A new approach to the facile synthesis of 2-substituted-quinazolin-4(3H)- ones

Article abstract of DOI:10.1016/j.cclet.2011.01.034

A new approach to the facile synthesis of 2-substituted-quinazolin-4(3H)- ones and its derivatives using the condensation reaction of substituted 2-aminobenzamide and orthoesters is reported.

Full text of DOI:10.1016/j.cclet.2011.01.034

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 951–953
www.elsevier.com/locate/cclet
A new approach to the facile synthesis
of 2-substituted-quinazolin-4(3H)-ones
Bin Wang a,b,1, Zeng Li a,1, Xiao Ning Wang a, Jia Heng Tan a,
Lian Quan Gu a, Zhi Shu Huang a,
*
a School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
b Department of Chemistry and Life Science, Xiangnan University, Chenzhou 423000, China
Received 3 November 2010
Available online 19 May 2011
Abstract
A new approach to the facile synthesis of 2-substituted-quinazolin-4(3H)-ones and its derivatives using the condensation
reaction of substituted 2-aminobenzamide and orthoesters is reported.
# 2011 Zhi Shu Huang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Quinazolin-4(3H)-ones; Synthesis; Aminobenzamide; Orthoester
Quinazolin-4(3H)-one derivatives possess a broad spectrum of biological and pharmaceutical activities. Several
successfully clinical drugs are based on this scaffold. In particular, the 2-substituted quinazolinones have been utilized
as peptidomimetic scaffolds with specificity for cholecystokinin, angiotensin and cell adhesion receptors [1–6].
Therefore, considerable efforts have been made to explore simple and direct approaches for the construction of 4(3H)-
quinazolinone skeletons [7].
The most common approach for quinazolinones involves the amidation of 2-aminobenzonitrile, 2-aminobenzoic
acid, or its derivatives followed by oxidative ring closure under basic conditions. Among them, the main synthetic
routes employ 2-aminobenzoic acid, isatoic anhydride, N-arylnitrilium salts and 3,1-benzoxazinones as appropriate
precursors [8–15]. In addition to the reactions mentioned above, quinazolinones have been obtained by the reaction of
2-aminobenzonitrile and orthoesters catalyzed by Keggin-type heteropolyacids or under basic conditions in different
solvent [16–18]. However, most of these reported methods suffer from low yields or tedious procedures. Herein, we
report a facile synthesis of 2-substituted quinazolin-4(3H)-ones and its derivates in high yields using condensation
reaction of substituted 2-aminobenzamide and orthoesters (Scheme 1).
In the present study, the target compounds were successfully synthesized within 1.5–3 h via condensation of 2-
aminobenzamide or 2-amino-5-nitrobenzamide with the corresponding variety of commercially available orthoesters
under mild conditions (Table 1). In addition to 3a, this reaction proceeds without organic solvent and in the absence of
some types of basic or acidic catalyst. In all cases, the crude products precipitated from the reaction mixtures after
* Corresponding author.
E-mail address: ceshzs@mail.sysu.edu.cn (Z.S. Huang).
1
These authors contributed equally to this paper.
1001-8417/$ – see front matter # 2011 Zhi Shu Huang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.01.034

[()TD$FIG]
952
B. Wang et al. / Chinese Chemical Letters 22 (2011) 951–953
Scheme 1. Synthesis of 2-substituted-quinazolin-4(3H)-ones.
Table 1
Reaction conditions and results.
Entry
Product
R
R0
Time (h)
Yield (%)
Mp (8C)
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
H
H
1.5
1.5
2
61
84
97
81
80
86
215–216
235–237
237–238
275–276
278–279
297–299
H
Et
Ph
H
H
NO2
NO2
NO2
1.5
3
Et
Ph
3
[()TD$FIG]
Scheme 2. The cyclization mechanism of 2-substituted-quinazolin-4(3H)-ones.
cooling were purified by recrystallization with high yield. Furthermore, this method is suitable for the preparation of 2-
substituted-quinazolin-4(3H)-ones and its derivatives.
The reaction may proceed through the intermediacy of the imidicester 4 which undergoes nucleophilic attack by the
carboxyl oxygen to produce the cyclized product with the elimination of a molecule of alcohol (Scheme 2).
The structures of compounds 3a–f were confirmed by 1H, 13C NMR and MS spectral analysis and their physical
properties were identical with those of authentic samples prepared by reported procedures (see Supplementary data).
In conclusion, we have developed a simple and highly efficient practical method for one-pot synthesis of the title
compounds without solvent under classical heating. Due to the simplicity of the procedure which is eco-friendly, and
can be expected to find utility in the construction of 4(3H)-quinazolinone skeletons.
1. Experimental
1H and 13C NMR spectra were recorded using TMS as the internal standard in DMSO-d6 with a Bruker BioSpin
GmbH spectrometer at 400.132 MHz and 100.614 MHz, respectively; MS spectra were recorded on a Shimadzu

B. Wang et al. / Chinese Chemical Letters 22 (2011) 951–953
953
LCMS-2010A instrument with an ESI or ACPI mass selective detector. Melting points were determined using an SRS-
OptiMelt automated melting point instrument without correction.
Procedures for preparation of 4(3H)-quinazolinone 3a: A mixture of 2-aminobenzamide (2 mmol) and triethyl
orthoacetate (2 mmol) in ethanol (10 mL) was stirred at room temperature for 1.5 h. The reaction was monitored by
TLC. The reaction mixture was then allowed to cool to 0 8C and the precipitate thus, obtained was filtered off and
recrystallized from ethanol to give white needles of 3a.
General procedure for preparation of 2-substituted quinazolin-4(3H)-ones and its derivates 3b–f: A stirred mixture
of 2-aminobenzamide or 2-amino-5-nitrobenzamide (20 mmol) and the orthoester (40 mmol) was heated under reflux
for 1.5–3 h. The reaction was monitored by TLC. The reaction mixture was cooled to 0 8C and the white or buff
precipitate thus obtained was filtered off and recrystallized from ethanol to give white or buff needles of 3b–f.
Acknowledgments
We thank the Natural Science Foundation of China (Nos. U0832005, 90813011, 20772159, 30801436), the
Ministry of Education of the People’s Republic of China (No. 200805581163), the Guangdong Natural Science
Foundation (No. 8451008901000214), and the Science Foundation of Guangzhou (No. 2009A1-E011-6) for financial
support of this study.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at doi:10.1016/
j.cclet.2011.01.034.
References
[1] J.H. Chan, J.S. Hong, L.F. Kuyper, J. Heterocycl. Chem. 34 (1997) 145.
[2] S.L. Gackenheimer, J.M. Schaus, D.R. Gehlert, Exp. Ther. 73 (1996) 113.
[3] R.O. Dempcy, E.B. Skibo, Biochemistry 30 (1991) 8480.
[4] R.P. Maskey, M. Shaaban, I.G. Wollny, J. Nat. Prod. 67 (2004) 1131.
[5] T.L. Gilchrist, J. Chem. Soc. Perkin Trans. 1 (2001) 2491.
[6] T.L.J. Gilchrist, J. Chem. Soc. Perkin Trans. 1 (1999) 2849.
[7] D.J. Connolly, D. Cusack, T.P. Sullivan, Tetrahedron 61 (2005) 10153.
[8] P. Salehi, M. Dabiri, M.A. Zolfigolc, et al. Tetrahedron Lett. 46 (2005) 7051.
[9] M. Bakavoli, O. Sabzevari, M. Rahimizadeh, Chin. Chem. Lett. 18 (2007) 533.
[10] R.J. Abdel-Jalil, W. Voelterb, M. Saeed, Tetrahedron Lett. 45 (2004) 3475.
[11] I.K. Kostakis, A. Elomri, E. Seguin, Tetrahedron Lett. 48 (2007) 6609.
[12] M.S. Khajavi, N. Montazari, S.S. Hosseini, J. Chem. Res. (S) (1997) 286.
[13] K.R. Moghadam, M.S. Khajavi, J. Chem. Res. (S) (1998) 702.
[14] A. Witt, J. Bergman, J. Bergman, Tetrahedron 56 (2000) 7245.
[15] V. Segarra, M.I. Crespo, F. Pujol, Bioorg. Med. Chem. Lett. 8 (1998) 505.
[16] M. Tobe, Y. Isope, H. Tomizawa, Bioorg. Med. Chem. Lett. 11 (2001) 545.
[17] P. Scheiner, L. Frank, I. Giusti, J. Heterocycl. Chem. 21 (1984) 1817.
[18] M.M. Heravi, S. Sadjadi, N.M. Haj, Tetrahedron Lett. 50 (2009) 943.