Synthesis of N-phenylanthranilic acid derivatives using water as solvent in the presence of ultrasound irradiation

Article abstract of DOI:10.1081/SCC-120018938

An improved synthesis of N-phenylanthranilic acid using water as solvent can be achieved by ultrasound irradiation. A number of N-phenylanthranilic acids were prepared in good yields in a very short reaction time.

Full text of DOI:10.1081/SCC-120018938

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Synthesis of N-Phenylanthranilic Acid Derivatives
Using Water as Solvent in the Presence of Ultrasound
Irradiation
a
a
Maite L. Docampo Palacios & Rolando F. Pellón Comdom
a
Centro de Química Farmacéutica, La Habana, Cuba
Version of record first published: 17 Aug 2006.
To cite this article: Maite L. Docampo Palacios & Rolando F. Pellón Comdom (2003): Synthesis of N-Phenylanthranilic Acid
Derivatives Using Water as Solvent in the Presence of Ultrasound Irradiation, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 33:10, 1771-1775
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 10, pp. 1771–1775, 2003
Synthesis of N-Phenylanthranilic Acid
Derivatives Using Water as Solvent in the
Presence of Ultrasound Irradiation
Maite L. Docampo Palacios and Rolando F. Pello
´
n Comdom*
Centro de Quımica Farmaceutica, La Habana, Cuba
´ ´
ABSTRACT
An improved synthesis of N-phenylanthranilic acid using water
as solvent can be achieved by ultrasound irradiation. A number of
N-phenylanthranilic acids were prepared in good yields in a very
short reaction time.
The synthesis of N-phenylanthranilic acid has been reported using
[1]
[2]
DMF and MEK under sonication. Sonochemistry is an important
method for increasing reaction rates of chemical reactions, thus allowing
in many cases, for milder reaction conditions. In homogeneous systems,
bond-breaking often initiates the sonochemical reaction. In heterogeneous
*
Correspondence: Rolando F. Pello
´
Farmaceutica, Apartado 16042, La Habana, Cuba; Fax: (537) 336471; E-mail:
´
n
Comdom, Centro de Quımica
´
pellonrf@cqf.co.cu.
1
771
DOI: 10.1081/SCC-120018938
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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1
772
Docampo Palacios and Pellon Comdom
´
systems there is the additional benefit that ultrasound is a very efficient
[
tool for increasing mass transport.
3–5]
A study of some parameters which influence the Ullmann-Goldberg
reaction of o-chlorobenzoic acid and substituted anilines for the synthesis
of N-phenylanthranilic acids was done, showing that these acids can be
obtained efficiently using water as solvent, in presence of copper as
[
6]
catalyst and potassium carbonate as acid acceptor.
The use of pyridine as cocatalyst has been reported by us to obtain
N-phenylanthranilic acid in water or amyl alcohol as solvent in order to
reduce the reaction times.
[7]
In the present work we decided to examine the effect of ultrasound on the
Ullmann-Goldberg reaction in the synthesis of N-phenylanthranilic acids
from o-chlorobenzoic acid and substituted anilines using water as solvent.
RESULTS AND DISCUSSION
In a previous communication we reported the synthesis of N-phenyl-
anthranilic acid by the Ullmann-Goldberg reaction using water as solvent.
The best yield was obtained with 1 equivalent of potassium carbonate,
3% (by weight) of copper and 2 equivalents of amine per mole of
o-chlorobenzoic acid in 5 h reaction time.
[
6]
When we used these conditions for the reaction of o-chlorobenzoic
acid with aniline under ultrasonic irradiation the N-phenylanthranilic
acid was obtained in 81% yield after only 20 min.
It is noteworthy that with longer ultrasonic irradiation times the
yield of the acid remains constant. With less than 20 min irradiation
the reaction yield is reduced, e.g., 15 min gives a yield of only 58%.
Table 1 shows the N-phenylanthranilic acid derivatives synthesized
using water as solvent with and without ultrasonic irradiation and its
corresponding melting points.
All experiments performed in this work were repeated five times.
The yields reported represent an average of the values obtained for
each reaction with an standard deviation of 1.5 in all cases.

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Synthesis of N-Phenylanthranilic Acid Derivatives
1773
Table 1. Results of the syntheses of N-phenylanthranilic acid derivatives.
% Yield (using
water as solvent)
ꢀ
M.p. ( C)
uncorrected
R
5
h
R4 Reflux
20 min
Ultras.
No.
R1
R2
R3
Lit.
Obt.
[
8]
1
2
3
4
5
6
7
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
86
63
79
58
78
80
86
88
65
81
61
79
82
90
183–84
[
184
9]
COOH
H
290
[
294
289–90
293–94
234–35
218–219
131–32
181–82
10]
11]
COOH
H
[
NO
H
2
235
219
[
9]
NO
H
2
[
12]
13]
OCH3
H
H
OCH
132
[
H
3
181
Calculated and experimental microanalysis
Calculated (%) Experimental (%)
No.
Formula
C
H
C
H
1
2
3
4
5
6
7
C H NO
1
73.24
65.37
65.37
53.33
60.46
69.14
69.14
5.16
4.28
4.28
3.08
3.88
5.35
5.35
73.38
65.49
65.21
53.19
60.26
69.26
68.91
5.28
4.19
4.34
3.18
4.01
5.41
5.23
3
11
2
4
4
C
C
14
H
11NO
14
H11NO
C H ClN O
1
3
9
2
4
C
C
13
H
H
10
N
2
O
4
14
13NO
3
3
C H NO
1
4
13
With pyridine as cocatalyst the reaction between o-chlorobenzoic
acid and aniline in water to give N-phenylanthranilic acid is accelerated
[
7]
and complete after 2 h.
Using the conditions mentioned in this article i.e., 1 eq. K CO /mole
2
3
o-chlorobenzoic acid, 2 moles of aniline, Cu powder (3% w/w referred
to o-chlorobenzoic acid) but adding pyridine as cocatalyst (15% w/w
referred to o-chlorobenzoic) in presence of ultrasonic irradiation
(
20 kHz) the reaction was complete after 15 min.

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1
774
Docampo Palacios and Pellon Comdom
´
As was previously mentioned using 15 min without pyridine only
8% yield was obtained. So this fact demonstrated that in presence of
ultrasonic irradiation pyridine catalyzed the reaction.
5
These conditions were employed for each derivative obtained in
Table 1 using 15 min reaction time. In all cases, the yield obtained was
similar to those obtained after 20 min, when no pyridine was present.
EXPERIMENTAL PART
Standard Procedure
A mixture of o-chlorobenzoic acid (6.26 g; 0.04 mol), aniline (7.45 g;
.08 mol), anhydrous potassium carbonate (2.76 g; 0.02 mol), copper
0
powder (0.2 g), pyridine (1.58 g; 0.02 mol) and water 25 mL was treated
for 20 min with ultrasonic irradiation using a sonic horn at 20 kHz.
ꢀ
The reaction mixture was cooled to 10 C and acidified with diluted
HCl (1:1). The solid was filtered and washed with water, and extracted
with boiling water. The N-phenylanthranilic acid obtained can be
recrystallized of EtOH/H O (1:1).
2
CONCLUSIONS
The use of ultrasound irradiation accelerated the synthesis of
N-phenylanthranilic acid using water as solvent. A number of N-phenyl-
anthranilic acid derivatives were prepared in good yield in a very short
reaction time.
REFERENCES
1
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´ ´
of ultrasound in the synthesis of N-arylanthranilic acids by the
Ullmann-Goldberg reaction. Synth. Commun. 1989, 19 (11&12),
2077–2080.
2
. Hanoun, J.P.; Tensglia, A. A convenient synthesis of N-arylanthra-
nilic acid using ultrasound in the Ullmann-Goldberg condensation.
Synth. Commun. 1995, 25 (16), 2443–2448.
3. Abdulla, R.F. Ultrasound in organic synthesis. Aldrichimica Acta
1988, 21, 31–42.

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2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
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(
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1
Received in the USA August 16, 2002

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