Ultrasound-accelerated one-pot synthesis of N-acetyl-2-aryl-1,2-dihydro-4H- 3,1-benzoxazin-4-ones

Article abstract of DOI:10.1007/s10593-011-0883-0

The one-pot synthesis of N-acetyl-2-aryl-1,2-dihydro-4H-3,1-benzoxazin-4- one derivatives from the condensation reaction of anthranilic acids with heteroaromatic aldehydes in the presence of excess amount of acetic anhydride has been explored. The reactio

Full text of DOI:10.1007/s10593-011-0883-0

Chemistry of Heterocyclic Compounds, Vol. 47, No. 9, December, 2011 (Russian Original Vol. 47, No. 9, September, 2011)
ULTRASOUND-ACCELERATED ONE-POT
SYNTHESIS OF N-ACETYL-2-ARYL-
1,2-DIHYDRO-4H-3,1-BENZOXAZIN-4-ONES
D. Azarifar1* and D. Sheikh1
The one-pot synthesis of N-acetyl-2-aryl-1,2-dihydro-4H-3,1-benzoxazin-4-one derivatives from the
condensation reaction of anthranilic acids with heteroaromatic aldehydes in the presence of excess
amount of acetic anhydride has been explored. The reactions proceed smoothly under ultrasound
irradiation and without catalyst at 35−40°C to afford the title products in high yields.
Keywords: acetic anhydride, N-acetyl-2-aryl-1,2-dihydro-4H-3,1-benzoxazin-4-one, anthranilic acid,
heteroaromatic aldehyde, ultrasound.
Among the naturally occurring heterocycles are 4H-3,1-benzoxazin-4-ones [1, 2], which have recently
received considerable attention [3, 4] as an important class of heterocyclic compounds having significant
biological activities as inhibitors of human leukocyte elastase (HLE) [5, 6], and various serine proteases [7],
and as potent inhibitors of chymotrypsin [8-9] and HSV-1 [10]. These compounds have been utilized as valuable
starting materials in the synthesis of various heterocycles such as 2,3-disubstituted quinazolin-4(3H)-ones,
1,4-benzodiazepine-2,5-diones, indoxyls and other related structures [11-22], and as linking units in polymer
chemistry [23]. Only very few routes have been reported so far for the synthesis of N-substituted 1,2-dihydro-
4H-3,1-benzoxazin-4-one derivatives [24-26]. Regarding the biological and synthetic importance of 1,2-di-
hydro-4H-3,1-benzoxazin-4-one derivatives, the development of new methods for their synthesis appears to be
an interesting challenge. A previously reported method for the synthesis of the respective N-acetyl derivatives
involves the reaction of N-acylated anthranilic acids with paraformaldehyde in refluxing AcOH [12]. The
cyclization of 2-(benzylideneamino)benzoic acids for the synthesis of N-acetyl-2-aryl-1,2-dihydro-4H-3,1-benz-
oxazin-4-ones has been recently utilized [27]. A solid-phase synthesis of 4H-3,1-benzoxazin-4-ones mediated
by silica-bound benzyl chloride has been reported [28]. One-pot multicomponent reactions are shown to be more
advantageous than conventional linear-type synthesis [29] since the multistep reactions usually suffer from
complex isolation procedures and produce significant amounts of waste products. In addition, one-pot processes
promise access by rapid and efficient organic transformations to diverse polyfunctionalized heterocycles of
biological importance [5].
_______
*To whom correspondence should be addressed, e-mail: azarifar@basu.ac.ir.
1Department of Chemistry, University of Bu-Ali Sina, Hamedan 65178, Iran.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1372-1380, September, 2011.
Original article received February 8, 2011. In revised form August 23, 2011.
1128
0009-3122/11/4709-1128©2011 Springer Science+Business Media, Inc.

TABLE 1. Effect of Reaction Conditions on the Yield of Oxazinone 3c
Entry
Conditions
Method
Time, min
40
Yield, %
74
Ac2O (exc.) / 35−40°C
ultrasound
1
2
MeOH / 35−40°C
MeCN / 35−40°C
EtOAc / 35−40°C
CHCl3 / 35−40°C
CCl4 / 35−40°C
Et2O / 35−40°C
n-hexane / 35−40°C
Ac2O (exc.) / rt
Ac2O (exc.) / 60°C
Ac2O (exc.) / 100°C
Ac2O (exc.) / 138−140°C
MeOH / rt
ultrasound
60
60
45
43
42
43
54
38
42
29
25
22
18
28
24
25
30
26
27
23
19
3
ultrasound
4
ultrasound
60
5
ultrasound
60
6
ultrasound
60
7
ultrasound
60
8
ultrasound
60
9
conventional
conventional
conventional
conventional
conventional
conventional
conventional
conventional
conventional
conventional
conventional
conventional
360
360
360
360
480
480
480
480
480
480
480
480
10
11
12
13
14
15
16
17
18
19
20
MeCN / rt
EtOAc /rt
DMF / rt
CHCl3 / rt
Et2O / rt
CCl4 / rt
n-hexane / rt
TABLE 2. Ultrasound-accelerated and Conventional Synthesis of
Compounds 3a−o
Method
Compound
Sonication
Time, min
Conventional (rt)
Yield, %
Time, min
Yield, %
3a
3b
3c
3d
3e
3f
55
65
40
70
80
85
95
50
55
75
70
95
24
22
19
80
72
74
72
54
68
64
82
83
46
57
40
89
86
88
360
420
360
540
600
660
480
600
540
550
520
700
90
28
32
29
30
25
26
22
28
28
24
30
20
60
67
48
3g
3h
3i
3j
3k
3l
3m
3n
3o
150
180
1129

1130

1131

It is also evident from the increasing number of reports that application of ultrasound in the so-called
"sonochemistry" has generated a considerable interest as a versatile and challenging technique in synthetic
organic chemistry. The ultrasound irradiation technique has been employed not only to increase the rate, but
also to improve yields in a large variety of organic reactions [30−35]. The beneficial effects of ultrasound on
chemical reactions stem from the phenomenon that is based on acoustic cavitation which create localized hot
spots that can be considered as microreactors in which the energy of sound is transformed into high temperature
and pressure [31].
The objective of the present work is to take joint advantage of ultrasound irradiation and one-pot
processes in the synthesis of N-acetyl-2-heteroaryl-1,2-dihydro-4H-3,1-benzoxazin-4-one derivatives.
In connection with our continuing interest in the application of ultrasound irradiation as a clean and
useful method in the synthesis of heterocyclic compounds [36], we explored the utilization of ultrasound irradiation
in the one-pot condensation reaction of anthranilic acids 1 with aromatic aldehydes 2 in the presence of acetic
anhydride as a new approach to 2-aryl-substituted 1,2-dihydro-4H-3,1-benzoxazin-4-ones 3 (Scheme 1).
Scheme 1
O
ArCHO
2a–i
R
R
CO2H
O
R
CO2H
NH2
Ar
Ac2O
N
N
H
ultrasound
(35–40°C)
or rt
O
3a–o
H
Ar
Me
1a–c
1a, 3a–c,j–o R = H; 1b R = OH; 3d–f R = OAc; 1c, 3g–i R = Cl; 2a, 3a,d,g Ar = 2-pyrrolyl;
2b, 3b,e,h Ar = 2-thienyl; 2c, 3c,f,i Ar = 2-furyl; 2d, 3j Ar = 4-pyridyl; 2e, 3k Ar = 3-pyridyl;
2f, 3l Ar = 3-indolyl; 2g Ar = 2-HOC6H4; 3m Ar = 2-AcOC6H4; 2h, 3n Ar = 3-BrC6H4;
2i, 3o Ar = 4-FC6H4
In order to find the optimal conditions for the reaction, we initially examined the condensation of
anthranilic acid (1a) with furfural (2c) to oxazinone 3c as a model reaction in the presence of excess amount of
acetic anhydride without using any catalyst. The effects of solvent and temperature were investigated by
conducting the reaction under both ultrasonication and conventional reaction conditions (Table 1). The best
results in terms of yield (74%) and reaction time (40 min) were obtained when the reaction was conducted under
ultrasound irradiation at 35−40°C using excess amount of acetic anhydride without any other solvent (entry 1).
The yields obtained under conventional conditions in different solvents and at various temperatures were lower
compared to those obtained under solvent-free ultrasound irradiation conditions. Increasing the reaction
temperature under conventional conditions in the presence of excess Ac2O resulted in the reduction of the yield
(entries 9−12).
To explore the scope of this reaction, we applied it to a variety of anthranilic acids 1a−c and aromatic
aldehydes 2a−i using the optimized conditions under ultrasonication (at 35−40°C in excess Ac2O) and
conventional conditions at room temperature (Table 2). The experimental results indicated that, under
ultrasound irradiation, all the reactions proceeded smoothly in relatively short reaction times (19−95 min) to
afford the respective N-acetyl-2-aryl-1,2-dihydro-4H-3,1-benzoxazin-4-ones 3a−o in moderate to high yields
(40−89%) in comparison with the yields obtained under conventional conditions (20−67%) at room temperature
(Table 2). The structures of the products were fully characterized on the basis of their elemental analysis and
spectral (IR, 1H NMR, 13C NMR, MS) data.
1132

TABLE 4 1H and 13C NMR Spectra of Compounds 3a−o
Product
1H NMR: δ, ppm (J, Hz)
13C NMR: δ, ppm
2.12 (3H, s, COCH3);
25.4; 85.5; 117.4; 120.3; 123.0; 126.6;
131.5; 134.2; 137.1; 141.3; 144.3; 147.2;
169.0; 170.0
3a
7.10–7.15 (2H, m, H-2, H Ar);
7.54–7.58 (2H, m, H Ar);
7.96–7.98 (2H, m, H Ar);
8.44–8.46 (2H, m, H Ar); 11.21 (1H, s,
NH)
2.13 (3H, s, COCH3);
25.5; 88.2; 116.9; 120.4; 123.1; 129.0;
131.6; 134.5; 136.1; 141.3; 145.5; 149.3;
168.9; 169.9
3b
3c
3d
7.12–7.16 (2H, m, H-2, H Ar);
7.55–7.60 (2H, m, H Ar);
7.96–7.99 (2H, m, H Ar);
8.44–8.47 (2H, m, H Ar)
2.10 (3H, s, COCH3);
25.3; 81.1; 117.0; 120.3; 123.0; 127.9;
131.7; 134.4; 138.1; 141.3; 145.1; 148.9;
169.0; 170.0
7.11–7.16 (2H, m, H-2, H Ar);
7.55–7.60 (2H, m, H Ar);
7.96–7.98 (2H, m, H Ar);
8.43–8.45 (2H, m, H Ar)
2.11 (3H, s, COCH3);
2.25 (3H, s, OCOCH3);
7.08−8.52 (7H, m, H-2, H Ar);
11.03 (1H, s, NH)
20.1; 22.2; 79.7; 119.4; 122.4; 124.3;
125.8; 129.8; 132.2; 135.0; 138.3; 143.1;
145.8; 167.4; 167.8; 169.6
2.07 (3H, s, COCH3);
2.21 (3H, s, OCOCH3);
7.52−7.85 (7H, m, H-2, H Ar)
22.6; 25.5; 88.7; 124.3; 126.6; 126.9;
127.1; 127.5; 128.3; 130.4; 131.7; 134.7;
135.5; 169.6; 171.5; 175.1
3e
3f
2.08 (3H, s, COCH3);
2.23 (3H, s, OCOCH3);
7.35−7.91 (7H, m, H-2, H Ar)
21.5; 23.4; 84.2; 120.2; 124.5; 125.0;
129.3; 133.5; 134.9; 136.5; 140.7; 142.6;
145.1; 161.6; 167.4; 170.1
2.11 (3H, s, COCH3);
7.49−8.47 (7H, m, H-2, H Ar);
10.96 (1H, s, NH)
25.5; 83.0; 116.5; 116.8; 120.5; 122.7;
131.8; 132.1; 135.2; 135.6; 145.2; 148.9;
173.1; 173.5
3g
3h
3i
1.53 (3H, s, COCH3);
6.96−7.85 (7H, m, H-2, H Ar)
20.5; 86.1; 118.2; 121.2; 126.3; 127.0;
127.6; 130.3; 133.6; 137.3; 139.8; 142.4;
168.4; 175.3
2.09 (3H, s, COCH3);
25.5; 86.4; 113.8; 120.5; 122.7; 127.5;
131.7; 135.6; 142.1; 145.4; 147.6; 150.1;
169.4; 171.4
7.45–7.55 (3H, m, H-2, H Ar);
7.61–7.82 (3H, m, H Ar);
8.40–8.42 (1H, m, H Ar)
2.10 (3H, s, COCH3);
7.10–8.34 (9H, m, H-2, H Ar)
25.1; 87.3; 112.8; 116.6; 116.9; 120.4;
123.1; 126.5; 128.7; 131.4; 134.3; 138.9;
141.0; 169.1; 169.8
3j
3k
3l
2.12 (3H, s, COCH3);
7.59−8.50 (9H, m, H-2, H Ar)
22.2; 82.7; 119.5; 121.4; 123.0; 124.0;
126.3; 127.3; 128.7; 130.0; 134.6; 138.3;
142.3; 161.4; 169.8
2.28 (3H, s, COCH3);
22.6; 83.1; 103.8; 106.8; 119.4; 123.1;
125.2; 126.3; 129.2; 132.0; 135.0; 137.8;
139.1; 143.7; 148.4; 153.2; 161.6; 170.4
7.12–7.17 (3H, m, H-2 + H Ar);
7.59–7.64 (3H, m, H Ar);
8.12–8.15 (2H, m, H Ar);
8.73–8.76 (2H, m, H Ar); 10.95 (1H, s,
NH)
2.35 (3H, s, COCH3);
2.37 (3H, s, OCOCH3);
6.90−8.15 (9H, m, H-2, H Ar)
22.9; 23.6; 83.7; 121.9; 122.2; 124.3;
125.2; 126.3; 129.8; 131.3; 133.2; 134.5;
137.2; 139.2; 148.8; 169.9; 170.6; 172.2
3m
3n
3o
2.44 (3H, s, COCH3);
6.47 (1H, s, H-2); 7.25−7.95 (8H, m,
H Ar)
22.4; 82.4; 123.0; 124.1; 124.6; 126.6;
129.0; 130.3; 130.5; 132.1; 132.3; 134.8;
134.9; 138.3; 138.6; 169.9
2.45 (3H, s, COCH3);
6.85−7.95 (9H, m, H-2, H Ar)
22.5; 83.1; 115.4; 116.3; 119.8; 124.1;
126.6; 127.8; 128.2; 130.3; 131.9; 134.8;
138.6; 157.3; 161.3; 169.9
1133

This reaction seems to proceed through the corresponding imine A produced by the reaction of
anthranilic acid 1 with aromatic aldehyde 2. Intermediate A undergoes subsequent cyclization to the product 3
in the presence of Ac2O (Scheme 2). To prove this mechanism, the imine A was separately prepared as a stable
compound from the reaction of anthranilic acid (1a) with 2-pyrrolecarbaldehyde (2a) in MeOH. It was then
treated with Ac2O under ultrasound irradiation at 35–40°C, which resulted in the formation of the expected
product 3a in 85% yield after crystallization from EtOH.
Scheme 2
AcO–
O
H
O
–
Ac2O
OH
– AcO
– AcOH
3a
1a
2a
+
H
O
Ultrasound
or rt
N
H
N+
Ar
A
Ar
Me
O
Me
O
O
Me
O
In summary, we have explored the application of ultrasonic irradiation as a rapid and reliable protocol
in the synthesis of N-acetyl-2-aryl-1,2-dihydro-4H-3,1-benzoxazin-4-ones from the one-pot reaction of aromatic
aldehydes with anthranilic acid derivatives in the presence of excess acetic anhydride. The reaction provides the
products in shorter reaction times and higher yields than those obtained under conventional conditions.
EXPERIMENTAL
1
IR spectra were recorded on a Perkin Elmer GX FT IR spectrometer in KBr pellets. H and 13C NMR
spectra were recorded using a Bruker Avance instrument in DMSO-d6 at 400 and 100 MHz, respectively
(compounds 3a−c, 3g, 3i, 3l and imine A) or JEOL FX 90Q instrument at 90 and 22.5 MHz, respectively, in
DMSO-d6 (compounds 3d−f, 3h, 3j, 3k) or CDCl3 (compounds 3m−o) with TMS as internal standard. Electron
impact mass spectra were recorded on a Finnigan-MAT 8430 spectrometer operating at an ionization potential
of 70 eV. Melting points were measured on an SMPI apparatus. Elemental analyses were performed using a
Perkin–Elmer 2400 series analyzer. Ultrasonication was performed in a Transsonic 660/H ultrasound cleaner
with a frequency of 35 kHz and an output power of 70 W. The reactions were performed in open vessels.
Chemicals used in this work were purchased from Fluka and Merck and used without purification.
Synthesis of N-acetyl-2-heteroaryl-1,2-dihydro-4H-3,1-benzoxazin-4-ones (3) (General Method). A
flask containing a mixture of anthranilic acid 1 (1 mmol), aldehyde 2 (1 mmol), and acetic anhydride (5 ml, 53
mmol) was placed in a water bath and ultrsonicated at 35−40°C (or stirred at rt without sonication) for the
appropriate time (Table 2). Following the completion of the reaction as monitored by TLC (n-hexane–EtOAc,
10:1), the reaction mixture was treated with ice water and filtered to give a solid product which was crystallized
from EtOH (compounds 3a–i, m–o) or EtOH–EtOAc, 4:1 (compounds 3j–l).
2-[1H-Pyrrol-2-ylmethylidene)amino]benzoic acid (A) [37]. A mixture of anthranilic acid (1a) (0.137 g,
1 mmol) and 2-pyrrolecarbaldehyde (2a) (0.095 g, 1 mmol) in MeOH (10 ml) was stirred for about 1 hour at
room temperature. After completion of the reaction as monitored by TLC, the solvent was removed under
reduced pressure to leave a yellow solid which was crystallized from EtOH to give 0.18 g (85%) of imine A; mp
1
207−209°C (decomp.). IR spectrum, ν, cm–1: 3108, 2250, 1650, 1600, 1445, 1263, 1158, 756. H NMR
1134

spectrum, δ, ppm (J, Hz): 6.34 (1H, s, N=CH); 6.95–8.50 (7H, m, H Ar); 12.14 (1H, s, NH); 14.55 (1H, s,
COOH). 13C NMR spectrum, δ, ppm: 111.0; 116.0; 118.0; 119.4; 122.6; 125.5; 126.9; 129.1; 131.0; 133.6;
148.7; 166.7.
We wish to thank the Research Council of the University of Bu-Ali Sina for financial support to carry
out this research.
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