An efficient and facile ultrasonic-accelerated one-pot synthesis of N-acetyl-2-aryl-1, 2-dihydro-(4H)-3,1-benzoxazin-4-ones

Article abstract of DOI:10.1002/hc.20663

An application of ultrasonic irradiation in the one-pot synthesis of N-acetyl-2-aryl-1,2-dihydro-(4H)-3,1-benzoxazin-4-ones from the condensation reaction between aromatic aldehydes and anthranilic acid in the presence of excess amount of acetic anhydride

Full text of DOI:10.1002/hc.20663

Heteroatom Chemistry
Volume 22, Number 2, 2011
An Efficient and Facile Ultrasonic-Accelerated
One-Pot Synthesis of N-Acetyl-2-aryl-1,
2-dihydro-(4H)-3,1-benzoxazin-4-ones
Davood Azarifar and Davood Sheikh
Faculty of Chemistry, Buali Sina University, Hamedan 65178, Iran
Received 24 September 2010; revised 11 November 2010
that undergo subsequent implosive collapse in a liq-
ABSTRACT: An application of ultrasonic irradia-
tion in the one-pot synthesis of N-acetyl-2-aryl-1,2-
dihydro-(4H)-3,1-benzoxazin-4-ones from the con-
densation reaction between aromatic aldehydes and
anthranilic acid in the presence of excess amount
of acetic anhydride has been explored. The reactions
proceed smoothly under mild and solvent-free con-
ditions at room temperature in the absence of any
catalyst to afford the products in good to excellent
uid, which produces unusual chemical and physical
environments. These rapid and violent implosions
of the bubbles generate localized “hot spots” with a
transient temperature of roughly 5000◦C, and pres-
sures of about 1000 atm, and heating and cooling
rates are above 10 billion degree centigrades per
second [2]. Such localized hot spots can be consid-
ered as microreactors in which the energy of sound
is transformed into a useful chemical form.
ꢀ
C
yields. 2011 Wiley Periodicals, Inc. Heteroatom Chem
On the other hand, one-pot multicomponent re-
actions have proven to be more advantageous over
conventional linear-type synthesis [9–10], since the
multistep reactions usually suffer from complex iso-
lation procedures and produce a significant amount
of waste products. Moreover, one-pot processes pro-
vide rapid and efficient approach to organic trans-
formations including diverse synthesis of polyfunc-
tionalized heterocycles [11]. Among the important
heterocyclic compounds, 4H-3,1-benzoxazin-4-ones
are known as important class of compounds [12],
having significant biological activities as potent in-
activators of chymotrypsin [13–15], inhibitors of
human leukocyte elastase [16,17], and HSV-1 pro-
tease [18]. These compounds occur in nature [19,20]
and have also been used as linking units in poly-
mer chemistry [21] and as key intermediates in or-
ganic synthesis [12]. These compounds are also valu-
able starting materials in the synthesis of various
heterocycles such as 2,3-disubstituted quinazolin-
4(3H)-one [22–29]. In contrast to the parent 4H-3,1-
benzoxazin-4-one, only very few routes have ever
been reported on the synthesis of N-substituted-
1,2-dihydro-(4H)-3,1-benzoxazin-4-ones [30–32]. A
22:106–113, 2011; View this article online at wileyonlineli-
brary.com. DOI 10.1002/hc.20663
INTRODUCTION
As evident from the literature [1–7], application of
ultrasound in the so-called “sonochemistry” has re-
ceived enormous interests since it offers a versa-
tile and challenging technique in organic synthesis
[8]. Nowadays, ultrasonic irradiation technique has
been employed not only to decrease reaction times
but also to improve yields in a large variety of or-
ganic synthesis [1–7]. The phenomenon responsible
for the beneficial effects of ultrasound on chemical
reactions is based on acoustic cavitation. Namely,
the molecules of the liquid are separated during the
rarefaction cycle of the wave, generating bubbles
Correspondence to: D. Azarifar; e-mail: azarifar@basu.ac.ir.
Contract grant sponsor: Research Council of Buali Sina
University, Hamedan, Iran.
c
ꢀ
2011 Wiley Periodicals, Inc.
106

Ultrasonic-Accelerated One-Pot Synthesis of N-Acetyl-2-aryl-1,2-dihydro-(4H)-3,1-benzoxazin-4-ones 107
method was previously reported on the synthesis of
(4H)-3,1-benzoxazin-4-one under mild and green
N-acetyl-1,2-dihydro-4H-3,1-benzoxazin-4-one em-
ploying the reaction of N-acylated anthranilic acids
with paraformaldehyde in refluxing AcOH [33]. Re-
cently, silica-bound benzoyl chloride mediated solid
phase synthesis of 4H-3,1-benzoxazin-4-ones has
been reported [34].
4H-3,1-Benzoxazin-4-ones are useful synthons
in the synthesis of important heterocyclic com-
pounds such as 1,4-bezodiazepin-2,5-dione and in-
doxyls [30,33,35]. The chemistry of benzoxazin-4-
one is anticipated to play a vital role in the coming
years in the synthesis of medicinal and natural prod-
ucts [12]. However, most of these reported methods
suffer from certain drawbacks such as longer reac-
tion times, low yields, and use of severe reaction
conditions. To avoid such drawbacks, still there is
a great demand for the development of milder and
environmentally benign approaches to these hetero-
cycles.
conditions.
RESULTS AND DISCUSSION
As part of our ongoing research on the application
of ultrasonic irradiation technique as a clean and
useful protocol in organic synthesis [36] and also re-
garding the lack of sufficient reports on the synthe-
sis of substituted 1,2-dihydro-(4H)-3,1-benzoxazin-
4-one [31,32], we were encouraged, in this report,
to study the hitherto unreported useful application
of ultrasound in the synthesis of N-acetyl-2-aryl-
1,2-dihydro-(4H)-3,1-benzoxazin-4-one. We prelim-
inarily examined the condensation reaction of 2-
hydroxybenzaldehyde 1c as the test compound with
anthranilic acid in the presence of acetic anhydride
under sonication and catalyst-free conditions.
To achieve suitable reaction conditions in terms
of reaction time, temperature, and yield, various sol-
vents and reaction conditions were investigated and
the results are summarized in Table 1. Effects of
solvent and temperature (only for thermal condition)
The objective of the present work is to ex-
plore the use of ultrasonic irradiation technique in
the one-pot synthesis of N-acetyl-2-aryl-1,2-dihydro-
TABLE 1 Effect of Reaction Conditionsa
O
O
O
O
Ultrasound or reflux (138-140 oC)
OH
H
+
Ac2O
N
H
OH
NH2
OAc
2c
1c
CH3
O
Entry
Conditions
Method
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
Ac2O (exc.)/35–40◦C
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
Ultrasound
Ultrasound
Ultrasound
Ultrasound
Ultrasound
Ultrasound
Ultrasound
Ultrasound
Thermal
Thermal
Thermal
Thermal
Thermal
Thermal
Thermal
Thermal
Thermal
Thermal
Thermal
Thermal
18
45
58
50
65
55
60
45
180
150
120
90
120
130
180
105
150
180
165
180
98
45
48
55
58
60
48
65
40
45
55
63
35
45
50
55
58
60
62
50
9
10
11
12
13
14
15
16
17
18
19
20
Ac2O (exc.)/60◦C
Ac2O (exc.)/100◦C
Ac2O (exc.)/138–140◦C
MeOH/reflux
MeCN/reflux
EtOAc/reflux
DMF/reflux
CHCl3/reflux
Et2O/reflux
CCl4/reflux
n-hexane/reflux
aAnthranilic acid (1 mmol), acetic anhydride (5 mL, 53 mmol), 2-hydroxybenzaldehyde (1 mmol), solvent (5 mL).
bIsolated yields.
Heteroatom Chemistry DOI 10.1002/hc

108 Azarifar and Sheikh
SCHEME 1 Synthesis of N-acetyl-2-aryl-1,2-dihydro-(4H)-3,1-benzoxazin-4-one 2a–p.
on the reaction was studied using different solvents
such as MeOH, EtOAc, MeCN, DMF, CHCl3, Et2O,
CCl4, and n-hexane. As seen in Table 1, the reac-
tion worked out best under sonication conditions
in the absence of any solvent but excess amount of
acetic anhydride at ambient temperature (35–40◦C)
to provide the highest possible yield (98%, entry 1)
in 18 min compared with the yield obtained under
optimum thermal condition (reflux, solvent-free) in
90 min (63%, entry 12). Apparently, increasing the
temperature under solvent-free thermal conditions
showed an improving effect on the yield as well as
the reaction rate (entries 9–12).
perature. The reactions proceeded under solvent-
free condition to provide the products in shorter re-
action times and higher yields than those obtained
under the conventional reflux condition.
EXPERIMENTAL
Material and Instruments
Chemicals used in this work were purchased from
Fluka (Buchs, Switzerland) and Merck (Hohen-
brunn, Germany) and used without purification. IR
spectra were recorded on a Perkin Elmer GX FT
1
IR spectrometer from KBr pellets. H and 13C NMR
To develop the scope of the reaction, we were en-
couraged to extend this reaction to a variety of aro-
matic aldehydes 1a–p carrying different substituents
under the determined optimum conditions (sonica-
tion, solvent-free, at 35–40◦C or reflux) (Scheme 1).
All the reactions proceeded smoothly to provide the
corresponding products 2a–p in satisfactory yields,
and the results are summarized in Table 2. Also, the
experimental results in Table 2 clearly indicate that
under ultrasonic irradiation all the reactions pro-
ceed in shorter reaction times (7–30 min) and higher
yields (90–98%) when compared with the reaction
times (1–6 h) and yields (55–75%) obtained under
reflux conditions.
This reaction seems to proceed through the in-
termediacy of a corresponding imine derivative (A)
of the anthranilic acid in reaction with aromatic
aldehyde 1, which undergoes subsequent cyclization
to the product 2 in the presence of Ac2O (Scheme 2).
To approve this mechanism, the imine (A) was ob-
tained in a separate experiment as a stable com-
pound from the reaction of anthranilic acid with
benzaldehyde as a test compound in MeOH (92%) or
Ac2O (95%). This imine was then separately treated
with Ac2O both under sonication at 35–40◦C and
reflux conditions, which resulted in the respective
product 2a in 90% and 75% yields, respectively.
In summary, we have explored the application of
ultrasonic irradiation technique as a rapid and reli-
able protocol in the synthesis of N-acetyl-2-aryl-1,2-
dihydro-(4H)-3,1-benzoxazin-4-one from the one-
pot reaction of aromatic aldehydes with anthranilic
acid in the presence of acetic anhydride at room tem-
spectra were measured for samples in CDCl3 with
a JEOL FX 90Q instrument at 90 and 22.5 MHz,
respectively, using Me4Si as an internal standard.
Mass spectra were recorded with a spectrometer
Finnigan-MAT 8430 operating at an ionization po-
tential of 70 ev. Melting points were measured on a
SMPI apparatus. Elemental analyses for C, H, and N
atoms were performed using a Perkin–Elmer 2400
series analyzer. Ultrasonication was performed in
a Transsoni 660/H ultrasound cleaner with a fre-
quency of 35 KHz and an output power of 70 W.
The reactions were performed in open vessels.
Typical Procedure for the Synthesis of
N-Acetyl-2-aryl-1,2-dihydro-(4H)-3,1-
benzoxazin-4-one (2)
A mixture of aldehyde 1 (1 mmol), anthranilic acid
(1 mmol), and acetic anhydride (5 mL, 53 mmol) in
a flask was placed in a water bath and sonicated at
35–40◦C (or refluxed without sonication) for an ap-
propriate time (Table 2) until the reaction was com-
pleted as monitored by TLC (n-hexane/EtOAc; 2:1)
analysis. The reaction mixture was then treated with
iced water and filtered to leave a solid product, which
was crystallized from ethanol to yield pure product.
All the products were characterized by their physical
1
and spectral data (IR, MS, H NMR,13C NMR) and
elemental analysis.
N-Acetyl-1,2-dihydro-2-(phenyl)-(4H)-3,1-benzo-
xazin-4-one (2a). Pale yellow solid; mp = 122–
124◦C; IR (KBr), ν: 3050, 2996, 1729, 1682, 1607,
Heteroatom Chemistry DOI 10.1002/hc

Ultrasonic-Accelerated One-Pot Synthesis of N-Acetyl-2-aryl-1,2-dihydro-(4H)-3,1-benzoxazin-4-ones 109
TABLE 2 Ultrasonic-Accelerated Synthesis of N-Acetyl-2-aryl-1,2-dihydro-(4H)-3,1-benzoxazin-4-one 2a–pa
Conditions
Sonication
Refluxing
Entry
ArCHO 1
Product 2
Time (min)
Yieldb (%)
Time (h)
Yieldb (%)
O
O
O
H
N
H
O
CH
3
2a
2b
2c
2d
2e
8
10
18
25
19
95
96
98
92
98
6
64
71
66
55
63
O
O
O
CH
3
H
N
H
O
CH
Me
3
3
O
O
O
H
N
H
OAc
O
CH
OH
3
1.5
2.5
2.5
O
O
O
H
N
OAc
H
OH
OAc
O
CH
3
OH
O
O
O
H
OMe
O
N
H
OMe
OMe
O
CH
3
O
O
OMe
MeO
MeO
H
N
H
OMe
O
CH
OMe
3
2f
10
14
97
90
2
3
64
57
O
O
O
H
N
H
Br
CH
O
Br
3
2g
O
O
H
O
N
H
Br
Br
CH
O
Br
3
2h
2i
17
15
94
90
2.5
3.5
74
61
O
O
O
H
N
H
CH
O
Br
3
O
O
O
H
N
H
Cl
CH
O
3
Cl
2j
12
94
3.5
59
(Continued )
Heteroatom Chemistry DOI 10.1002/hc

110 Azarifar and Sheikh
TABLE 2 Continued
Conditions
Sonication
Time (min)
Yieldb (%)
Refluxing
Time (h)
Yieldb (%)
Entry
ArCHO 1
Product 2
O
O
O
Cl
F
H
N
H
CH
O
O
Cl
F
3
2k
7
92
4
62
O
O
O
H
N
H
CH
3
2l
14
7
95
96
3
55
70
O
O
O
H
N
H
NO2
NO
CH3
O
O
2
2m
1.5
O
H
O
N
H
NO2
NO2
NO
CH3
2
O
2n
2o
9
98
98
1
2
75
63
O
O
O
H
H
N
NO
CH3
O
O
2
10
H
O
O
OH
N
H
OAc
CH3
O
2p
30
95
6
57
aAnthranilic acid (1 mmol), acetic anhydride (5 mL), aldehyde (1 mmol), sonication at 35-40◦C (or without sonication at 138–140◦C).
bIsolated yields.
1366, 1051; MS, m/z (%): 267 (M+, 11), 225 (M+
−
1
38); H NMR (CDCl3, 90 MHz): δ 2.57 (s, 3H, CH3),
3.75 (s, 3H, COCH3), 7.55–6.82 (m, 8H, Ar-H), 7.62
(s, 1H, CH); 13C NMR (CDCl3, 22.5 MHz): δ 22.7, 27.2,
84.5, 108.8, 114.6, 116.7, 122.8, 125.9, 133.0, 133.7,
134.5, 138.7, 149.8, 151.5, 156.6, 163.0, 170.6; Anal.
Calcd for C17H15NO3: C, 72.59; H, 5.33; N, 4.98%.
Found: C, 72.54; H, 5.30; N, 4.95%.
CH2CO, 45), 180 (M+ − CH2CO − CO2H, 27); H
NMR (CDCl3, 90 MHz): δ 2.30 (s, 3H, COCH3), 7.16
(s, 1H, CH), 8.08–7.45 (m, 9H, Ar-H); 13C NMR
(CDCl3, 22.5 MHz): δ 24.4, 85.0, 122.7, 123.4, 126.5,
129.0, 129.4, 130.4, 131.7, 132.4, 136.2, 136.5, 136.7,
140.5, 163.9, 171.3; Anal. Calcd for C16H13NO3: C,
71.91; H, 4.86; N, 5.24%. Found: C, 71.85; H, 4.82;
N, 5.18%.
1
2-(2-Acetoxyphenyl)-N-acetyl-1,2-dihydro-(4H)-3,
1-benzoxazin-4-one (2c). White solid; mp = 132–
135◦C; IR (KBr), ν: 3053, 2995,1764, 1739, 1709,
1583, 1349; MS, m/z (%): 325 (M+, 9), 283
(M+−CH2CO, 47), 241 (M+− 2CH2CO, 66), 196 (M+−
N-Acetyl-1,2-dihydro-2-(4-methylphenyl)-(4H)-3,
1-benzoxazin-4-one (2b). White solid; mp = 146–
148◦C; IR (KBr), ν: 3009, 2935, 1727, 1686, 1597,
1381. MS, m/z (%): 281 (M+, 45), 239 (M+ − CH2CO,
100), 194 (M+ − CH2CO − CO2H, 55), 179 (C12H9N+,
2CH2CO − CO2H, 30), 179 (C13H9N+, 95); H NMR
1
(CDCl3, 90 MHz): δ 2.35 (s, 3H, COCH3), 2.37 (s, 3H,
Heteroatom Chemistry DOI 10.1002/hc

Ultrasonic-Accelerated One-Pot Synthesis of N-Acetyl-2-aryl-1,2-dihydro-(4H)-3,1-benzoxazin-4-ones 111
SCHEME 2 Mechanism of the formation of N-Acetyl-2-aryl-1,2-dihydro-(4H)-3,1-benzoxazin-4-one 2a–p.
OCOCH3), 7.10 (s, 1H, CH), 7.29 (m, 4H, Ar-H), 7.87
(m, 4H, Ar-H); 13C NMR (22.5 MHz, CDCl3): δC 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; Anal. Calcd for C18H15NO5: C, 66.46; H, 4.61;
N, 4.30%. Found: C, 66.42; H, 4.56; N, 4.25%.
N-Acetyl-1,2-dihydro-2-(3,4,5-trimethoxyphenyl)-
(4H)-3,1-benzoxazin-4-one (2f). Pale yellow solid;
mp = 174–176◦C; IR (KBr), ν: 3072, 2974, 2943,
1736, 1702, 1589, 1346; MS, m/z (%): 357 (M+, 42),
315 (M+−CH2 C O, 100), 270 (M+ − CH2 C O −
CO2H, 57), 206 (C10H8NO+4 , 37), 179 (C9H9NO3+, 45),
1
107 (C7H7O+, 62); H NMR (CDCl3, 90 MHz): δ 2.03
(s, 3H, COCH3), 3.43 (s, 3H, OCH3), 3.53 (s, 3H,
OCH3), 3.64 (s, 3H, OCH3), 6.50 (s, 1H, CH), 7.80–
7.21 (m, 6H, Ar-H); 13C NMR (CDCl3, 22.5 MHz): δ
22.5, 30.5, 55.9, 59.9, 83.0, 103.7, 106.7, 119.3, 125.1,
126.2, 129.1, 131.9, 134.9, 137.7, 139.0, 153.1, 161.5,
170.3, 191.8; Anal. Calcd for C19H19NO6: C, 63.86; H,
5.32; N, 3.92%. Found: C, 63.84; H, 5.28; N, 3.90%.
N-Acetyl-2-(2,3-diacetoxyphenyl)-1,2-dihydro-
(4h)-3,1-benzoxazin-4-one (2d). Pale yellow solid;
mp = 165–168◦C; IR (KBr), ν: 3083, 2943, 1757, 1682,
1606, 1588, 1489, 1366; MS, m/z (%): 383 (M+, 10),
299 (M+− 2CH2CO, 19), 257 (M+ − 3CH2CO, 22),
212 (M+ −3CH2CO − CO2H, 30), 178 (C13H9N+, 95);
1H NMR (CDCl3, 90 MHz): δ 2.24 (s, 3H, COCH3),
2.34 (s, 3H, OCOCH3), 2.36 (s, 3H, OCOCH3), 7.05
(m, 4H, Ar-H), 7.27 (s, 1H, CH), 7.85 (m, 3H, Ar-
H); 13C NMR (CDCl3, 22.5 MHz): δ 20.1, 20.9, 22.2,
79.6, 119.4, 124.2, 124.6, 125.0, 126.1, 126.7, 129.0,
129.8, 135.0, 135.3, 138.3, 143.0, 161.0, 167.3, 167.7,
169.6; Anal. Calcd for C20H17NO7: C, 62.66; H, 4.43;
N, 3.65%. Found: C, 62.58; H, 4.41; N, 3.62%.
N-Acetyl-2-(2-bromophenyl)-1,2-dihydro-(4H)-3,
1-benzoxazin-4-one (2g). Pale yellow solid; mp =
80–82◦C; IR (KBr), ν: 3055, 2993, 1734, 1685, 1604,
1363, 1056; MS, m/z (%): 347 (M+ + 2, 3), 345
(M+, 4), 305 (M+ + 2 − CH2CO, 51), 303 (M+−
CH2CO, 49), 260 (M+ + 2 − CH2CO − CO2H, 12),
258 (M+ − CH2CO − CO2H, 27), 186 (C6H851BrO+,
48), 184 (C6H759BrO+, 49); 1H NMR (CDCl3, 90 MHz):
δ 2.35 (s, 3H, COCH3), 7.08 (s, 1H, CH), 8.0–7.25 (m,
8H, Ar-H); 13C NMR (CDCl3, 22.5 MHz): δ 22.4, 83.0,
120.7, 121.4, 124.5, 127.0, 127.4, 128.4, 129.7, 130.4,
134.2, 134.5, 134.7, 138.5, 161.9, 169.3; Anal. Calcd
for C16H12BrNO3: C, 55.49; H, 3.46; N, 4.04%. Found:
C, 55.43; H, 3.42; N, 3.97%.
N-Acetyl-1,2-dihydro-2-(2-methoxyphenyl)-(4H)-
3,1-benzoxazin-4-one (2e). White solid; mp = 132–
135◦C; IR (KBr), ν: 3003, 2926, 1718, 1675, 1597,
1373. MS, m/z (%): 297 (M+, 55), 255 (M+ − CH2CO,
100), 210 (M+−CH2CO − CO2H, 51), 195 (C13H9NO+,
55), 167 (C12H9N+, 33); 1H NMR (CDCl3, 90 MHz): δ
2.50 (s, 3H, COCH3), 3.85 (s, 3H, OCH3), 7.35–6.62
(m, 8H, Ar-H), 7.50 (s, 1H, CH); 13C NMR (CDCl3,
22.5 MHz): δ 22.7, 56.2, 82.5, 106.8, 110.6, 111.7,
120.8, 123.9, 130.0, 132.1, 133.0, 138.7, 147.8, 148.5,
154.6, 161.0, 170.1; Anal. Calcd for C17H15NO4: C,
68.68; H, 5.05; N, 4.71%. Found: C, 68.64; H, 5.03;
N, 4.67%.
N-Acetyl-2-(3-bromophenyl)-1,2-dihydro-(4H)-3,
1-benzoxazin-4-one (2h). White solid; mp = 180–
◦
182 C; IR (KBr), ν: 3084, 2987, 1739, 1690, 1602,
1367, 1072; MS, m/z (%): 347 (M+ + 2, 3), 345 (M+,
7), 305 (M+ + 2 − CH2CO, 40), 303 (M+−CH2CO,
Heteroatom Chemistry DOI 10.1002/hc

112 Azarifar and Sheikh
31), 260 (M+ + 2 − CH2CO − CO2H, 17), 258
(M+ − CH2CO − CO2H, 24), 158 (C6H851Br+, 48), 156
(C6H579Br+, 49); 1H NMR (CDCl3, 90 MHz): δ 2.44 (s,
3H, COCH3), 6.47 (s, 1H, CH), 7.58–7.17 (m, 8H,
Ar-H); 13C NMR (CDCl3, 22.5 MHz): δ 22.4, 82.4,
123.0, 124.1, 124.6, 126.6, 129.0, 130.3, 130.5, 132.1,
132.30, 134.8, 134.9, 138.3, 138.6, 169.9; Anal. Calcd
for C16H12BrNO3: C, 55.49; H, 3.46; N, 4.04. Found:
C, 55.41; H, 3.38; N, 4.00%.
N-Acetyl-1,2-dihydro-2-(4-fluorophenyl)-(4H)-3,
1-benzoxazin-4-one (2l). Pale yellow solid; mp =
133–136◦C; IR (KBr), ν: 3067, 2992, 1750, 1682,
1590, 1330, 1150; MS, m/z (%): 285 (M+, 10), 243
(M+−CH2CO, 21), 198 (M+ − CH2CO − CO2H, 16),
179 (C13H9N+, 46), 118 (C7H4NO+, 30), 77 (C6H+5 ,
23); 1H NMR (CDCl3, 90 MHz): δ 2.45 (s, 3H,
COCH3), 6.91 (s, 1H, CH), 7.65- 7.24 (m, 8H, Ar-H);
13C NMR (CDCl3, 22.5 MHz): δ 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; Anal. Calcd for
C16H12FNO3: C, 67.36; H, 4.21; N, 4.91%. Found: C,
67.32; H, 4.18; N, 4.87%.
N-Acetyl-2-(4-bromophenyl)-1,2-dihydro-(4H)-3,
1-benzoxazin-4-one (2i). Pale yellow solid; mp =
92–95◦C; IR (KBr), ν: 3084, 2985, 1739, 1693, 1602,
1363, 1064; MS, m/z (%): 347 (M+ + 2, 3), 345 (M+, 4),
305 (M+ + 2 − CH2CO, 45), 303 (M+−CH2CO, 45), 260
(M+ + 2 − CH2CO − CO2H, 16), 258 (M+ − CH2CO −
CO2H, 31), 158 (C6H851Br+, 48), 156 (C6H759Br+, 49);
1H NMR (CDCl3, 90 MHz): δ 2.47 (s, 3H, COCH3),
7.23 (s, 1H, CH), 7.90–7.43 (m, 8H, Ar-H); 13C NMR
(CDCl3, 22.5 MHz): δ 22.5, 82.4, 123.0, 124.1, 124.6,
126.6, 129.0, 130.3, 131.2, 132.1, 133.1, 134.9, 135.6,
138.3, 167.6, 169.9; Anal. Calcd for C16H12BrNO3: C,
55.49; H, 3.46; N, 4.04. Found: C, 55.39; H, 3.42; N,
3.93%.
N-Acetyl-1,2-dihydro-2-(2-nitrophenyl)-(4H)-3,1-
benzoxazin-4-one (2m). White solid; mp = 177–
180◦C; IR (KBr), ν: 3065, 2991, 1737, 1703, 1616,
1522, 1494, 1372, 1314; MS, m/z (%): 312 (M+, 12),
270 (M+ − CH2CO, 94), 225 (M+ − CH2CO − CO2H,
26), 179 (C3H3NO+5 , 41), 146 (C8H4NO+2 , 37), 119
1
(C7H5NO+, 67); H NMR (CDCl3, 90 MHz): δ 2.37
(s, 3H, COCH3), 7.27 (s, 1H, CH), 7.90–7.35 (m,
8H, Ar-H);13C NMR (CDCl3, 22.5 MHz): δ 22.5, 82.5,
119.5, 121.0, 124.0, 124.1, 127.0, 130.1, 130.6, 132.3,
135.1, 138.2, 138.4, 149.1, 161.0, 170.9; Anal. Calcd
for C16H12N2O5: C, 61.53; H, 3.84; N, 8.97%. Found:
C, 61.48; H, 3.79; N, 8.94%.
N-Acetyl-2-(2-chlorophenyl)-1,2-dihydro-(4H)-3,
1-benzoxazin-4-one (2j). Colorless solid; mp = 166–
169◦C; IR (KBr), ν: 3082, 2995, 1749, 1680, 1602,
1357, 1066. MS, m/z (%): 303 (M+ + 2, 2), 301 (M+, 5),
261 (M+ + 2-CH2CO, 26), 259 (M+−CH2CO, 52), 216
(M+ + 2 − CH2CO − CO2H, 23), 214 (M+ − CH2CO −
CO2H, 38), 142 (C7H357ClO+, 46), 140 (C7H355ClO+, 44);
1H NMR (CDCl3, 90 MHz): δ 2.40 (s, 3H, COCH3),
7.61–7.13 (m, 8H, Ar-H), 7.78 (s, 1H, CH); 13C NMR
(CDCl3, 22.5 MHz): δ 22.3, 81.6, 120.5, 124.4, 126.5,
126.8, 128.1, 129.7, 130.2, 130.7, 132.3, 132.7, 134.7,
138.4, 162.0, 169.0; Anal. Calcd for C16H12ClNO3: C,
63.68; H, 3.98; N, 4.64%. Found: C, 63.63; H, 3.95;
N, 4.58%.
N-Acetyl-1,2-dihydro- 2-(3-nitrophenyl)-(4H)-3,1-
benzoxazin-4-one (2n). White solid; mp = 182–
184◦C; IR (KBr), ν: 3055, 2994, 1741, 1720, 1609,
1516, 1499, 1377, 1312; MS, m/z (%): 312 (M+, 18),
270 (M+ − CH2CO, 100), 225 (M+ − CH2CO − CO2H,
31), 179 (C3H3NO+5 , 47), 146 (C8H4NO+2 , 40), 119
1
(C7H5NO+, 70); H NMR (CDCl3, 90 MHz): δ 2.41
(s, 3H, COCH3), 7.32 (s, 1H, CH), 7.94–7.45 (m,
8H, Ar-H);13C NMR (CDCl3, 22.5 MHz): δ 23.5, 83.1,
121.7, 122.4, 123.8, 124.6, 127.4 130.7, 131.4, 132.8,
134.1, 139.2, 141.4, 151.1, 165.0, 168.9; Anal. Calcd
for C16H12N2O5: C, 61.53; H, 3.84; N, 8.97%. Found:
C, 61.48; H, 3.79; N, 8.94%.
N-Acetyl-2-(4-chlorophenyl)-1,2-dihydro-(4H)-3,
1-benzoxazin-4-one (2k). Colorless solid; mp = 169–
172◦C; IR (KBr), ν: 3086, 2989, 1739, 1670, 1602,
1367, 1089; MS, m/z (%): 303 (M+ + 2, 2), 301 (M+, 5),
261 (M+ + 2 − CH2CO, 14), 259 (M+−CH2CO, 49), 216
(M+ + 2 − CH2CO − CO2H, 16), 214 (M+ − CH2CO −
CO2H, 31), 114 (C6H357Cl+, 46), 112 (C6H355Cl+, 44);
1H NMR (CDCl3, 90 MHz): δ 2.48 (s, 3H, COCH3),
7.24 (s, 1H, CH), 7.91–7.49 (m, 8H, Ar-H); 13C NMR
(CDCl3, 22.5 MHz): δ 22.2, 82.6, 119.4, 124.0, 126.2,
126.8, 127.2, 127.8, 128.1, 128.6, 129.4, 129.8, 134.6,
138.2, 161.3, 169.7; Anal. Calcd for C16H12ClNO3: C,
63.68; H, 3.98; N, 4.64%. Found: C, 63.61; H, 3.94;
N, 4.61%.
N-Acetyl-1,2-dihydro- 2-(4-nitrophenyl)-(4H)-3,1-
benzoxazin-4-one (2o). Pale yellow solid; mp = 190–
193◦C; IR (KBr), ν: 3078, 2989, 1748, 1695, 1604,
1510, 1487, 1363, 1303; MS, m/z (%): 312 (M+, 8),
270 (M+ − CH2CO, 100), 225 (M+ − CH2CO − CO2H,
19), 179 (C3H3NO+5 , 32), 146 (C8H4NO+2 , 31), 119
1
(C7H5NO+, 75); H NMR (CDCl3, 90 MHz): δ 2.47
(s, 3H, COCH3), 7.24 (s, 1H, CH), 8.15–7.54 (m, 8H,
Ar-H); 13C NMR (CDCl3, 22.5 MHz): δ 24.7, 80.5,
119.5, 121.0, 124.5, 125.1, 126.9, 131.0, 132.6, 134.2,
136.1, 138.6, 139.4, 148.5, 163.0, 171.9; Anal. Calcd
for C16H12N2O5: C, 61.53; H, 3.84; N, 8.97%. Found:
C, 61.51; H, 3.82; N, 8.92%.
Heteroatom Chemistry DOI 10.1002/hc

Ultrasonic-Accelerated One-Pot Synthesis of N-Acetyl-2-aryl-1,2-dihydro-(4H)-3,1-benzoxazin-4-ones 113
[16] Stein, R. L.; Strimpler, A. M.; Viscarello, B. R.;
Wildonger, R. A.; Mauger, R. C.; Trainor, D. A. Bio-
chemistry 1987, 26, 4126–4130.
[17] Krantz, A.; Spencer, R. W.; Tam, T. F.; Liak, T. J.;
Copp, L. J.; Thomas, E. M.; Rafferty, S. P. J Med
Chem 1990, 33, 464–479.
[18] Jarvest, R. L.; Parratt, M. J.; Debouck, C. M.; Gorniak,
J. G.; Jennings, L. J.; Serafinowska, H. T.; Strickler,
J. E. Bioorg Med Chem Lett 1996, 6, 2463–2466.
[19] Bouillant, M.-L.; Favre-Bonvin, J.; Ricci, P. Tetrahe-
dron Lett 1983, 24, 51–52.
[20] Niemann, G. J.; Liem, J.; Hoof, A. V. D. K. V.; Neissen,
W. M. A. Phytochemistry 1992, 31, 3761–3767.
[21] Ueda, M.; Komatsu, S. J Polym Sci, Polym Chem Ed
1989, 27, 1017–1089.
2 - (2 - Acetoxynaphthalen - 1 - yl) - N - acetyl - 1, 2-
dihydro-2-(4H)-3,1-benzoxazin-4-one (4p). Pale yel-
low solid; mp = 196–198◦C; IR (KBr), ν: 3057, 2946,
1776, 1736, 1674, 1514, 1367; MS, m/z (%): 375 (M+,
9), 315 (M+−CH2CO, 53), 273 (M+− 2CH2CO, 31), 228
(M+ − 2CH2CO − CO2H, 30), 118 (C7H4NO+, 30),
+
1
77 (C6H5 , 27); H NMR (CDCl3, 90 MHz): δ 2.21 (s,
3H, COCH3), 2.36 (s, 3H, COCH3), 6.74 (s, 1H, CH),
7.71–7.33 (m, 6H, Ar-H), 8.35–8.03 (m, 4H, Ar-H);
13C NMR (CDCl3, 22.5 MHz): δ 21.2, 22.3, 81.9, 120.1,
122.7, 122.8., 123.4, 124.9, 125.9, 127.6, 127.8, 128.7,
129.5, 131.2, 131.3, 131.6, 134.0, 138.5, 147.1, 162.7,
169.7, 169.8; Anal. Calcd for C22H17NO5: C, 70.40; H,
4.53; N, 3.73%. Found: C, 70.36; H, 4.48; N, 3.68%.
[22] Alajarin, M.; Vidal, A.; Ortina, M. M.; Bautista,
D. Synthesis 2005, 2426–2432.
[23] Madkour, H. M. F. Arkivoc 2004, 36–54.
[24] Mosaad, S. M.; Mohammed, K. I.; Ahmed, M. A.;
Abdel-Hamide, S. G. J Appl Sci 2004, 4, 302–307.
[25] Parkanyi, C.; Yuan, H. L.; Stromberg, B. H. E.;
Evenzahav, A. J Heterocycl Chem 1992, 29, 749–753.
[26] Kornet, M. J.; Varia, T.; Beaven, W. J Heterocycl
Chem 1983, 20, 1553–1555.
[27] Errede, L. A.; McBrady, J. J.; Oien, H. T. J Org Chem
1977, 42, 656–658.
[28] Lygin, A. V.; DeMeijere, A. J Org Chem 2009, 74,
4554–4559.
[29] Laeva, A. A.; Nosova, E. V.; Lipunova, G. N.;
Golovchenko, A. V.; Adonin, N. Yu.; Parmon, V. N.;
Charushin, V. N. Rus J Org Chem 2009, 45, 913–920.
[30] Legrand, L.; Lozach, N. Bull Soc Chem Fr 1967,
2067–2074.
[31] Wiklund, P.; Romero, I.; Bergman, J. Org Biomol
Chem 2003, 1, 367–372.
[32] Herib, N. J.; Jurcut, J. G.; Bergna, D. E.; Burgher,
K. L.; Hartman, H. B.; Kafca, S.; Kerman, L. L.;
Kongsamut, S.; Roehr, J. E.; Szewczak, M. R.; Woods-
Kettelberger, A. T.; Corbett, R. J Med Chem 1996, 39,
4044–4057.
[33] Wiklund, P.; Bergman, J. Tetrahedron Lett 2004, 45,
969–972.
REFERENCES
[1] Suslick, K. S. In Encyclopedia of Physical Science
and Technology; Academic Press: San Diego, CA,
2001; Vol. 17, 363–376.
[2] Mason, T. J.; Peters, D. Practical Sonochemistry; Ellis
Horwood: New York, 1991.
[3] Luche, J. L. Synthetic Organic Sonochemistry;
Plenum Press: New York, 1998.
[4] Mason, T. J. Ultrason Sonochem 2007, 14, 476–483.
[5] Kimmel, E. Crit Rev Biomed Eng 2006, 34, 105–161.
[6] Suslick, K. S. In Comprehensive Coordination Chem-
istry; Elsevier Science: New York, 2003; Vol. 2, 731–
739.
[7] Putterman, S. J.; Weninger, K. R. Ann Rev Fluid Mech
2000, 32, 445–476.
[8] Lim, H. J.; Keum, G.; Kang, S. B.; Chung, B. Y.; Kim,
Y. Tetrahedron Lett 1998, 39, 4367–4368.
[9] Do¨mling, A.; Ugi, I. Angew Chem, Int Ed 2000, 39,
3168–3210.
[10] Ugi, I.; Do¨mling, A. Endeavor 1994, 18, 115–122.
[11] Do¨mling, A. Chem Rev 2006, 106, 17–89.
[12] Coppola, G. M. J Heterocycl Chem 1999, 36, 563–
588.
[34] Rad-Moghadam, K.; Roihi, S. B. J Org Chem 2009, 5,
no. 13.
[13] Alazard, R.; Bechet, J.; Dupaix, A.; Yon, J. Biochim
Biophys Acta 1973, 309, 379–396.
[35] Wiklund, P.; Rogers-Evans, M.; Bergman, J. J Org
Chem 2004, 69, 6371–6376.
[14] Teshima, T.; Griffin, J. C.; Powers, J. C. J Biol Chem
1982, 257, 5085–5091.
[36] Azarifar, D.; Nejat-Yami, R. Heterocycles 2010, 81,
2063–2073.
[15] Hedstrom, L.; Moorman, A. R.; Dobbs, J.; Abeles,
R. H. Biochemistry 1984, 23, 1753–1759.
Heteroatom Chemistry DOI 10.1002/hc