A facile and convenient method to the one-pot synthesis of 2-mercapto-4(3H)-quinazolinones

Article abstract of DOI:10.3987/COM-09-11659

A facile and convenient method to the one-pot synthesis of 2-mercapto-4(3H)-quinazolinones is described from the reaction of anthranilic acid derivatives with thiourea in PEG.

Full text of DOI:10.3987/COM-09-11659

HETEROCYCLES, Vol. 78, No. 6, 2009
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HETEROCYCLES, Vol. 78, No. 6, 2009, pp. 1569 - 1571. © The Japan Institute of Heterocyclic Chemistry
Received, 19th January, 2009, Accepted, 19th February, 2009, Published online, 20th February, 2009
DOI: 10.3987/COM-09-11659
A FACILE AND CONVENIENT METHOD TO THE ONE-POT
SYNTHESIS OF 2-MERCAPTO-4(3H)-QUINAZOLINONES
Farzad Nikpour,* Roya Mozafari, and Touraj Paibast
Department of Chemistry, Faculty of Sciences, University of Kurdistan, P.O. Box
66315-416, Sanandaj, Iran
Abstract – A facile and convenient method to the one-pot synthesis of
2-mercapto-4(3H)-quinazolinones is described from the reaction of anthranilic
acid derivatives with thiourea in PEG.
2-Mercapto-4(3H)-quinazolinone derivatives represent one of the most active classes of heterocycles
possessing a wide spectrum of industrial1 and biological activities.2-5 Due to their diverse and remarkable
applications, considerable attention has been focused on their synthesis.3,6 The simplest and most
accessible method has proven to be the one based on the reaction of anthranilic acid or its functional
derivatives with a source of NH and thiocarbonyl such as thiocyanate salts and isothiocyanates.6a, 6c, 6f, 6g
Although some of these synthesis methods are very useful, most of them are associated with one or the
other limitations, such as involving two or more steps, use of very toxic chemicals, employment of harsh
reaction conditions, low reaction yields and moreover the low availability of starting materials. Certainly,
exploitation of simple reagents with good reaction yields and development of convenient methods to
synthesize or to modify such compounds is a worthwhile effort in heterocycles synthesis, and could be of
interest.
Here, we wish to report a convenient and simple procedure for the one-pot synthesis of
2-mercapto-4(3H)-quinazolinones 2 by direct cyclocondensation reaction of anthranilic acid derivatives 1
with thiourea in polyethyleneglycol (PEG). The reaction proceeds in neutral media and without use of any
catalyst (Scheme 1).
O
H
CO2H
NHR
PEG
N
H2N-CS-NH2
+
140-150 oC
S
N
R
X
X
1
2
Scheme 1

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HETEROCYCLES, Vol. 78, No. 6, 2009
The reaction conditions are mild and the reaction procedure is simple. Results are shown in Table 1.
Table 1. Reaction of anthranilic acid derivatives 1 with thiourea in PEG
1
Time/h
Yield 2 /% a,b
Mp/oC (lit.)
CO2H
NH2
a
b
c
d
e
f
5.5
80
292-295 (294-2966c)
CO2H
Cl
Br
4.5
4.5
4
72
74
82
70
30
351-354 (3557)
321-324 (323-3256b)
287-289 (288-2906b)
275-278 (2808)
NH2
CO2H
NH2
Me
CO2H
NH2
CO2H
4
N
NH2
CO2H
6.5
252-255 (255-2576c)
NHCH3
a In all cases, the products were identified and characterized by comparison of their physical
and spectral data with those of authentic samples. b Isolated yield.
The proposed mechanism is shown in Scheme 2. It is reasonable to assume that 2 results from an initial
addition of the amine group of 1 to thiourea and subsequent cyclocondensation of the unstable
intermediate 3 under the same reaction conditions.
O
OH
O
R1
R2
R1
R2
R1
R2
H
S
OH
NH2
R1
R2
CO2H
NHR3
S
N
N
+
H2N
NH2
- NH3
- H2O
SH
N
X
X
N
X
N
X
R3
S
R3
1
2a-f
2a-e
R3 = H
3
Scheme 2
As it is shown in Table 1, the yield of 2f is low, probably because of some steric of nucleophile. Also, it
cannot tautomerise to the stable aromatic structure.
The reactions were carried out in PEG as an excellent green solvent9 with high boiling point. It easily

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dissolves the polar anthranilic acid derivatives and thiourea. Also, it is miscible with water; therefore, it is
simple to remove the solvent and the residual thiourea in work-up process by washing of the reaction
mixture in water. In similar conditions, the reactions do not proceed in DMF and in EtOH.
In conclusion, the present procedure develops a simple and convenient method for the one-pot synthesis
of 2-mercapto-4(3H)-quinazolinones in neutral media and without need to use any catalyst. Also, this
procedure provides good yields of products with easy work-up of the reaction mixtures.
ACKNOWLEDGEMENTS
We are thankful to the University of Kurdistan Research Council for the partial support of this work.
REFERENCES AND NOTES
1. J. Kono and K. Ogi, JP Patent 60,170,843 (Chem. Abstr., 1984, 104, 119889c).
2. G. Kulcsár, T. Kálai, E. Ősz, C. P. Sár, J. Jekő, B. Sümegi, and K. Hideg, Arkivoc, 2003, 121.
3. A. G. A. El-Helbi and M. H. Abdel-Wahab, Acta Pharm., 2003, 53, 127; and references cited
4. Xth.eCreaini,.K. Kalcher, J. Lintschinger, and C. Neuhold, Mikrochimica Acta, 1993, 112, 135.
5. C. Y. Lin, A. C. Ho, H. C. Chiang, J. S. Sun, and S. Y. Sheu, Anticancer Res., 2002, 22, 937.
6. (a) V. K. Tiwari, D. D. Singh, H. A. Hussain, B. B. Mishra, and A. Singh, Monatsh. Chem., 2008, 139,
43; and references cited therin; (b) N. I. Mukarramov, B. A. Urakov, and K. M. Shakhidoyatov,
Chem. Heterocyclic Compounds, 2006, 42, 540; and references cited therein; (c) K. M. Pritchard, J.
M. Al-Rawi, and A. B. Hughes, Synth. Commun., 2005, 35, 1601; (d) V. N. Britsun, A. N. Esipenko,
A. A. Kudryavtsev, and M. O. Lozinskii, Russ. J. Org. Chem., 2005, 41, 1333.; (e) G. Calestani, L.
Capella, R. Leardini, M. Minozzi, R. Papa, D. Nanni, and G. Zanardi, Tetrahedron, 2001, 57, 7221;
(f) J. W. Chern, F. J. Shish, C. H. Chan, and K. C. Liu, Heterocycles, 1987, 26, 3193; and references
cited therein; (g) G. R. Dave, G. S. Mewada, and G. C. Amin, J. Indian Chem. Soc., 1950, 37, 595.
7. W. P. Fliedever, Chem. Ber., 1973, 106, 3149.
8. S. L. Shapiro, I. M. Rose, and L. Freadman, J. Am. Chem. Soc., 1957, 79, 281.
9. J. Chen, S. K. Spear, J. G. Huddleston, and R. D. Rogers, Green Chem., 2005, 7, 64.
10. General reaction procedure: In a 25 mL round flask a mixture of anthranilic acids 1a-f (5 mmol),
o
0.38 g (5 mmol) of thiourea, and 1 mL PEG was heated at 140-150 C for the times as indicated in
Table 1. The reaction mixture was cold to rt; then, H2O (5 mL) was added and mixed with the
contents and decanted (three times). The raw products were washed with 10% aqueous NaHCO3 to
remove the residual of anthranilic acid derivatives. The products collected and dried first in air then
in oven (100 oC). They may be recrystallized from EtOH or EtOH/EtOAc, if needed.