Chemistry Letters Vol.34, No.10 (2005)
1439
References and Notes
O
1
F. D. Therkelsen, A. L. Hansen, E. B. Pedersen, and C.
Nielsen, Org. Biomol. Chem., 1, 2908 (2003).
M. M. Baraka, Boll. Chim. Farm., 140, 90 (2001).
I. A. Rivero, K. Espinoza, and R. Somanathan, Molecules,
9, 609 (2004), and references cited therein.
R1
OH
NH2
Y
X
2
3
R2
N
O
R3
4
5
6
7
8
9
S. V. Voitekhovich, P. N. Gaponik, A. S. Lyakhov, and
O. A. Ivashkevich, Pol. J. Chem., 75, 253 (2001).
C.-S. Kim, C. Diez, and K. C. Russell, Chem.—Eur. J., 6,
1555 (2000).
3a−3f
O
O
_
R1
R2
R1
R2
O
Y
X
OH
NH
Y
X
_
NH2
M. M. Vogtle and A. L. Marzinzik, QSAR & Combinatorial
¨
N
N
Science, 23, 440 (2004), and references cited therein.
A. K. Bose, B. K. Banik, and M. S. Manhas, Tetrahedron
Lett., 36, 213 (1995).
J. S. Yadav, B. V. S. Reddy, R. S. Rao, V. Naveenkumar,
and K. Nagaiah, Synthesis, 2003, 1610.
a) S. J. Tu, F. Fang, C. B. Miao, H. Jiang, and D. Q. Shi,
Chin. J. Chem., 21, 706 (2003). b) P. Salehi, M. Dabiri,
M. A. Zolfigol, and M. A. B. Fard, Tetrahedron Lett., 44,
2889 (2003). c) A. K. Mitra and K. Banerjee, Synlett,
2003, 1509.
O
O
R3
R3
4a−4e
Figure 1.
yield of 2c in H2O is very low; also, 2f is not produced in DMAC
or H2O at all. The reasons are as follows:
First of all, in the case of 1c, high nucleophilicity of amine,
owing to the presence of a methoxy group in para-position, in-
creases the reaction rate in the first step, but substitution of an-
other methoxy group in para-position to the carboxylic acid, de-
creases the cyclization reaction rate of 4c; therefore, this reaction
is carried out in DMAC (bp 166 ꢀC), but because of the lower
boiling point of H2O in comparison with DMAC, the heat trans-
fer to the reaction mixture, is not accomplished completely and
before completion of the reaction, the water is evaporated.
Similarly, the solvent plays as a heat transfer in the reaction of
1d with KOCN; however, in H2O, owing to the steric hindrance
of nucleophile, the reaction is not fulfilled completely but is
accomplished in DMAC entirely.
Secondly, substitution of two nitrogen atoms in the benzene
ring of 1f, makes it a very week nucleophile, which can not
attack KOCN in neutral media. Therefore, the intermediate 4f
is not formed and 2f is not obtained.
In conclusion, the present procedure demonstrates a simple
and fast method for the synthesis of 2,4-(1H,3H)-quinazoline-
diones in neutral media without use of any catalyst, which
can be used for a variety of substituents. Also, especially when
urea is used in H2O, this method is clean and safe, which
provides excellent yields of the desired products of high purity
with simple work-up and shows a green and environmentally
friendly reaction.
10 C. T. Brain and J. T. Steer, J. Org. Chem., 68, 6814 (2003).
11 N. Kaval, W. Dehaen, P. Matyus, and E. V. Eycken, Green
Chem., 6, 125 (2004); for review of the microwave assisted
organic reactions see: M. Nuchter, B. Ondruschka, W.
¨
Bonrath, and A. Gum, Green Chem., 6, 128 (2004).
12 N. A. Lange and F. E. Sheibley, Org. Synth., Coll. Vol. II,
79.
13 M. S. Khajavi, M. Hajihadi, and F. Nikpour, J. Chem. Res.,
Synop., 1996, 94.
14 Microwave irradiations were carried out in a Butane oven
Model MB310. Substances were commercially prepared
(Merck and Fluka) and used.
Caution! For more safety, especially when DMAC are used
as solvent, all experiments should be performed in an effi-
cient hood in order to avoid the contact of vapors.
General procedure: A mixture of 5 mmol anthranilic acids
1a–1f, 0.3 g (5 mmol) of urea or 0.4 g (5 mmol) of potassium
cyanate, and 0.5 mL of DMAC or 1 mL distilled water (hot
water in the case of 1d) contained in a 30 mL tall beaker
(equipped with a simple funnel on it) was placed in the mi-
crowave oven and irradiated with power and time as indicat-
ed in Table 1. The reaction mixture was cold to room temper-
ature, then 5 mL of H2O was added and mixed with the con-
tents and decanted (three times). The products collected and
dried first in air then in oven (100 ꢀC). The raw products were
recrystallized from ethanol, or ethanol/acetic acid.
We are thankful to the Kurdistan University Research
Council for partial support of this work.
Published on the web (Advance View) September 24, 2005; DOI 10.1246/cl.2005.1438