Y.; El-Bayouki, K. A.; Basyouni, W. M. Synth.
Commun. 2016, 46, 993.
4. Liu, J. F.; Lee, J.; Dalton, A. M.; Bi, G.; Yu, L.; Baldino, C. M.;
McElory, E.; Brown, M. Tetrahedron Lett. 2005, 46, 1241.
5. Giri, R.; Lam, J. K.; Yu, J. Q. J. Am. Chem. Soc. 2010, 132,
686.
29. Wang, G. W.; Miao, C. B.; Kang, H. Bull. Chem. Soc. Jpn.
2006, 79, 1426.
1
1
6. Connolly, D. J.; Guiry, P. J. Synlett 2001, 1707.
7. Vidyacharan, S.; Chaitra, N. C.; Sagar, A.; Sharada, D. S.
Synth. Commun. 2015, 45, 898.
30. Upadhyaya, K.; Thakur, R. K.; Shukla, S. K.; Tripathi, R. P.
J. Org. Chem. 2016, 81, 5046.
1
8. Abdel-Jalil, R. J.; Voelter, W.; Saeed, M. Tetrahedron Lett.
31. Kausar, N.; Roy, I.; Chattopadhyay, D.; Das, A. R. RSC Adv.
2016, 6, 22320.
2
004, 45, 3475.
9
67