Catalyst-Free Microwave-Assisted Amination of
2-Chloro-5-nitrobenzoic Acid
Younis Baqi and Christa E. Mu¨ller*
Pharmaceutical Chemistry I, UniVersity of Bonn,
An der Immenburg 4, D-53121 Bonn, Germany
FIGURE 1. Structures of drug molecules derived from N-substituted
anthranilic acids.
ReceiVed April 7, 2007
anticancer and antimalarial drugs,5 and the MEK-1 inhibitor
2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-di-
fluorobenzamine (CI-1040, PD184352),6 which has been evalu-
ated in clinical trials as a novel anticancer agent (Figure 1).
Because of their importance as drug molecules and building
blocks for drugs, interest has grown in the development of
methods for the efficient and rapid synthesis of N-arylanthranilic
acids. The classical and still most widely used strategy for the
synthesis of N-arylanthranilic acids utilizes the Ullmann cou-
pling reaction,7 or the related Ullmann-Goldberg coupling
reaction,8 which involve the reaction of a halobenzoic acid with
an alkyl- or aryl-amine, or conversely, the coupling of an
anthranilic acid derivative with an aryl halide, in the presence
of a catalytic amount of copper (the metal, its oxide, or a salt).9
A carboxylate group adjacent to the amine or to the halogen
atom is essential for Ullmann type reactions. They typically
require harsh conditions, such as high temperatures and long
reaction times (130 °C for up to 24 h).9a,b Microwave irradiation
has recently been shown to accelerate and improve Ullmann
coupling reactions.10 More recently, the Buchwald-Hartwig
amination reaction has gained importance for the preparation
of N-alkyl- and N-arylanthranilic acid derivatives and related
compounds, in which aryl chlorides and aliphatic or aromatic
amines undergo palladium-catalyzed C-N cross-coupling.11
The synthesis of N-substituted 5-nitroanthranilic acid deriva-
tives 3a-w was achieved by a new, mild, microwave-assisted,
regioselective amination reaction of 5-nitro-2-chlorobenzoic
acid (1a) with a diverse range of aliphatic and aromatic
amines 2a-w without added solvent or catalyst. Up to >99%
isolated yield was obtained within 5-30 min at 80-120 °C.
The reaction, which is suitable for upscaling, yielded new
compounds that are of considerable interest as useful building
blocks and as potential drugs.
N-Substituted anthranilic acid derivatives possess various
pharmacological activities, e.g., N-arylanthranilic acids, such
as mefenamic and flufenamic acid, are therapeutically used as
nonsteroidal antiinflammatory drugs (NSAIDs) (Figure 1).1
Recently, these compounds have been identified as promising
lead structures for the development of novel therapeutics for
neurodegenerative and amyloid diseases, such as Alzheimer’s
disease, because of their potency to inhibit plaque formation.1,2
On the other hand, N-aralkylanthranilic acid derivatives, such
as 2-benzylamino-5-nitrobenzoic acid (3t) and 5-nitro-2-phen-
ethylaminobenzoic acid (3u), have been shown to interact with
the cystic fibrosis transmembrane conductance regulator (CFTR)
causing blockade of the chloride channel and have therefore
potential as novel antiarrhythmic drugs.3
(4) Goodell, J. R.; Madhok, A. A.; Hiasa, H.; Ferguson, D. M. Bioorg.
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Teresa, B.; Ramos, A. Curr. Pharm. Des. 2001, 7, 1745. (c) Girault, S.;
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(6) Chen, M. H. G.; Magano, J. Preparation of 2-phenylaminobenzoic
acids by coupling of 2-halobenzoic acids with anilines in the presence of
alkali metal hexamethyldisilazide. (Warner-Lambert Company). WO
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Furthermore, N-arylanthranilic acids are important precursors
required for the synthesis of drug molecules, e.g., acridones and
acridines, which have been developed as antiherpes agents,4
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* Corresponding author. Tel.: +49-228-73-2301, Fax.: +49-228-73-2567.
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10.1021/jo070731i CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/22/2007
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J. Org. Chem. 2007, 72, 5908-5911