An efficient metal-free synthesis of 2-amino-substituted-4(3H)-quinazolinones

Article abstract of DOI:10.1016/j.tetlet.2015.11.085

2-Amino-substituted-4(3H)-quinazolinones have been synthesized via an efficient metal-free reaction between 2-aminobenzamide derivatives and carbonimidic dibromides. The reaction proceeds in the presence of K₂CO₃ affording cyclized products in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2015.11.085

Accepted Manuscript
An Efficient Metal-free Synthesis of 2-Amino-Substituted-4(3H)-Quinazoli-
nones
Behrooz Mirza
PII:
S0040-4039(15)30393-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.11.085
TETL 47025
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
3 August 2015
18 November 2015
26 November 2015
Please cite this article as: Mirza, B., An Efficient Metal-free Synthesis of 2-Amino-Substituted-4(3H)-
Quinazolinones, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.11.085
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1
Tetrahedron Letters
An Efficient Metal-free Synthesis of 2-Amino-Substituted-4(3H)-Quinazolinones
Behrooz Mirzaa,
aDepartment of Applied Chemistry, Faculty of Science, Islamic Azad University, Tehran, Iran
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
2-Amino-substituted-4(3H)-quinazolinones have been synthesized via an efficient metal-free
reaction between 2-aminobenzamide derivatives and carbonimidic dibromides. The reaction
proceeds in the presence of K2CO3 affording cyclized products in good to excellent yields.
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
2-Amino benzamide
Isocyanide
One-pot
Quinazolinone
Metal-free
1. Introduction
properties.11
Meanwhile,
2-amino-substituted-4(3H)-
quinazolinone, demonstrates antifungal activities against
Gibberella zeae and F. oxysporum, and antibacterial activities
against Ralstonia solanacearum and Xanthomonas oryzae.12 It is
worth mentioning that this core is an integral part of nolatrexed13
and acyclovir14 which are employed for the treatment of cancer
and herpes simplex virus infections respectively. Methods for the
The fascinating reactivity of isocyanides in different reactions
offers a powerful tool for the synthesis of heterocycles.1 This
utility arises from the dual nucleophilicity and electrophilicity of
isocyanides which leads to a variety of interesting scaffolds. The
association of isocyanides in various named reactions such as
Ugi,2 Passerini,3 Nef4 as well as insertion reactions5 form part of
the reported applications of isocyanides in organic synthesis.
Moreover, isocyanides can be converted into dihalogen
isocyanides under the action of chlorine or bromine, providing
new insights for further cyclization in a one-pot manner.6 These
stable intermediates have been applied to the construction of
cyclic compounds7 and simple organic molecules (e.g.,
isocyanates,8 isothiocyanates,9 and carbodiimides10) which are
classified as important substrates in the synthesis of heterocycles.
preparation
of
2-amino-substituted-4(3H)-quinazolinones
utilizing transition metals such as palladium-catalyzed isocyanide
insertion15 or molybdenum-mediated cyclocarbonylation have
been reported.16 In another approach, higher temperatures were
needed in a multi-step protocol, starting from anthranilic acid.17
Regarding the drawbacks of the above-mentioned methods such
as the toxicity of metal catalysts and higher temperatures, the
development of novel, metal-free and mild methodologies has
added interest for the construction of 2-amino-substituted-4(3H)-
quinazolinones with possible pharmaceutical values.
In line with recently reported applications of 2-amino
benzamides in the synthesis of new heterocyclic compounds,18
herein, an efficient reaction of these derivatives with
carbonimidic dibromide was developed.
First, we began our study with in situ preparation of
carbonimidic dibromide 6, using 1 equiv. of cyclohexyl
isocyanide and 1 equiv. of bromine in acetonitrile at room
temperature. Next, K2CO3 and 2-amino-N-phenyl benzamide
were added and heated at reflux for 8 h. 2-Amino-N-substituted
benzamide derivatives were obtained as a solid via the
Figure 1. Structures of acyclovir 1 and nolatrexed 2.
Quinazolinones are found as a privileged structure in
numerous natural products exhibiting diverse biological
———
 Corresponding author. Tel.: +98-21-884-97470; fax: +98-21-8832-549; e-mail: b_mirza@azad.ac.ir; behroozemirza@gmail.com

2
Tetrahedron
Scheme 1. One-pot, two-step synthetic route for the synthesis of quinazolin-4(3H)-ones.
reaction of isatoic anhydride and aryl or heteroaryl primary
amines in water.19
Table 2. The synthesis of 2-amino-substituted quinazolin-4(3H)-ones 8a-8i
(Scheme 1) a
As depicted in Table 1, we surveyed different inorganic and
organic bases such as Et3N, DABCO, t-BuOK, t-BuONa, and
K2CO3 to optimize the model reaction. K2CO3 was found to be
superior in terms of isolated yields (Table 1, entries 1-5). The
presence of base was necessary for reaction progression due to
the need for HBr scavenging (Table 1, entry 6). Among different
amounts of K2CO3 tested, 2.5 equiv. furnished better results for
the preparation of 8a, giving 73 % yield (Table 1, entries 7, 8).
Entry
product
R1
R2
Yield
(%)b
1
2
3
4
5
6
8a
8b
8c
8d
8e
8f
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
C6H5
73
76
C6H5CH2
4-MeOC6H4CH2 85
2-ClC6H4CH2
4-ClC6H4CH2
69
72
70
Table 1. Optimization of the reaction conditions.
Entry
Base (equiv.)a
K2CO3 (2)
Et3N (2)
Yield %b
71
Furan-2-yl-
methyl
1
2
3
4
5
6
7
8
7
8
8g
8h
8i
tert-butyl
tert-butyl
tert-butyl
C6H5CH2
4-MeC6H4CH2
4-FC6H4CH2
78
80
71
41
DABCO (2)
t-BuOK (2)
t-BuONa (2)
-
56
9
29
a
General condition: 5 (1 mmol), Br2 (1 mmol), room temperature, 10 min.
Then, 7 (1 mmol) and K2CO3 (2.5 mmol) were added, reflux, 8 h.
b Isolated yields.
58
trace
73
K2CO3 (2.5)
K2CO3 (3)
Acknowledgments
66
Support of this investigation by the Islamic Azad University
Tehran South Branch through a grant is gratefully acknowledged.
aAll reactions conducted at reflux in acetonitrile.
bIsolated yields.
References and notes
Next, the scope of the reaction was examined using
cyclohexyl and tert-butyl isocyanides and different 2-amino-N-
substituted benzamide derivatives. Interestingly, heterocyclic
rings such as furan and electron-rich and electron-deficient
substituents at the meta or para position of the phenyl group
afforded the target compounds in good to excellent isolated
yields (Table 2).
1.
2.
Ruijter, E.; Scheffelaar, R.; Orru, R. V. A. Angew. Chem. Int. Ed.
2011, 50, 6234.
Ugi, I.; Meyr, R.; Fetzer, U.; Steinbrückner, C. Angew. Chem.
1959, 71, 386-388.
3.
4.
5.
6.
Passerini, M. Gazz. Chim. Ital. 1921, 51, 126–129.
Nef, J.U. Justus Liebigs Ann. Chem. 1892, 270, 267–335.
Qiu, G.; Ding, Q.; Wu, J. Chem. Soc. Rev. 2013, 42, 5257-5269.
Kuhle, E.; Anders, B.; Klauke, E.; Tarnow, H.; Zumach, G.
Angew. Chem. Int. Ed. 1969, 8, 20-34.
In conclusion, a straightforward one-pot, two-step strategy for
the synthesis of 2-amino-substituted quinazolin-4(3H)-ones was
investigated. This transformation proceeds via the formation of
two new C-N bonds in a sequential manner. Carrying out this
reaction via a simple one-pot procedure and under metal-free
7.
El Kaim, L.; Grimaud, L.; Patil, P. Org. Lett. 2011, 13, 1261-
1263.
8.
9.
Sell, E.; Zierold, G. Ber. Dtsch. Chem. Ges. 1874, 7, 1228-1234.
Dickore, K.; Kuhle, E. Angew. Chem. Int. Ed. 1965, 4, 430-430.
10. Neidlein, R.; Heukelbach, E. Arch. Pharm. 1966, 299, 944-952.
11. Khan, I.; Ibrar, A.; Abbas, N.; Saeed, A. Eur. J. Med. Chem. 2014,
76, 193-244.
12. Wang, X.; Li, Z.; Yin, J.; He, M.; Xue, W.; Chen, Z.; Song, B.-A.
J. Agr. Food. Chem. 2013, 61, 9575-9582.
condition simplifies this reaction and introduces
a new
methodology which is amenable for the synthesis of libraries of
important bioactive compounds.
13. Zhao, X.; Li, F.; Zhuang, W.; Xue, X.; Lian, Y.; Fan, J.; Fang, D.
Org. Process Res. Dev. 2010, 14, 346-350.

3
14. Lucero, B. A.; Gomes, C. R. B.; Frugulhetti, I. C. de P. P.; Faro,
L. V.; Alvarenga, L.; de Souza, M. C. B. V.; de Souza, T. M. L.;
Ferreira, V. F. Bioorg. Med. Chem. Lett. 2006, 16, 1010-1013.
15. (a) Vidyacharan, S.; Chaitra, N.C.; Sagar, A.; Sharada, D.S. Synth.
Commun. 2015, 45, 898-907; (b) Sharma, S.; Jain, A. Tetrahedron
Lett. 2014, 55, 6051-6054; (c) Sharma, S.; Maurya, R.A.; Min, K.-
I, Jeong, G.-Y.; Kim, D.-P. Angew. Chem. Int. Ed. 2013, 52, 7564-
7568; (d) Ji, F.; Lv, M.-F.; Yi, W.-B.; Cai, C. Org. Biomol. Chem.
2014, 12, 5766-5772; (e) Vlaar, T.; Cioc, R.C.; Mampuys, P.;
Maes, B.U.W.; Orru, R.V.A.; Ruijter, E. Angew. Chem. Int. Ed.
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43, 2936-2942.
19. General procedure for the synthesis of 2-(Cyclohexylamino)-3-
phenylquinazolin-4(3H)-one (8a): Bromine (1 mmol) was added
to a stirred solution of cyclohexyl isocyanide (1 mmol) in
acetonitrile (5 mL). After 10 minutes, K2CO3 (2.5 mmol) and 2-
amino-N-phenylbenzamide (1 mmol) were added and the mixture
heated at reflux for 8h. After this time, the solvent was removed
under reduced pressure and the residue purified by column
chromatography (petroleum ether/ethyl acetate 10:1) to obtain 8a
as a white solid. Yield: 73%, White solid. m.p. 156–158 °C; IR
1
(KBr) (νmax, cm-1): 3284, 2917, 2844, 1732, 1624, 1412, 1017; H
NMR (500 MHz, DMSO-d6): δ = 7.95 (d, J = 8.0 Hz, 1H), 7.57 (t,
J = 8.5 Hz, 1H), 7.23-7.33 (m, 6H), 7.11 (d, J = 7.5 Hz, 1H), 6.40
(d, J = 7.5 Hz, 1H), 3.96 (m, 1H), 1.83-1.85 (m, 2H, cyclohexyl),
1.58-1.70 (m, 3H, cyclohexyl), 1.27-1.31 (m, 5H, cyclohexyl); 13
C
18. (a) Shafii, B.; Saeedi, M.; Mahdavi, M.; Foroumadi, A.; Shafiee,
A. Synth. Commun. 2014, 44, 215-221; (b) Farzipour, S.; Saeedi,
M.; Mahdavi, M.; Yavari, H.; Mirzahekmati, M.; Ghaemi, N.;
Foroumadi, A.; Shafiee, A. Synth. Commun. 2014, 44, 481-487;
NMR (125 MHz, DMSO-d6): δ = 162.0, 149.3, 149.1, 136.4,
134.2, 128.4, 127.1, 126.7, 126.6, 124.5, 121.6, 116.1, 42.8, 31.9,
25.3, 24.7; Anal. Calcd for C20H21N3O: C, 75.21; H, 6.63; N,
13.16; Found: C, 75.48; H, 6.19; N, 12.99.