A facile and convenient approach for the one-pot synthesis of 2,4(1H,3H)-quinazolinediones

Article abstract of DOI:10.1016/j.cclet.2012.01.027

A fast and efficient method is described for the one-pot synthesis of 2,4(1H,3H)-quinazolinediones by cyclization reaction of anthranilic acid derivatives with potassium cyanate and acetic acid in PEG. Good to high yields of the products obtain in short reaction times with simple work-up.

Full text of DOI:10.1016/j.cclet.2012.01.027

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Chinese Chemical Letters 23 (2012) 431–433
www.elsevier.com/locate/cclet
A facile and convenient approach for the one-pot synthesis of
2,4(1H,3H)-quinazolinediones
*
Mahnaz Sharafi-Kolkeshvandi, Farzad Nikpour
Department of Chemistry, Faculty of Sciences, University of Kurdistan, P.O. Box 66315-416, Sanandaj, Iran
Received 15 November 2011
Available online 3 March 2012
Abstract
A fast and efficient method is described for the one-pot synthesis of 2,4(1H,3H)-quinazolinediones by cyclization reaction of
anthranilic acid derivatives with potassium cyanate and acetic acid in PEG. Good to high yields of the products obtain in short
reaction times with simple work-up.
# 2012 Farzad Nikpour. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Anthranilic acid; Potassium cyanate; Quinazolinediones; Benzoylenurea; Cyclization reaction
2,4(1H,3H)-Quinazolinediones and their derivatives are versatile intermediates in the synthesis of heterocycles
with high pharmacological [1] and biological [2] activities. Owing to the potent activity of quinazoline-2,4-diones,
considerable attention has been focused on their synthesis [3]. Although some of these synthesis methods are very
useful, many of them have drawbacks such as involving two or more steps, long reaction times, use of very toxic
chemicals, employment of harsh reaction conditions, unsuitable for sensitive substituents, low reaction yields and
moreover the low availability of starting materials. For example, in the general method for the synthesis of
2,4(1H,3H)-quinazolinedione [4], the reaction begins by the use of potassium cyanate (KOCN) in acetic acid solution
followed by the use of concentrate solution of sodium hydroxide overnight and addition of sulfuric acid solution for
neutralization. Undoubtedly, this procedure is not an appropriate method for the synthesis of quinazolinediones with
sensitive substitutions. Therefore, there is further scope to explore a mild and efficient method for the synthesis of the
title compounds. Herein, we wish to report a simple and efficient protocol for the one-pot synthesis of 2,4(1H,3H)-
quinazolinediones using condensation reaction of anthranilic acid derivatives 1a-i with KOCN in the presence of
acetic acid in polyethyleneglycol (PEG). The products were obtained under mild reaction conditions without any
catalyst.
In continuation of our investigation on the synthesis of quinazolinone derivatives [3g,8], here, the cyclization
reaction of anthranilic acids 1 by KOCN and AcOH was studied. We observed when the anthranilic acids 1 are heated
in PEG with KOCN and AcOH, a cyclization reaction occurs and 2,4(1H,3H)-quinazolinediones 2 are obtained in
good to high yields, in short reaction times and without need to use of any catalyst (Scheme 1). The reaction conditions
* Corresponding author.
E-mail address: fnikpour@uok.ac.ir (F. Nikpour).
1001-8417/$ – see front matter # 2012 Farzad Nikpour. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2012.01.027

432
M. Sharafi-Kolkeshvandi, F. Nikpour / Chinese Chemical Letters 23 (2012) 431–433
O
R1
R2
R1
R2
CO2H
NH2
PEG
-
NH
+
K +
O
N
+
CH3CO2H
50-60 oC
10-90 min
X
X
N
H
O
78-95%
1
2
Scheme 1.
are mild and the reaction procedure is simple with very simple work-up. Also, this method could be utilized for the
synthesis of a variety of substituents on aromatic rings. Results are summarized in Table 1.
The plausible mechanism is proposed in Scheme 2. It seems that the nucleophilic attack of the amine to the
produced cyanic acid following with cyclization of the interdediate 3 leads to the desired compounds 2.
The reactions were carried out in PEG as an excellent green solvent [9]. It easily dissolves the polar starting
materials. Also, it is miscible with water; therefore, it is simple to remove the solvent and the residual KOCN in work-
up process by washing of the reaction mixture with water.
The products were characterized by their physical and spectroscopic data [3–7,10,11]. In IR spectra of
compounds 2, CO-stretching bands of the amide and the urea carbonyl groups are about 1730 and 1665 cmÀ1
respectively. In 1H NMR, the peaks of the two N-H groups appear as two singlets or sometimes as one broad singlet
in about 11.35–10.00 ppm. In 13C NMR spectrum, two CO-peaks are observed at about 163 and 150 ppm related to
the amide and the urea carbonyl groups respectively. Also, in all cases, molecular ion-peaks with highest abundances
appear in the Ms-spectra.
In conclusion, we have reported a simple and convenient procedure for the one-pot synthesis of 2,4(1H,3H)-
quinazolinediones by an addition reaction of anthranilic acid derivatives to acidic solution of potassium cyanate and
then, cyclization reaction of the obtained intermediate in PEG as an excellent green solvent. The reactions were carried
Table 1
Synthesis of compounds 2a from the cyclization reaction of anthranilic acid derivatives 1 (1 mmol) with KOCN (1.3 mmol) and AcOH (2 mmol) in
PEG-400 (0.3 mL).
Entry
2
X
R1
R2
Time/min.
Yield/%b
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
CH
CH
CH
CH
CH
CH
CH
CMe
N
H
H
10
45
20
15
20
30
60
30
90
95
85
85
90
80
84
80
82
78
OH
Cl
H
H
H
Cl
Br
MeO
H
H
MeO
COOH
H
g
h
i
H
H
H
a
The identification and characterization of the products were carried out by their physical and spectroscopic data and comparison of them with
authentic samples.
b
Isolated yields.
[K OCN + AcOH]
O
O
R1
R2
CO2H
NH2
R1
R2
OH
R1
R2
H-N=C=O
NH
- H2O
X
X
NH2
N
H
X
N
H
O
O
1
3
2
Scheme 2.

M. Sharafi-Kolkeshvandi, F. Nikpour / Chinese Chemical Letters 23 (2012) 431–433
433
out under mild conditions which can be used for a variety of substituents on aromatic ring. Good to high yields of the
products were obtained in high purity with simple work-up.
Acknowledgments
We are thankful to the University of Kurdistan Research Council for the partial support of this work.
References
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(b) T. Mizuno, T. Iwai, Y. Ishino, Tetrahedron Lett. 45 (2004) 7073;
(c) K.C. Russell, Ch.S. Kim, Ch. Diez, Chem. Eur. J. 6 (2000) 1555;
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(f) D. Schwinn, H. Glatz, W. Bannwarth, Helv. Chem. Acta 86 (2003) 188;
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(h) T. Mizuno, M. Mihara, T. Nakai, et al. Synthesis (2007) 2524;
(i) K. Malagu, H. Duggan, K. Menear, et al. Bioorg. Med. Chem. Lett. 19 (2009) 5950;
(j) J. Gao, L.N. He, C.X. Miao, et al. Tetrahedron 66 (2010) 4063.
[4] N.A. Lange, F.E. Sheibley, Organic Syntheses Coll., vol. 2, John Wiley & Sons, New York, 1943, p. 79.
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[7] M. Pfleiderer, W. Pfleiderer, Heterocycles 33 (1992) 905.
[8] F. Nikpour, R. Mozafari, T. Paibast, Heterocycles 78 (2009) 1569.
[9] J. Chen, S.K. Spear, J.G. Huddleston, R.D. Rogers, Green Chem. 7 (2005) 64.
[10] R.P. Maskey, M. Shaaban, I. Gru¨n-Wollny, et al. J. Nat. Prod. 67 (2004) 1131.
[11] Melting points were measured with an Electrothermal 9100 apparatus. IR spectra were measured with a Shimadzu IR-460 spectrometer. NMR
spectra were recorded with a Bruker DRX-250 AVANCE instrument (250.1 MHz for 1H and 62.9 MHz for 13C). Chemical shifts are given in
ppm (d) relative to internal TMS, and coupling constants J are reported in Hz. Mass spectra were recorded with an Agilent-5975C mass
spectrometer operating at an ionization potential of 70 eV. PEG with molecular weight 400 was used in reactions. General reaction procedure:
A mixture of an anthranilic acid derivative 1 (1 mmol) in PEG-400 (0.3 mL) and KOCN (1.3 mmol, 0.11 g) was stirred in room temperature for
a short time and then AcOH (2 mmol, 0.11 mL) was added to the mixture and heated for the times as indicated in Table 1. After completion of
the reaction, the precipitate was washed with cold water (three times) to remove the residual of KOCN, AcOH and PEG. The raw products were
washed with 10% NaHCO3 (except for 2g) and then with H2O to remove the trace residual of 1 and then were dried in air. In the case of 2g, the
trace residual of 1e was washed with dilute solution of HCl and then with H2O. The raw products were recrystallized from ethanol, or ethanol/
acetic acid. Quinazoline-2,4(1H,3H)-dione (2a): White powder, mp > 350 8C (Lit. > 350 8C) [4,5], Yield: 95%. 6-Hydroxyquinazoline-
2,4(1H,3H)-dione (2b): White powder, mp: 309–312 8C [6], Yield: 85%. IR (KBr): y 3245 and 3170 (2NH), 1740–1667 (CO) cmÀ1. 1H NMR
(DMSO-d6): d 11.15 (brs, 1H, NH), 10.87 (brs, 1H, NH), 9.64 (brs, 1H, OH), 7.20 (s, 1H–Ar), 7.11–6.89 (m, 2H–Ar). 13C NMR (DMSO-d6): d
ꢀ
163.2, 153.1, 150.5, 133.9, 124.2, 117.1, 115.5, 111.1. EI-MS (70 eV): m/z (%) 178 (M+ , 100). 6-Chloroquinazoline-2,4(1H,3H)-dione (2c):
White powder, mp: 320–323 8C (Lit. > 300 8C) [5], Yield: 85%. 7-Chloroquinazoline-2,4(1H,3H)-dione (2d): White powder, mp: 290–
292 8C, Yield: 90%. R (KBr): y 3305 and 3160 (2NH), 1740 (CO), 1681 (CO) cmÀ1. 1HNMR (DMSO-d6): d 11.35 (brs, 1H, NH), 11.20 (brs,
1H, NH), 7.83 (d, 3JHH = 9.0 Hz, 1H–Ar), 7.17–7.13 (m, 2H–Ar). 13C NMR (DMSO-d6): d 162.5, 150.6, 142.3, 139.7, 129.4, 122.9, 115.1,
113.7. EI-MS (70 eV): m/z (%) 198 [(M+. + 2), 33], 196 (M+., 100). 6-Bromoquinazoline-2,4(1H,3H)-dione (2e): White powder, mp: 318–
321 8C (Lit. > 300 8C) [3j], Yield: 80%. 6,7-Dimethoxyquinazoline-2,4(1H,3H)-dione (2f): White powder, mp: 321–324 8C (Lit. > 300 8C)
[5], Yield: 84%. 8-Methylquinazoline-2,4(1H,3H)-dione (2h): White powder, mp: 296–299 8C (Lit. 297–299 8C) [10], Yield: 82%. Quinazo-
line-2,4(1H,3H)-dione-7-carboxylic acid (2g): White powder, mp: > 350 8C, Yield: 80%. IR (KBr): (3350 (NH), 3305–2500 (NH and OH),
1740 (CO), 1700 (COOH), 1681 (CO) cmÀ1. 1HNMR (DMSO-d6): d 10.88 (brs, 1H, COOH), 10.01 (brs, 2H, 2NH), 8.97–7.62 (m, 3H–Ar). 13
C
ꢀ
NMR (DMSO-d6): d 169.2, 169.1, 166.9, 141.0, 135.6, 131.6, 123.5, 121.4, 120.8. EI-MS (70 eV): m/z (%) 206 (M+ , 100). Pyrido[2,3-
d]pyrimidine-2,4(1H,3H)-dione (2i): White powder, mp: > 350 8C [7], Yield: 78%. R (KBr): y 3250 and 3180 (2NH), 1740 (CO), 1685 (CO)
cmÀ1. 1HNMR (DMSO-d6): d 11.67 (brs, 1H, NH), 11.45 (brs, 1H, NH), 8.59–7.99 (m, 3H–Ar). 13C NMR (DMSO-d6): d 161.5, 150.4, 152.9,
ꢀ
146.3, 139.7, 122.9, 115.1. EI-MS (70 eV): m/z (%) 163 (M+ , 100).