Catalyst-free microwave-assisted amination of 2-chloro-5-nitrobenzoic acid

Article abstract of DOI:10.1021/jo070731i

(Chemical Equation Presented) The synthesis of N-substituted 5-nitroanthranilic acid derivatives 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

Full text of DOI:10.1021/jo070731i

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.
christa.mueller@uni-bonn.de
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.
Med. Chem. 2006, 14, 5467.
(5) (a) Demeunynck, M.; Charmantray, F.; Martelli, A. Curr. Pharm.
Des. 2001, 7, 1703. (b) Brana, M. F.; Cacho, M.; Gradillas, A.; De Pascual-
Teresa, B.; Ramos, A. Curr. Pharm. Des. 2001, 7, 1745. (c) Girault, S.;
Grellier, P.; Berecibar, A.; Maes, L.; Mouray, E.; Lemiere, P.; Debreu, M.-
A.; Davioud-Charvet, E.; Sergheraert, C. J. Med. Chem. 2000, 43, 2646.
(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
2000064856 A1, 2000.
(7) (a) Ullmann, F. Chem. Ber. 1903, 36, 2382. (b) Ullmann, F. Chem.
Ber. 1904, 37, 853. (c) Ma, D.; Xia, C. Org. Lett. 2001, 3, 2583. (d) Lindley,
J. Tetrahedron 1984, 40, 143.
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
(8) (a) For review see: Ley, S. V.; Thomas, A. W. Angew. Chem., Int.
Ed. 2003, 42, 5400. (b) Goldberg, I. Chem. Ber. 1906, 39, 1691. (c)
Goldberg, A. A.; Kelly, W. J. Chem. Soc. 1947, 595. (d) Goldberg, A. A.;
Alan, A.; Kelly, W. J. Chem. Soc. 1946, 102. (e) Goodell, J. R.; Puig-
Basagoiti, F.; Forshey, B. M.; Shi, P-Y.; Ferguson, D. M. J. Med. Chem.
2006, 49, 2127. (f) Okano, K.; Tokuyama, H.; Fukuyama, T. Org. Lett.
2003, 5, 4987. (g) Bauman, D. R.; Rudnick, S. I.; Szewczuk, L. M.; Jin,
Y.; Gopishetty, S.; Penning, T. M. Mol. Pharmacol. 2005, 67, 60.
(9) (a) Mei, X.; August, A. T.; Wolf, C. J. Org. Chem. 2006, 71, 142.
(b) Wolf, C.; Liu, S.; Mei, X.; August, A. T.; Casimir, M. D. J. Org. Chem.
2006, 71, 3270. (c) Yuhong, J.; Varma, R. S. J. Org. Chem. 2006, 71, 135.
(d) Yuhong, J.; Varma, R. S. Green Chem. 2004, 6, 219. (e) Wu, Y.-J.;
He, H.; L’Heureux, A. Tetrahedron Lett. 2003, 44, 2417. (f) Ma, D.; Cai,
Q.; Zhang, H. Org. Lett. 2003, 5, 2453. (g) Ma, D.; Cai, Q. Org. Lett.
2003, 5, 3799. (h) Li, F.; Wang, Q.; Ding, Z.; Tao, F. Org. Lett. 2003, 5,
2169. (i) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793. (j) Xu,
G.; Wang, Y.-G. Org. Lett. 2004, 6, 985.
* Corresponding author. Tel.: +49-228-73-2301, Fax.: +49-228-73-2567.
(1) (a) Green, N. S.; Palaninathan, S. K.; Sacchettini, J. C.; Kelly, J. W.
J. Am. Chem. Soc. 2003, 125, 13404. (b) Oza, V. B.; Smith, C.; Raman, P.;
Koepf, E. K.; Lashuel, H. A.; Petrassi, H. M.; Chiang, K. P.; Powers, E.
T.; Sachettinni, J.; Kelly, J. W. J. Med. Chem. 2002, 45, 321. (c) Klabunde,
T.; Petrassi, H. M.; Oza, V. B.; Raman, P.; Kelly, J. W.; Sacchettini, J. C.
Nat. Struct. Biol. 2000, 7, 312.
(2) (a) Oza, V. B.; Petrassi, H. M.; Purkey, H. E.; Kelly, J. W. Bioorg.
Med. Chem. Lett. 1999, 9, 1. (b) Baures, P. W.; Oza, V. B.; Peterson, S.
A.; Kelly, J. W. Bioorg. Med. Chem. 1999, 7, 1339.
(3) (a) Schultz, B. D.; Singh, A. K.; Devor, D. C.; Bridges, R. J. Physiol.
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53, 539.
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

TABLE 1. Synthesized N-Arylanthranilic Acid Derivativesa
SCHEME 1. Microwave-Assisted Synthesis of
N-Arylanthranilic Acid Derivatives
Our medicinal chemistry projects directed toward the devel-
opment of nucleotide (P2) receptor antagonists12 required gram
amounts of a variety of 5-amino-N-substituted anthranilic acid
derivatives as building blocks. The N-substituted 5-nitroanthra-
nilic acids were selected as suitable precursors which can easily
be converted to the required aniline derivatives by reduction of
the nitro function. In the present study we report on a new,
regioselective synthetic procedure providing convenient access
to a wide range of N-aryl- and N-alkyl-5-nitroanthranilic acid
derivatives. The coupling of 2-chloro-5-nitrobenzoic acid with
amines proceeds smoothly and neatly upon microwave irradia-
tion without added solvent or catalyst (see Scheme 1, Tables 1
and 2).
Previous reports on the synthesis of N-substituted 5-nitro-
anthranilic acid derivatives employed (a) micellar catalysis
(cetyltrimethylammonium bromide) in water for the preparation
of 3a from 2-fluoro-5-nitrobenzoic acid and aniline,13 or (b)
strong base (LiHMDS) for the reaction of 2-fluoro-5-nitroben-
zoic acid with p-fluoroaniline yielding 3b,6 or (c) bronze as a
catalyst in the presence of bases for the reaction of 2-chloro-
5-nitrobenzoic acid with anilines in 1-pentanol yielding 3f14 and
3g14 (for structures of compounds see Table 1). Furthermore,
the synthesis of 2-benzylamino-5-nitrobenzoic acid (3t) has been
described by a three-step procedure starting from 2-fluoro-5-
nitrobenzoic acid involving acid protection.15 All of the
described reactions did not appear to be generally applicable
and suffered from further drawbacks, such as reaction at -78
°C and application of strong base,6 long reaction times,6,14,15
need for chromatographic purification,6 need for protecting the
carboxylic acid function,15 or moderate yields.14
T
reaction
products 3
entry
R1
R2
R3
R4
(°C) time (min) (yield [%])b
1
2
3
4
5
6
7
8
9
CO2H NO2
CO2H NO2
CO2H NO2
CO2H NO2
CO2H NO2
CO2H NO2
CO2H NO2
CO2H NO2
CO2H NO2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
100
120
120
120
120
120
110
120
80
10
10
30
30
15
15
10
20
5
3a (80)
3b (80)
3c (50)
3d (60)
3e (30)
3f (67)
3g (75)
3h (58)
3i (76)
3j (75)
3k (78)
3l (58)
3m (70)
3n (70)
3o (70)
3p (85)
3q (78)
3x (0)
4-F
2-Cl
3-Cl
3-Br
2-OCH3
3-OCH3
2-CH2CH3
3-CH2CH3
4-CH2CH3
10 CO2H NO2
11 CO2H NO2
12 CO2H NO2
13 CO2H NO2
14 CO2H NO2
15 CO2H NO2
16 CO2H NO2
17 CO2H NO2
100
10
15
5
2-OCH2CH3 120
4-OCH2CH3 100
2,3-di-CH3 120
2,4-di-CH3 100
2,5-di-CH3 120
3,5-di-CH3 120
2-CH3, 4-Cl 120
30
10
20
10
30
180
180
180
18 CO2H
19
20
H
NO2
NO2 CO2H
H
H
H
200
200
200
H
H
3y (0)
3z (0)
a Reaction mixtures were irradiated for 5-30 min without added solvent
or catalyst at 80-120 °C. b Isolated yields (purity of products g95% as
determined by HPLC-UV (254 nm)-ESI-MS) calculated based on starting
compound 1a.
TABLE 2. Synthesized N-(Ar)alkylanthranilic Acid Derivatives
Using Primary and Secondary Aminesa
Initially, we attempted to obtain the target compounds 3 by
microwave-assisted Ullmann-Goldberg coupling reaction of
2-amino-5-nitrobenzoic acid with bromo- or chlorobenzene, but
no product was obtained under various conditions.16,17 Subse-
quently, the amino and halogen functionalities of the starting
compounds were exchanged, and 2-chloro-5-nitrobenzoic acid
(1a) was reacted with aniline (2a) and aniline derivatives. We
discovered that the reaction proceeded rapidly and smoothly
reaction time
(min)
products 3
entry
amine
T (°C)
(yield [%])b
1
2
3
4
5
6
cyclopentylamine (2r)
cyclohexylamine (2s)
benzylamine (2t)
phenethylamine (2u)
dipropylamine (2v)
pyrrolidine (2w)
120
120
120
120
100
80
5
5
10
10
5
3r (>99)
3s (>99)
3t (60)
3u (50)
3v (>99)
3w (>99)
(10) (a) Baqi, Y.; Mu¨ller, C. E. Org. Lett. 2007, 9, 1271. (b) Kappe, C.
O. Angew. Chem., Int. Ed. 2004, 43, 6250. (c) Vera-Luque, P.; Alajarin,
R.; Alvarez-Builla, J.; Vaquero, J. J. Org. Lett. 2006, 8, 415. (d) Martin,
A. M.; Pellon, R. F.; Mesa, M.; Docampo, M. L.; Gomez, V. J. Chem.
Res. 2005, 9, 561.
(11) (a) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653. (b) Rivas, F. M.;
Riaz, U.; Giessert, A.; Smulik, J. A.; Diver, S. T. Org. Lett. 2001, 3, 2673.
(c) Chakraborti, D.; Colis, L.; Schneider, R.; Basu, A. K. Org. Lett. 2003,
5, 2861. (d) Suo, Z.; Drobizhev, M.; Spangler, C. W.; Christensson, N.;
Rebane, A. Org. Lett. 2005, 7, 4807. (e) Kantchev, E. A. B.; O’Brien, C.
J.; Organ, M. G. Aldrichim. Acta 2006, 39, 97.
5
a Reaction mixtures were irradiated for 5-10 min without added solvent
or catalyst at 80-120 °C. b Isolated yields (purity of products g97% as
determined by HPLC-UV (254 nm)-ESI-MS) calculated based on starting
compound 1a.
upon microwave irradiation, even in the absence of solvent and
catalyst. Optimized reaction conditions were found to be as
follows: excess of amine (6 equiv), 80-120 °C, 5-30 min (see
Scheme 1, Tables 1 and 2). The new amination procedure was
then applied to a number of aryl- and alkylamines including
primary and secondary amines. Different substituents were
present on the mono- or disubstituted aniline derivatives
(12) Mu¨ller, C. E. Curr. Pharm. Des. 2002, 8, 2353.
(13) Broxton, T. J.; Marcou, V. J. Org. Chem. 1991, 56, 1041.
(14) Csuk, R.; Barthel, A.; Raschke, C. Tetrahedron 2004, 60, 5737.
(15) South, M. S.; Case, B. L.; Dice, T. A.; Franklin, G. W.; Hayes, M.
J.; Jones, D. E.; Lindmark, R. J.; Zeng, Q.; Parlow, J. J. Comb. Chem.
High Throughput Screen. 2000, 3, 139.
(16) Martin, A.; Mesa, M.; Docampo, M.; Gomez, V.; Pellon, R. Synth.
Commun. 2006, 36, 271.
J. Org. Chem, Vol. 72, No. 15, 2007 5909

employed, including deactivating groups such as halogen (F,
Cl, Br) or activating groups such as alkyl (CH3, C2H5) or alkoxy
(OCH3, OC2H5), in order to investigate the scope of the reaction
(Tables 1 and 2).
5-nitroanthranilic acid derivatives. The reaction tolerates various
functionalities as demonstrated by reacting a diverse range of
aliphatic primary and secondary amines, and aromatic amine
derivatives, including sterically hindered ones and anilines
bearing electron-withdrawing substituents on the benzene ring.
It proceeds with notable regioselectivity, which is probably
because of the accelerating effect of the adjacent carboxylate
group in the presence of the nitro group in the para-position
with regard to the chlorine atom in starting compound 1a. The
reaction proceeds fast, clean, and under mild conditions. No
strong bases are required, allowing the presence of base-labile
groups and avoiding side-reactions. Carboxylic acid groups do
not need to be protected. The procedure is insensitive to air
and moisture and does not require an inert atmosphere. It can
easily be upscaled to multigram quantities and provides a
practical approach for the preparation of the target compounds
which represent an important class of drug molecules and which
are in addition valuable intermediate products for the synthesis
of pharmacologically active compounds. In a simple reduction
step the nitro group may be reduced, yielding the corresponding
amines as useful building blocks. The described catalyst-free
amination reaction, which does not require the addition of
solvent, provides a less expensive, operationally simple alterna-
tive to palladium-catalyzed Buchwald-Hartwig cross-coupling
reactions and is also superior to copper-catalyzed Ullmann-
Goldberg reactions for the preparation of 2-aryl- and 2-(ar)-
alkylamino-5-nitrobenzoic acid derivatives.
In conclusion, we have developed a convenient, fast, mild,
and efficient methodology for the synthesis of N-substituted
5-nitroanthranilic acid derivatives without addition of catalysts
or solvents. The method has been used to synthesize several
new compounds (Table 1, entries 5, 8-11, 15-17, and Table
2, entry 5), that have, to the best of our knowledge, not been
described in the literature. In addition we have synthesized and
characterized several compounds (Table 1, entries 3, 4, 12-
14, and Table 2, entries 1, 2, 4, 6) for which neither synthetic
procedures, nor spectral data, have previously been described.
Because of its simplicity, cost-effectiveness and general ap-
plicability with respect to the amine component, it may find
broad academic as well as industrial application.
Importantly, the new amination procedure proceeds with
notable chemo- and regioselectivity because only the chloride
adjacent to the carboxylic acid group and in the para-position
to the nitro group is replaced (see Table 1, entries 2-5 and
17). Moreover the new protocol is suitable for the synthesis of
sterically hindered N-arylanthranilic acids as shown by the
reaction of ortho-substituted anilines (Table 1, entries 3, 6, 8,
11, 13-15 and 17). The new amination procedure can also be
applied to arylalkylamines such as benzylamine and phenethyl-
amine to synthesize 2-benzylamino-5-nitrobenzoic acid and
5-nitro-2-phenethylaminobenzoic acid (Table 2, entries 3 and
4). Reaction of aliphatic primary and secondary amines (cy-
clopentylamine, cyclohexylamine, dipropylamine, pyrrolidine)
even requires milder conditions and proceeds faster resulting
in quantitative yields within only 5 min (Table 2, entries 1, 2,
5 and 6).
The workup of this very clean reaction involves only a simple
extraction step (water/sodium hydroxide-dichloromethane) in
order to remove unreacted amine (organic phase), followed
by precipitation of the product from the water phase by the
addition of hydrochloric acid, and filtration of the precipitate,
which is subsequently washed with water. Using this simple
purification protocol the desired products are obtained in high
purity (g95%) as determined by LC-MS. Structures were
confirmed by 1H and 13C NMR analyses (see Supporting
Information). Products were mostly obtained in good to excellent
yields (typically 60 to >99% isolated). Only in few cases, yields
were somewhat lower, e.g., 2-chloroaniline derivative 3c (50%),
3-bromoaniline derivative 3e (30%), and phenethylamine de-
rivative 3u (50%). Reasons for somewhat reduced yields were
presumably electronic and steric effects (3c), instability of the
starting compound (3e), and failure to quantitatively isolate the
product (3u).
In further experiments, we investigated the importance of the
electron-withdrawing nitro function as well as the carboxylic
acid group on the chlorobenzene derivative 1a. o-Chlorobenzoic
acid (1b) lacking the nitro group in the para-postion was not
reactive under the applied conditions (up to 250 W, 200 °C, 3
h). Also, p-nitrochlorobenzene (1c) lacking the carboxylate
group in the ortho-position did not react with aniline, even under
harsh reaction conditions (up to 250 W, 200 °C, 3 h). When
the carboxylate group was in the meta-position with respect to
the chlorine atom (5-chloro-2-nitrobenzoic acid (1d)) the
reaction was also not successful indicating that both, a car-
boxylate group in the ortho-position and an electron-withdrawing
nitro function in the para-position of the chlorobenzene deriva-
tive, are required for the reaction to proceed. On the other hand,
no restrictions were observed for the amine reaction partner.
The described substitution reaction is likely to proceed via an
SNAr addition-elimination mechanism.
Experimental Section
Typical Microwave-Amination Procedure. To an 80 mL
microwave reaction vessel equipped with a magnetic stirring
bar were added 2-chloro-5-nitrobenzoic acid (2.520 g, 12.5
mmol) and 3,5-dimethylaniline (8.8 mL, 75 mmol) to obtain a
homogeneous mixture. The vessel was sealed, and the mixture
was irradiated in a microwave oven (CEM Focused Microwave
type Discover) for 10 min at 100 °C. Then the reaction mixture
was cooled to rt, and the product was subsequently purified
using the following procedure: the contents of the vial were
dissolved in ca. 300 mL of dichloromethane, and the organic
solution was extracted with diluted 0.1 M aq sodium hydroxide
solution (ca. 500 mL). The extraction procedure was repeated
until the aqueous layer became light yellow (three to four times).
Then the aqueous layer was collected and acidified using
concentrated aq hydrochloric acid (37%) until pH e 3 and the
desired product precipitated in the acidic medium. The precipi-
tated solid was filtered off and dried in an oven at 100 °C, and
2-(3,5-dimethylphenylamino)-5-nitrobenzoic acid (3p, 3.04 g,
10.63 mmol, 85% yield) was obtained as a yellow solid, mp
The results show that the new amination protocol provides a
new convenient access to a wide range of N-substituted
(17) Typical Procedure. To an 80 mL microwave reaction vial equipped
with a magnetic stirring bar were added 2-amino-5-nitrobenzoic acid (2.275
g, 12.5 mmol), 1 equiv of the halobenzene, and 2 equiv of K2CO3 dissolved
in an appropriate amount of water, and a mixture of finely powdered copper
(Cu(0)) and cupper(II) sulfate (CuSO4). The mixture was irradiated in the
microwave oven at 150 °C for up to 2 h.
1
278-279 °C. H NMR (500 MHz, DMSO-d6): δ ) 2.48 (s,
5910 J. Org. Chem., Vol. 72, No. 15, 2007

6H, 2CH3), 6.88 (br, 1H), 6.93 (br, 2H), 7.11 (d, 1H, J ) 9.5
Hz), 8.13 (dd, 1H, J ) 2.9 Hz, J ) 9.5 Hz), 8.70 (d, 1H, J )
2.9 Hz), 10.47 (br, 1H, NH), 13.5 (br, 1H, COOH). 13C NMR
(126 MHz, DMSO-d6): δ ) 20.9, 111.7, 113.3, 121.5, 127.3,
128.5, 129.2, 136.5, 138.2, 139.2, 152.5, 168.8. LC-MS (m/z):
287 [M]+, 304 [M + NH4+]+, 285 [M]-, 241 [M - COO-]-.
Anal. Calcd for C15H14N2O4‚0.5H2O: C, 61.00; H, 5.12; N, 9.49.
Found: C, 61.18; H, 4.86; N, 9.44. Purity by HPLC-UV (254
nm)-ESI-MS: 99%.
Acknowledgment. Y.B. thanks the Deutscher Akademischer
Austauschdienst (DAAD) for a Ph.D. Fellowship. Support by
the Deutsche Forschungsgemeinschaft (DFG, GRK804) is
gratefully acknowledged.
Supporting Information Available: Experimental procedures
and analytical data for all compounds (3a-w). This material is
available free of charge via the Internet at http://pubs.acs.org.
JO070731I
J. Org. Chem, Vol. 72, No. 15, 2007 5911