Condensation reaction of ethyl 4-oxo-4h-benzo[d][1,3]-oxazine-2- carboxylates with potassium cyanate: 2,4(1H,3H)-quinazolinediones synthesis

Article abstract of DOI:10.3987/COM-12-12551

The condensation reaction of ethyl 4-oxo-4H-benzo[d][1,3]oxazine-2- carboxylates with acidic solution of potassium cyanate offers a novel and expedient route to the synthesis of 2,4(1H,3H)-quinazolinediones under mild reaction conditions..

Full text of DOI:10.3987/COM-12-12551

HETEROCYCLES, Vol. 85, No. 11, 2012
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HETEROCYCLES, Vol. 85, No. 11, 2012, pp. 2745 - 2748. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 21st July, 2012, Accepted, 30th August, 2012, Published online, 3rd September, 2012
DOI: 10.3987/COM-12-12551
CONDENSATION REACTION OF ETHYL 4-OXO-4H-BENZO[d][1,3]-
OXAZINE-2-CARBOXYLATES
WITH
POTASSIUM
CYANATE:
2,4(1H,3H)-QUINAZOLINEDIONES SYNTHESIS
Farzad Nikpour,* Forugh Havasi, and Zeinab Arzegar
Department of Chemistry, Faculty of Sciences, University of Kurdistan, P. O. Box
66315-416, Sanandaj, Iran; E-mail: fnikpour@uok.ac.ir
Abstract – The condensation reaction of ethyl 4-oxo-4H-benzo[d][1,3]oxazine-
2-carboxylates with acidic solution of potassium cyanate offers a novel and
expedient route to the synthesis of 2,4(1H,3H)-quinazolinediones under mild
reaction conditions.
4H-3,1-Benzoxazin-4-ones are known as important class of heterocycles having significant biological
activities. The electronically unsaturated character of 4H-3,1-benzoxazinones causes they are active
elctrophiles and play a vital role as starting materials for further transformations in design and synthesis
of heterocyclic products.1-5
Many biological and pharmacologically active agents incorporate quinazoline-2,4-dione moiety as
structural fragment.6 Although numbers of approaches have been reported for their synthesis,7 the
development of novel and more efficient methods with mild reaction conditions and improved yields is
highly desired.
In continuation of our investigation on the synthesis of 2-substituted 4H-3,1-benzoxazin-4-one
derivatives,8 we have now focused our attention on the synthesis of biologically active heterocycles using
3,1-benzoxazin-4-ones moiety. The reaction of 4H-3,1-benzoxazin-4-one with a number of nitrogen
nucleophiles has been reported.1 They are not satisfactorily stable rings and chemically active functional
groups on C-2 position affect on their reactivity. Herein, we have disclosed the condensation reaction of
ethyl 4-oxo-4H-benzo[d][1,3]oxazine-2-carboxylates 1 with acidic solution of KOCN and preparation of
2,4(1H,3H)-quinazolinediones (Scheme 1). The reaction conditions are mild and the reaction procedure is
simple. Good to high yields of the products are obtained in high purity with simple work-up of the
reaction mixture. Also, this method could be utilized for the synthesis of a variety of substituents on
aromatic rings. Results are summarized in Table 1.

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HETEROCYCLES, Vol. 85, No. 11, 2012
O
O
N
PEG
NH
O
AcOH
KOCN
+
+
50-60 oC
N
H
O
CO2Et
X
X
1
2
Scheme 1
Table 1. Reaction of benzoxazin-4-ones 1 with acidic solution of KOCN in PEG-400 at 50-60 oC.
Entry
1
O
2
O
Time/min
Yield 2 /% a,b Mp/oC (lit.)
NH
O
1
25
92
90
82
>350 (9)
N
H
O
N
CO2Et
O
O
NH
O
2
3
20
45
290-292 (9)
320-323 (9)
Cl
Cl
N
H
O
O
O
O
Cl
Cl
N
O
CO2Et
CO2Et
O
O
NH
N
O
N
H
O
Br
Br
NH
4
5
6
50
85
74
75
318-323 (7a)
297-300 (9)
297-300 (10)
N
CO2Et
N
H
Me
O
Me
O
O
NH
135
120
N
O
CO2Et
N
H
O
O
O
O
NH
N
CO2Et
N
H
O
Me
Me
O
MeO
MeO
MeO
MeO
NH
NH
O
7
8
155
15
80
85
80
78
321-324 (9)
336-338 (9)
>350 (11)
N
H
O
O
N
O
CO2Et
O2N
O2N
O
N
H
O
O
N
O
CO2Et
NH
NH
CO2Et
9
30
O2N
HO
N
H
O
O
O2N
N
O
EtO2C-O
NH
NH
CO2Et
10
90
309-312 (12)
N
H
O
N
a All the products were identified and characterized by comparison of their physical and spectral data with those of
authentic samples. b Isolated yield.

HETEROCYCLES, Vol. 85, No. 11, 2012
2747
Electron-withdrawing effect of the ethyl carboxylate group on C-2 position of 4H-3,1-benzoxazinones 1
causes the easily influence of C-4 carbonyl against nucleophilic attacks probably because they increase
the electrophilic strength of C-4 carbonyl. Also, as it is observed in Table 1, electron-withdrawing groups
on benzene ring increase the reaction rate; however, electron-donating substituents decrease the coupling
reaction rate. The plausible mechanism is proposed in Scheme 2. Although we have made no attempts to
characterize the produced intermediates, it seems that the reaction begins by nucleophilic attack of the
cyanic acid to the C-4 carbonyl of benzoxazin-4-ones 1. The subsequent nucleophilic attack of another
molecule of cyanic acid to the intermediate 3 following with fast cyclization of the produced adduct, leads
to the desired compounds 2.
KOCN
AcOH
+
O
N
O
O
N=C=O
O
N
O H
NH
N
O
H
CO2Et
- (O=C=N-CO-CO2Et)
CO2Et
N
N
H
O
X
X
H
X
O
1
3
2
Scheme 2
The reactions were carried out in PEG as an excellent green polar solvent. 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.
In conclusion, condensation reaction of ethyl 4-oxo-4H-benzo[d][1,3]oxazine-2-carboxylates with acidic
solution of potassium cyanate under mild conditions, proposes
a
novel approach for
4H-3,1-benzoxazinones as starting material in design and synthesis of 2,4(1H,3H)-quinazolinediones. The
reactions procedure is simple and can be used for a variety of substituents on aromatic ring. Good to high
yields of the products obtain in high purity with simple work-up.
EXPERIMENTAL
Melting points were measured with an Electrothermal 9100 apparatus and are uncorrected. PEG with
molecular weight 400 was used in reactions. The synthesis of the benzoxazin-4-ones 1 was achieved by
using the recent published methods.8
General reaction procedure: A mixture of a 4H-3,1-benzoxazin-4-one derivative 1 (1 mmol) was
dissolved in PEG (0.5 mL), then, KOCN (2.1 mmol, 0.18 g) and AcOH (2.2 mmol, 0.12 mL) were added
to the mixture (in the case of entry 10, 3 mmol KOCN and 3.2 mmol AcOH were used) 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 recrystallized
from EtOH, or EtOH/AcOH.

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HETEROCYCLES, Vol. 85, No. 11, 2012
ACKNOWLEDGEMENT
We are thankful to the University of Kurdistan Research Council for the partial support of this work.
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