A new synthesis of 2-substituted 4H-3,1-benzoxazin-4-ones by cyanuric chloride cyclodehydration of N-benzoyl- and N-acylanthranilic acids

Article abstract of DOI:10.3987/COM-05-10364

A new and a convenient method for the synthesis of aryl- and alkyl-2-substituted 4H-3,1-benzoxazin-4-ones by cyclodehydration of N-benzoyl- and N-acylanthranilic acid by cyanuric chloride is described.

Full text of DOI:10.3987/COM-05-10364

HETEROCYCLES, Vol. 65, No. 5, 2005
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HETEROCYCLES, Vol. 65, No. 5, 2005, pp. 1159 - 1165
Received, 3rd February, 2005, Accepted, 25th February, 2005, Published online, 1st March, 2005
A NEW SYNTHESIS OF 2-SUBSTITUTED 4H-3,1-BENZOXAZIN-4-ONES
BY CYANURIC CHLORIDE CYCLODEHYDRATION OF N-BENZOYL-
AND N-ACYLANTHRANILIC ACIDS
Mohammad S. Khajavi* and Seyed M. Shariat
Department of Chemistry, Faculty of Sciences, Shahid Beheshti University,
Shahid Chamran Highway, Evin 19834, Tehran, Iran
E-mail: mskhajavi@hotmail.com
Abstract - A new and a convenient method for the synthesis of aryl- and alkyl-2-
substituted 4H-3,1-benzoxazin-4-ones by cyclodehydration of N-benzoyl- and N-
acylanthranilic acid by cyanuric chloride is described.
INTRODUCTION
Cyanuric chloride activates carboxylic acids by formation of active esters.1 These in situ prepared active
esters can be utilized for the synthesis of a variety of functional groups, such as amides,2-3 acid chlorides,3
esters,3 peptides,3 macrocyclic lactones,4 β-lactams,5-6 acylazides,7 hydroxamic acids8 and diazocarbonyl
compounds.9 Also cyanuric chloride has been used for the preparation of nitriles by dehydration of
aldoximes,10 sulfides from sulfoxides,11 nitriles from amides and thioamides12 and sulfonyl chlorides.13
Furthermore, cyanuric chloride has been used to activate other class of organic compounds such as
dimethyl sulfoxide in Swern oxidation of alcohols14-15or in preparation of disulfides16 and DMF for the
conversion of alcohols into the corresponding formates,17 alcohols to alkyl chlorides,18 ketoxime to
amides19-20 and aldoximes to nitrile.19 Among other applications, the utilization of cyanuric chloride in the
field of carbohydrate microarrays for monitoring of carbohydrate-protein interaction,21 the production of
new class of UV filters for use in cosmetic sunscreens22 and in molecular imprinting can be mentioned.23
Following our earlier research works on the efficient synthesis of 2-substituted 4H-3,1-benzoxazin-4-ones
by the condensation of anthranilic acid with various orthoesters under classical heating or microwave
irradiation24 and application of cyanuric chloride in stereospecific synthesis of β-lactams,5 here we wish
to report a convenient procedure for the synthesis of aryl- and alkyl-2-substituted 4H-3,1-benzoxazin-4-
ones from the readily available N-benzoyl- and N-acylanthranilic acid by cyanuric chloride (4).

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HETEROCYCLES, Vol. 65, No. 5, 2005
4H-3,1-benzoxazin-4-ones are an important class of condensed heterocyclic compounds exhibiting a wide
spectrum of biological activities. Many compounds containing this core structure have shown interesting
biological properties such as anti-neoplastic activity,25 fungicidal properties,26 as lipoprotein elevators for
the treatment of hyperlipoproteinemia and associated diseases27 or as serine protease and human
leukocyte elastase inhibitors.28 Furthermore, they are valuable starting materials for the synthesis of a
variety of 2,3-disubstituted 4(3H)-quinazolinones.29
RESULTS AND DISCUSSION
We have found that cyanuric chloride reacts smoothly with N-benzoylanthranilic acid (3a), which can be
readily prepared from anthranilic acid (1) and benzoyl chloride (2a), in refluxing toluene in the presence
of triethylamine to give 2-phenyl-4H-3,1-benzoxazin-4-one (5a) in 83% yield. During the process of this
cyclodehydration reaction cyanuric acid is converted to hydoxydichloro[1,3,5]triazine which can be easily
separated from the desired product (due to its solubility in water or its insolubility in non-polar organic
solvents). The reaction is very clean and the product can be isolated with high purity by usual workup.
The results with some derivatives of N-benzoylanthranilic acid (3a-f) for the preparation of 2-aryl-4H-
3,1-benzoxazin-4-one are summarised in Table1. In all cases the required amide intermediates (3a-f) were
prepared from aroyl chloride and anthranilic acid.
O
O
Cl
O
Et3N
OH
OH
N
N
+
+
R
Cl
NH2
NHCOR
Cl
N
Cl
1
3a-j
2a-j
4
a R = Ph
4-
Et3N
O
b R = MeC6H4
c R = ClC H
4-
d R = BrC H
6
4
4-
6
4
e R = NO C H
4-
2
6
4
O
f R = NO C H
3-
2
6
4
g R = CH=CH-Ph
h R = Me
N
R
i R= Et
5a-j
j R = CH2C6H5
Scheme 1

HETEROCYCLES, Vol. 65, No. 5, 2005
1161
The method also works well for the synthesis of 2-alkyl-4H-3,1-benzoxazin-4-one (5h-j). Since the 2-
akyl substituted benzoxazinones are hydroscopic and they are hydrolysed easily to 2-acetaminobenzoic
acids we only modified the workup procedure (EXPERIMENTAL) to avoid such kind of hydrolysis
during the isolation of the products. The results for the preparation of 2-alkyl-4H-3,1-benzoxazin-4-one
are summarised in Table 1. Furthermore, the employment of sodium or potassium salt of N-
benzoylanthranilic acid or its derivatives instead of acid itself in this reaction did not appreciably increase
the yields of the products (Method B, see Table 1).
A proposed mechanism for this reaction is depicted in Scheme 2. The nucleophilic attack of the
carboxylic group of anthranilic acid to cyanuric chloride (CC) via formation of the σ adduct (6) will
produce the active ester (7) which in the next step can cyclized to produce (5). The alternative pathway of
the formation of imidic ester intermediate (8) where the carboxylic group attacks to imidate to produce
the cyclized product have a lower probability.
Cl
Cl
N
N
O
_
Cl
O
N
N
O
N
+
Et3N
N
Cl
3a-j
N
Cl
O
CC
+
+
O
O
- Et3NH
- Et3N.HCl
N
H
6
+ Et3N
R
R
H
- Et3N.HCl
7
H
O
..
..
O
O
N
O
O
O
N
C-R
Me
N
Cl
O
N
Cl
N
H
R
O
N
N
N
N
5a-j
8
Cl
Cl
Scheme 2
The structures of all synthesized compounds were confirmed by the analyses of their spectra data (IR, 1H
and 13C NMR). Products (3a-j) and (5a-j) are known compounds and their physical properties were
identical with those of authentic samples.

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Table 1: Reaction of N-benzoyl- and N-acylanthranilic acid with cyanuric chloride
Entry Product
R
Method
Yield (%)
Mp (T/°C)
123-124
154-155
190-191
183-184
202-204
166
Lit. mp (T/°C)
124-125,30123-12431
154.5,31 15532
19032
18432
20331
16632
14832
80-8131
85-8631
1
2
3
4
5
6
7
8
9
10
5a
5b
5c
5d
5e
5f
Ph
A & B
83a
75a
81
87
82
80
78
76
72
75
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
3-NO2C6H4
CH=CH-Ph
Me
A & B
A
A
A
A
A
C
C
C
5g
5h
5i
148-149
80-82
Et
84-86
5j
CH2C6H5
90-91
90.533
a Yields of the isolated products with Method A. The yields with Method B were within ± 5 % as of
Method A.
In conclusion we have found that cyanuric chloride is an effective reagent for the cyclodehydration of N-
aroylanthranilic acid and 2-acetamonobenzoic acid. This method is convenient for the synthesis of a
variety of aryl- and alkyl-2-substituted 4H-3,1-benzoxazin-4-one.
EXPERIMENTAL
1
IR spectra were recorded as KBr pellets on a Shimadzu IR-470 spectrophotometer. H and 13C NMR
spectra were measured using a JEOL EX-90A spectrometer at 90 and 22.63 MHz respectively. Melting
points were determined in open capillary tubes using a Thomas-Hoover apparatus and are uncorrected.
Anthranilic acid, cyanuric chloride and all the acid chlorides were purchased from Aldrich or Fluca and
were used without further purification. Toluene was freshly distilled from sodium.
Preparation of 2-aryl-4H-3,1-benzoxazin-4-ones – The general procedure is illustrated with 2-
phenyl-4H-3,1-benzoxazin-4-ones (5a), (Method A): A solution of benzoyl chloride (1.41 g, 10 mmol)
in 10 mL of dichloromethane was added dropwise to a stirred solution of anthranilic acid (1.37g, 10
mmol) and triethylamine (1.11 g, 11 mmol) in 40 mL of dichloromethane at rt. After 5 h, the reaction
mixture was washed with water, dried (MgSO4). Evaporation of the solvent and recrystallisation from
chloroform gave the N-benzoylanthranilic acid (2.24 g 93%). A suspension of cyanuric chloride (0.92 g, 5
mmol) in anhydrous toluene (20 mL) was added dropwise over 10 min to a stirred solution of a mixture
of N-benzoylanthranilic acid (1.20 g, 5 mmol) and triethylamine (0.60 g, 6 mmol) in 30 mL of toluene at
rt. Following the addition, the reaction mixture was refluxed overnight and then washed with water, 5%

HETEROCYCLES, Vol. 65, No. 5, 2005
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NaHCO3 solution and at the end with brine and dried with MgSO4. After solvent evaporation the crude
product was recrystallised from ether-chloroform (1:2) mixture to afford the title compound (0.93 g 83%),
1
mp 123-124 °C (lit.,124-12530, 123-12431); IR (KBr): vmax/cm-11769, 1625, 1622, 1600; H NMR
(CDCl3): δ ppm 7.25-8.51 (m, 9H, Ar-H); 13C NMR (CDCl3): δ ppm 116.8 (C4a), 126.9 (C8), 127.9 (C6),
128.0 (C2'), 128.2 (C5), 128.4 (C3'), 129.9 (C1'), 132.3 (C4'), 136.1 (C7), 146.6 (C8a), 156.7 (C2), 158.9
(CO).
Preparation of 2-p-tolyl-4H-3,1-benzoxazin-4-ones (5b), (Method B): N-(p-Toluoyl)anthranilic acid
was prepared as described for (3a). The crystallised compound was treated with equivalent amount of
potassium hydroxide dissolved in ethanol. The potassium salt that separated was filtered and washed with
ether and air-dried. To a suspension of potassium N-(p-toluoyl)anthranilate (1.46 g, 5 mmol) in toluene
(30 mL) at rt was added dropwise with stirring cyanuric chloride (0.92 g, 5 mmol) in 20 mL of toluene.
Stirring is continued at rt for 30 min and then the reaction mixture was refluxed overnight. Workup of the
reaction mixture as described for method A gave the crude product which was recrystallised from ether-
chloroform (1:2) mixture to give 5b (0.89 g 75%), mp 154-155°C (lit., 154.531, 15532); IR (KBr): vmax/cm-1
1
1767, 1609, 1612, 1604; H NMR (CDCl3): δ ppm 2.37 (s, 3H, CH3), 7.45-8.36 (m, 8H, Ar-H); 13C
NMR (CDCl3): δ ppm 21.5 (CH3), 116.9 (C4a), 127.2 (C8) 127.4 (C1'), 127.9 (C6), 128.3 (C2'), 128.4 (C5),
129.5 (C3'), 136.5 (C7), 143.4 (C4'), 147.3 (C8a), 157.3 (C2), 159.8 (CO).
Preparation of 2-alkyl-4H-3,1-benzoxazin-4-ones The general procedure is illustrated with 2-
methy-4H-3,1-benzoxazin-4-one (5h), (Method C): To a stirred solution of anthranilic acid (1.37 g, 10
mmol) and triethylamine (1.11g, 11 mmol) in 40 mL of dichloromethane a solution of acetyl chloride
(0.78 g, 10 mmol) in 10 mL of dichloromethane is added. The stirring is continued at rt for 4 h. Then the
reaction mixture is poured into a mixture of ice and water. The precipitated material was separated and
recrystallised from ethanol to give N-acetaminobenzoic acid (1.7 g 95%). To a stirred mixture of N-
acetaminobenzoic acid (0.89 g, 5 mmol), triethylamine (0.60 g, 6 mmol) and 30 mL of toluene in a flame
dried 100 mL flask equipped with a condenser attached to a drying tube filled with dry calcium chloride,
was added a suspension of cyanuric chloride (0.92 g, 5 mmol) in toluene (20 mL) at rt. The mixture stirred
for 30 min at rt and refluxed overnight. After evaporation of toluene the residue was extracted with
petroleum ether (30-60°) and finally recrystallised with heptane to afford the desired compound (5h)
(0.61 g 76%), mp 80-82°C (lit., 80-8131); IR (KBr): vmax/cm-11755, 1650, 1610; 1H NMR (CDCl3): δ ppm
13
2.43 (s, 3H, CH3), 7.40-8.42 (m, 4H, Ar-H); C NMR (CDCl3): δ ppm 21.2 (CH3), 116.5 (C4a), 126.2
(C8), 127.9 (C6), 128.1 (C5), 136.2 (C7), 146.3 (C8a), 159.2 (CO), 160.0 (C2).

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ACKNOWLEDGEMENT
The authors are appreciating the assistance of Mr. M. Hajihadi, M.Sc. student, of Shahid Beheshti
University for repeating some of the experiments presented in this article.
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