Fast synthesis of substituted N-phenylanthranilic acids using Ullmann condensation under microwave irradiation in dry media

Article abstract of DOI:10.1080/00397910500374955

Substituted N-phenylanthranilic acids using the Ullmann condensation under microwave irradiation in dry media were obtained in good yield and short reaction times. Copyright Taylor & Francis LLC.

Full text of DOI:10.1080/00397910500374955

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Fast Synthesis of Substituted
N‐Phenylanthranilic Acids Using Ullmann
Condensation Under Microwave Irradiation in
Dry Media
Ana Martín a , Miriam Mesa a , Maite L. Docampo a , Victoria Gómez a
Rolando F. Pellón a
a Center of Pharmaceutical Chemistry, Havana, Cuba
Version of record first published: 19 Aug 2006.
&
To cite this article: Ana Martín, Miriam Mesa, Maite L. Docampo, Victoria Gómez & Rolando F. Pellón (2006):
Fast Synthesis of Substituted N‐Phenylanthranilic Acids Using Ullmann Condensation Under Microwave
Irradiation in Dry Media, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 36:3, 271-277
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Synthetic Communicationsw, 36: 271–277, 2006
Copyright # Taylor & Francis LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500374955
Fast Synthesis of Substituted
N-Phenylanthranilic Acids Using Ullmann
Condensation Under Microwave
Irradiation in Dry Media
´
Ana Martın, Miriam Mesa, Maite L. Docampo,
´
´
Victoria Gomez, and Rolando F. Pellon
Center of Pharmaceutical Chemistry, Havana, Cuba
Abstract: Substituted N-phenylanthranilic acids using the Ullmann condensation
under microwave irradiation in dry media were obtained in good yield and short
reaction times.
Keywords: Microwave irradiation, N-phenylanthranilic acid, Ullmann condensation
N-Phenylanthranilic acid and its derivatives have been studied as anti-
inflammatory agents and as precursors of acridones and acridines that
present bioactive properties such as anti-HIV, antibacterial, and antifungal
activities.[1]
In previous work, the Ullmann condensation of 2-chlorobenzoic acid with
aniline for the synthesis of N-phenylanthranilic acid was carried out using
water as solvent.
Under these conditions, the yield obtained was 76% after a reaction time
of 5 hours.[2]
This reaction was also performed under ultrasonic irradiation and a yield
of 81% was obtained after 20 min.[3]
Received in the USA July 28, 2005
´
´
´
Address correspondence to Rolando F. Pellon, Centro de Quımica Farmaceutica,
Calle 200 y 21, Atabey, Playa, Apartado 16042, Ciudad de La Habana, Cuba.
Fax: (537) 273 6471; E-mail: rolando.pellon@infomed.sld.cu
271

´
A. Martın et al.
272
In the past decade, the use of microwave heating in organic synthesis,
mainly in dry media, has seen exponential growth. At present, it is possible
to carry out chemical reactions rapidly under mild conditions in a domestic,
commercially available microwave oven. The risk of explosions was elimi-
nated, the purity and the yield of the product increased, and the reaction
times shortened by 10- to 500-fold; as such, these reaction are friendly to
the environment.[4,5]
In the present work, we examined the effect of microwave irradiation on
the Ullman condensation in dry media for the synthesis of N-phenylanthranilic
acid derivatives.
RESULTS AND DISCUSSION
In previous work, Ullmann condensation conditions were optimized for the
synthesis of N-phenylanthranilic acid in the presence of 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 2-chlorobenzoic
acid, and a reaction time of 5 h.[2]
To short the reaction time and improve the yield we examined the effect of
microwave irradiation on the Ullmann condensation in dry media using the
reaction of 2-chlorobenzoic acid with aniline in the presence of anhydrous
copper sulfate catalyst as a model to optimize the reaction conditions.
To establish the power necessary for the reaction, we scanned various
levels from 240–800 W. In all cases we could observe that when exceeding
240 W, decomposition of the reaction products increased after 3 min. The
best yield of N-phenylanthranilic acid (98%) was obtained at 90 s and 240 W.
To study the effect of the inorganic support in the synthesis of N-pheny-
lanthranilic acid, bentonite was chosen. In a previous article this support was
used successfully in the synthesis of diphenylamine under microwave
irradiation.[6] In our case, however, no increase in yield was observed, and
neither did the reaction time decrease.
Table 1 shows several N-phenylanthranilic acids synthesized under
microwave irradiation at 240 W. The 1H NMR data and melting points
(uncorrected) reported are compared with those obtained using traditional
conditions reported in literature. Table 2 reports microanalysis data and
molecular ion in mass spectra that was obtained.
To check the possibility of intervention of specific (not purely thermal)
microwave effects, the synthesis of these compounds was performed, changing

Substituted N-Phenylanthranilic
273
d

´
A. Martın et al.
274
d

Substituted N-Phenylanthranilic
275
Table 2. Microanalysis data and molecular ion in mass spectra of substituted
N-phenylanthranilic
Experimental (%)
Calculated (%)
H
Molecular
ion m/z
No.
Formula
C
H
N
C
N
1
2
C13H11NO2
C14H13NO3
C15H15NO2
C14H12N2O4
C13H10N2O4
73.22 5.20
69.12 5.39
74.67 6.27
61.76 4.44
6.57 73.28 4.95
5.76 68.92 5.44
5.81 74.85 6.15
9.72 61.80 4.42
6.63
5.50
5.90
9.70
213
243
3
241
272
4
5
60.47 3.90 10.85 60.39 4.08 10.93
258
6
C13H10ClNO2 63.04 4.07
C14H12ClNO3 60.55 4.36
5.66 62.97 4.22
5.04 61.00 4.48
9.72 58.10 4.18
9.27 55.60 3.44
5.44 65.46 4.27
5.35 65.33 4.65
5.83
4.94
9.96
8.97
5.30
5.79
247/249
277/279
288
7
8
C14H12N2O5
C14H10N2O6
C14H11NO4
58.33 4.20
55.63 3.33
65.37 4.31
9
302
257
10
11
C14H12ClNO2 64.25 4.62
261/263
only the heating mode and using a thermoregulated oil bath for the same reaction
times and temperatures. In all cases no reaction was detected (TLC).
EXPERIMENTAL
Starting materials came from commercial sources. Melting points were
measured using a Gallenkanmp hot apparatus and are uncorrected. The
reactions were carried out in a Panasonic domestic microwave oven, which
allows the selection of output power up to 800 W. TLC analyses were run on
60 F254 silica-gel chromatoplates from Merck using a mixture of n-buthanol–
acetic acid–water 6 : 1 : 1 as an eluent and a visualisation at 254-nm with a
UV lamp. 1H NMR spectra were recorded on a Bruker AC 250 Z spectrometer
at 300 K. Chemical shifts are expressed in ppm relative to TMS as internal
standard and DMSO-d6 as a solvent. Mass spectra were recorded with a spec-
trometer TRIO 1000 Fisions Instruments by electronic impact (EI). Microana-
´
lyses were performed by the Servicio de Microanalisis del Instituto de
Biorganica de la Universidad de La Laguna, Tenerife, Espan˜a.
´
Standard Procedure
Synthesis of N-phenylanthranilic Acid under Microwave Irradiation in
Dry Media
A mixture of 2-chlorobenzoic acid (1.56 g, 0.01 mol), aniline (1.86 g,
0.02 mol), anhydrous potassium carbonate (0.69 g, 0.005 mol), and anhydrous

´
A. Martın et al.
276
copper sulfate (0.25 g, 0.0016 mol) was completely triturated, placed into a
Pyrexw open Erlenmeyer flask, and irradiated in a domestic microwave
oven for 1–5 min. When the irradiation was stopped, the final temperature
was measured with a +0.5 8C error by introducing a glass thermometer into
the reaction mixture. The mixture was allowed to cool to 10 8C and
acidified with diluted HCl (1 : 1). The solid was filtered off, washed with
water, and extracted with boiling water. N-Phenylanthranilic acid was
recrystallized from EtOH/H2O (1 : 1).
All experiments performed in this work were repeated five times. The
yield reported represents an average of the values obtained for each
reaction. The identity of the products was checked by elemental analyses,
1H NMR spectra, mass spectra, and by comparison of TLC with authentic
samples.
Synthesis of N-Phenylanthranilic Acid under Microwave Irradiation
in Dry Media with Bentonite as Support
Natural bentonite (Smectita) (4 g) was added to thus reaction mixture of as
support. The bentonite is original from Cuba and has the following compo-
sition: SiO2 (50.3%), Al2O3 (19.3%), CaO (11.4%), Fe2O3 (9.9%), MgO
(3.0%), Na2O (2.8%), K2O (5%), MnO (0.4%).
CONCLUSIONS
The use of microwave irradiation enhanced the Ullmann condensation in dry
media for the synthesis of N-phenylanthranilic. A number of N-phenylanthra-
nilic acid derivatives was prepared in good yield in a very short reaction time.
ACKNOWLEDGMENT
Financial support by the Project SECAB-CYTED is gratefully acknowledged.
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´
´
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´
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Substituted N-Phenylanthranilic
277
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