Regioselective copper-catalyzed amination of chlorobenzoic acids: Synthesis and solid-state structures of N-aryl anthranilic acid derivatives

Article abstract of DOI:10.1021/jo0518809

A chemo- and regioselective copper-catalyzed cross-coupling reaction for effective amination of 2-chlorobenzoic acids with aniline derivatives has been developed. The method eliminates the need for acid protection and produces a wide range of N-aryl anthranilic acid derivatives in up to 99% yield. The amination was found to proceed with both electron-rich and electron-deficient aryl chlorides and anilines and also utilizes sterically hindered anilines such as 2,6-dimethylaniline and 2-tert-butylaniline. The conformational isomerism of appropriately substituted N-aryl anthranilic acids has been investigated in the solid state. Crystallographic analysis of seven anthranilic acid derivatives showed formation of two distinct supramolecular architectures exhibiting trans-anti and unprecedented trans-syn dimeric structures.

Full text of DOI:10.1021/jo0518809

Regioselective Copper-Catalyzed Amination of Chlorobenzoic
Acids: Synthesis and Solid-State Structures of N-Aryl Anthranilic
Acid Derivatives
Xuefeng Mei, Adam T. August, and Christian Wolf*
Department of Chemistry, Georgetown UniVersity, Washington, D.C. 20057
cw27@georgetown.edu
ReceiVed September 7, 2005
A chemo- and regioselective copper-catalyzed cross-coupling reaction for effective amination of
2-chlorobenzoic acids with aniline derivatives has been developed. The method eliminates the need for
acid protection and produces a wide range of N-aryl anthranilic acid derivatives in up to 99% yield. The
amination was found to proceed with both electron-rich and electron-deficient aryl chlorides and anilines
and also utilizes sterically hindered anilines such as 2,6-dimethylaniline and 2-tert-butylaniline. The
conformational isomerism of appropriately substituted N-aryl anthranilic acids has been investigated in
the solid state. Crystallographic analysis of seven anthranilic acid derivatives showed formation of two
distinct supramolecular architectures exhibiting trans-anti and unprecedented trans-syn dimeric structures.
3
4
5
Introduction
tions utilizing anilines, amides, imidazoles, and other het-
6
7
erocycles, â-amino alcohols, and aliphatic amines have also
8
Cross-coupling reactions resulting in carbon-heteroatom
been developed.
bond formation have received increasing attention in recent
years. Significant progress has been reported for Pd-catalyzed
Copper-mediated amination of 2-chlorobenzoic acid was first
accomplished by Ullmann. Since then, various efforts to
1
9
amination reactions proceeding with aryl halides under mild
conditions. Alternatively, copper-mediated cross-coupling reac-
improve the efficiency of this reaction involving the use of
ultrasound-assisted methods have been reported. We have
2
10
(
1) (a) Lindley, J. Tetrahedron 1984, 40, 1433-1456. (b) Subramanian,
V.; Batchu, V. R.; Barange, D.; Pal, M. J. Org. Chem. 2005, 70, 4778-
783. (c) Klapars, A.; Parris, S.; Anderson, K. W.; Buchwald, S. L. J. Am.
(3) (a) Gajare, A. S.; Toyota, K.; Yoshifuji, M.; Ozawa, F. Chem.
Commun. 2004, 1994-1995. (b) Ferreira, I. C. F. R.; Queiroz, M.-J. R. P.;
Kirsch, G. Tetrahedron 2002, 58, 7943-7949. (c) Gujadhur, R. K.; Bates,
C. G.; Venkataraman, D. Org. Lett. 2001, 42, 4791-4793. (d) Goodbrand,
H. B.; Hu, N.-X. J. Org. Chem. 1999, 64, 670-674.
4
Chem. Soc. 2004, 126, 3529-3533. (d) Beletskaya, I. P.; Bessmertnykh,
A. G.; Averin, A. D.; Denat, F.; Guilard, R. Eur. J. Org. Chem. 2005, 281-
3
7
05.
(4) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 7421-7428.
(2) (a) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120,
369-7370. (b) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy,
(5) (a) Son, S. U.; Park, I. K.; Park, J.; Hyeon, T. Chem. Commun. 2004,
778-779. (b) Choudary, B. M.; Sridhar, C.; Kantam, M. L.; Venkanna, G.
T.; Sreedhar, B. J. Am. Chem. Soc. 2005, 127, 9948-9949.
(6) (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727-7729. (b) Zhang, H.; Cai, Q.; Ma, D. J. Org.
Chem. 2005, 70, 5164-5173.
K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575-5580. (c)
Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1997, 62, 6066-6068. (d)
Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120,
9
2
722-9723. (e) Hartwig, J. F. Angew. Chem., Int. Ed. Engl. 1998, 37,
046-2067. (f) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L.
Acc. Chem. Res. 1998, 31, 805-818.
(7) Job, G. E.; Buchwald, S. L. Org. Lett. 2002, 4, 3703-3706.
10.1021/jo0518809 CCC: $33.50 © 2006 American Chemical Society
1
42
J. Org. Chem. 2006, 71, 142-149
Published on Web 11/25/2005

Cu-Catalyzed Amination of Chlorobenzoic Acids
TABLE 1. Copper-Catalyzed Amination of 2-Chlorobenzoic Acida
FIGURE 1. Structures of anthranilic acid derivatives used as NSAIDs
and for the treatment of amyloidogenic diseases.
catalyst
(mol %)
reaction
time (h)
yield
(%)
b
entry
1
2
3
4
5
6
7
8
9
CuI (4)
Cu2O (4)
Cu (9)
Cu (9), CuI (4)
Cu (9), Cu O (4)
Cu (12), Cu2O (4)
Cu (9), Cu2O (4)
Cu (6), Cu2O (4)
Cu (4), Cu2O (4)
24
24
24
24
24
5
5
5
5
55
56
55
51
76
66
71
51
51
recently described a copper-catalyzed amination protocol for
the synthesis of substituted N-aryl anthranilic acids, which were
further utilized as precursors for ring construction of 9-chloro-
and 9-bromoacridines.11 N-Aryl anthranilic acids, such as
flufenamic and mefenamic acid, are important nonsteroidal
antiinflammatory drugs (NSAIDs) and promising candidates for
the therapy of neurodegenerative and amyloid diseases (Figure
2
1
2
1
). They are also important precursors for the synthesis of
a
Reaction conditions: 2-chlorobenzoic acid (1.38 g, 8.83 mmol), 1.05
equiv of 2-methylaniline, and 2.0 equiv of potassium carbonate in 3 mL of
-ethoxyethanol at 130°C. b Isolated yields.
substituted acridines which have been used as antimalarial and
1
3
anticancer drugs. Buchwald et al. developed an effective Pd-
catalyzed amination procedure that is applicable to aryl chlorides
2
1
4
with free carboxylic acid groups in the meta or para position.
evaporation, we were able to obtain single crystals of a series
of N-aryl anthranilic acid derivatives. Crystallographic analysis
revealed two distinctive packing motifs exhibiting either a syn
or an anti arrangement of anthranilic acid dimers which are
stabilized by two centrosymmetric CdO‚‚‚H-O hydrogen
bonds. The unprecedented interdependence of the dimeric
arrangement and crystal structure of substituted anthranilic acids
is closely related to supramolecular conformational isomerism.
A complementary copper-catalyzed amination reaction that
proceeds with ortho-chlorobenzoic acid, albeit with only moder-
ate yields, has been reported.15 As a result, N-aryl anthranilic
acid derivatives are usually prepared through the Ullmann-
Jourdan reaction or the Buchwald-Hartwig amination with alkyl
16
2
-iodobenzoates and subsequent hydrolysis. We wish to report
a general synthetic procedure providing substituted N-aryl
anthranilic acids in high to excellent yields via Cu-catalyzed
amination of ortho-chlorobenzoic acids. Through isothermal
Results and Discussion
(
8) (a) Okano, K.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2003, 5,
4
7
987-4990. (b) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793-
For the initial screening of suitable reaction conditions, we
decided to study the formation of N-(2-methylphenyl)anthranilic
acid, 3, from 2-chlorobenzoic acid, 1, and 2-methylaniline, 2,
through copper-catalyzed amination using potassium carbonate
as the base and 2-ethoxyethanol as solvent. The desired
anthranilic acid 3 was obtained in moderate yields with catalytic
amounts of CuI, Cu2O, or Cu (Table 1, entries 1-3). However,
results improved significantly in the presence of both Cu and
Cu2O, and 3 was produced in 71% and 76% yields after 5 and
96. (c) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453-2455. (d)
Lu, Z.; Twieg, R. J.; Huang, S. D. Tetrahedron. Lett. 2003, 44, 6289-
6
292. (e) Maes, B. U. W.; Loones, K. T. J.; Hostyn, S.; Diels, G.; Rombouts,
G. Tetrahedron 2004, 60, 11559-11564. (f) Ezquerra, J.; Pedregal, C.;
Lamas, C.; Barluenga, J.; Perez, M.; Garcia-Martin, M. A.; Gonzalez, J.
M. J. Org. Chem. 1996, 61, 5804-5812. (g) Cacchi, S.; Fabrizi, G.;
Goggiamani, A.; Zappia, G. Org. Lett. 2001, 3, 2539-2541. (h) Artamkina,
G. A.; Sergeev, A. G.; Beletskaya, I. P. Tetrahedron Lett. 2001, 42, 4381-
4
394.
(
9) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382-2384.
(
10) (a) Hanoun, J. P.; Tensglia, A. Synth. Commun. 1995, 25, 2443-
2
4 h, respectively (Table 1, entries 5 and 7). Variation of the
2
2
448. (b) Docampo Palacios, M. L.; Pellon Comdom, R. F. Synth. Commun.
003, 33, 1771-1775.
Cu/Cu2O ratio and replacement of Cu2O by CuI did not further
increase the yields (Table 1, entries 4 and 6-9).
(
11) (a) Wolf, C.; Mei, X. J. Am. Chem. Soc. 2003, 125, 10651-10658.
(
b) Mei, X.; Wolf, C. J. Org. Chem. 2005, 70, 2299-2305. (c) Mei, X.;
We then decided to study the effect of solvent and base on
the amination reaction. Anthranilic acid 3 was obtained in 75%
and 76% yields, respectively, using Cu/Cu2O as the catalyst in
n-butanol or 2-ethoxyethanol in the presence of two equivalents
of potassium carbonate, whereas only poor yields were obtained
in water and ethylene glycol (Table 2, entries 1-4). We were
pleased to find that yields of 3 could be enhanced to 90% when
diethylene glycol or 2-ethoxyethanol was used as the solvent
(Table 2, entries 5 and 12). The Cu/Cu2O-catalyzed amination
of 2-chlorobenzoic acid proved to depend significantly on the
base employed. Comparison of the results obtained with Na2-
CO3, Cs2CO3, K3PO4, NaOAc, tert-BuOK, and 2,2,6,6-tetra-
methylpiperidine (TMP) shows that yields of 3 obtained in
diethylene glycol vary from 5 to 90% (Table 2, entries 5-11).
We found that anthranilic acid 3 was produced in only 5-30%
yields in the presence of cesium carbonate, 2,2,6,6-tetrameth-
ylpiperidine, and tert-BuOK (Table 2, entries 6, 8, and 11). By
contrast, anthranilic acid 3 was formed in 90% and 82% yields
through Cu/Cu2O-catalyzed amination of 1 with 2 using
Wolf, C. J. Am. Chem. Soc. 2004, 126, 14736-14737. (d) Mei, X.; Wolf,
C. Chem. Commun. 2004, 2078-2079.
(12) (a) Oza, V. B.; Petrassi, H. M.; Purkey, H. E.; Kelly, J. W. Bioorg.
Med. Chem. Lett. 1999, 9, 1-6. (b) Green, N. S.; Palaninathan, S. K.;
Sacchettini, J. C.; Kelly, J. W. J. Am. Chem. Soc. 2003, 125, 13404-13414.
(
c) Oza, V. B.; Smith, C.; Raman, B.; 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, 321-332. (d) Baures, P. W.; Oza, V. B.; Peterson, S. A.;
Kelly, J. W. Bioorg. Med. Chem. 1999, 7, 1339-1347. (e) Klabunde, T.;
Petrassi, H. M.; Oza, V. B.; Raman, P.; Kelly, J. W.; Saccettini, J. C. Nat.
Struct. Biol. 2000, 7, 312-321.
(13) (a) Girault, S.; Grellier, P.; Berecibar, A.; Maes, L.; Mouray, E.;
Lemiere, P.; Debeu, M.-A.; Davioud-Charvet, E.; Sergheraert, C. J. Med.
Chem. 2000, 43, 2646-4654. (b) Demeunynck, M.; Charmantray, F.;
Martelli, A. Curr. Pharm. Des. 2001, 7, 1703-1724. (c) Brana, M. F.;
Cacho, M.; De Pascual-Teresa, B.; Ramos, A. Curr. Pharm. Des. 2001, 7,
1
1
745-1780. (d) Cain, B. F.; Seelye, R. N.; Atwee, G. J. J. Med. Chem.
974, 17, 922-928.
(14) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653-6655.
(15) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4,
5
81-584.
(
16) Csuk, R.; Barthel, A.; Raschke, C. Tetrahedron 2004, 60, 5737-
5
750.
J. Org. Chem, Vol. 71, No. 1, 2006 143

Mei et al.
TABLE 3. Arylation of Aryl Chlorides with Aryl Aminesa
TABLE 2. Screening of Solvents and Basesa
T
yield
b
entry
base
solvent
n-butanol
(°C)
(%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
K
K
K
K
K
2
2
2
2
2
CO
CO
CO
CO
CO
3
3
3
3
3
117
100
130
130
130
130
130
130
130
130
130
130
130
130
75
35
40
76
90
5
water
ethylene glycol
2-ethoxyethanol
diethylene glycol
diethylene glycol
diethylene glycol
diethylene glycol
diethylene glycol
diethylene glycol
diethylene glycol
2-ethoxyethanol
2-ethoxyethanol
2-ethoxyethanol
Cs
Na
t-BuOK
PO
2
CO
3
2
CO
3
82
11
70
66
30
92
75
K
3
4
0
1
2
3
4
NaOAc
TMP
d
2
Na CO
3
c
K
K
2
CO
CO
3
c,d
2
3
83
a
Reaction conditions: 2-chlorobenzoic acid (1.38 g, 8.83 mmol), 1.05
equiv of 2-methylaniline, 9 mol % of Cu, 4 mol % of Cu2O, 2.0 equiv of
base, and 3 mL of solvents, at 130°C for 24 h. Isolated yields. c Aniline
b
d
was used. 1.0 equiv of base was used.
K2CO3 or Na2CO3 in diethylene glycol (Table 2, entries 5 and
7). We also observed that the amination proceeds with excellent
yields with one equivalent of sodium or potassium carbonate
in 2-ethoxyethanol (Table 2, entries 12-14).
The copper-catalyzed C-N bond formation procedure was
then applied to a variety of aryl amines and chlorobenzoic acids
to produce a series of N-arylanthranilic acids (Table 3). We
found that the presence of one bulky ortho substituent does not
impede effective amination (Table 3, entries 2-5). For example,
2
-tert-butylaniline, 8, and 2-phenylaniline, 10, gave N-(2-tert-
butylphenyl)anthranilic acid, 9, in 86% yield and N-(2-biphenyl)-
anthranilic acid, 11, in 85% yield (Table 3, entries 4 and 5).
Incorporation of two ortho substituents to aniline, however, was
found to decrease yields; e.g., N-(2,6-dimethylphenyl)anthranilic
acid, 13, was obtained in only 65% yield (Table 3, entry 6).
Coupling of 1-aminonaphthalene or 1-aminopyrene gave the
corresponding products 21 and 23 in 96% and 73% yields (Table
3
, entries 10 and 11). Importantly, no significant electronic
effects were observed in the reaction of substituted anilines and
chlorobenzoic acids. For example, amination of 1 with 4-meth-
oxyaniline, 24, and 4-nitroaniline, 26, proceeded with 84% and
8
7% yields, respectively, and electron-deficient chlorobenzoic
acid 32 gave anthranilic acid 33 in 99% yield (Table 3, entries
2, 13, and 16). The copper-catalyzed amination was found to
1
proceed with high regio- and chemoselectivity. Amination only
occurs when the halide is located in ortho position to the
carboxylic acid moiety. For example, coupling of 2,4-dichlo-
robenzoic acid, 34, with 4-methoxyaniline, 24, gave anthranilic
acid 35 in 86% yield and amination of 5-bromo-2-chlorobenzoic
acid, 36, produced 37 in 85% yield (Table 3, entries 17 and
1
8). Aryl halide bonds located in the aniline moiety are also
not affected. The coupling reaction between 2-chlorobenzoic
acid and 3-chloroaniline, 28, gave 29 in 99% yield (Table 3,
entry 14). The ortho carboxylate group has been known to
effectively accelerate homogeneous copper-catalyzed exchange
reactions. Accordingly, our amination procedure affords high
regioselectivity and tolerates various functionalities thus comple-
a
Reaction conditions: 2-chlorobenzoic acid (1.38 g, 8.83 mmol), 1.05
equiv of amine, 1.0 equiv of K2CO3, 9 mol % of Cu, 4 mol % of Cu2O,
and 3 mL of 2-ethoxyethanol at 130°C for 24 h. Isolated yields. Na2CO3
was used as base. d 2.0 equiv of base were used.
b
c
1
7
menting other methods that allow effective amination of meta-
and para-chlorobenzoic acids.
(17) Couture, C.; Paine, A. J. Can. J. Chem. 1985, 63, 111-120.
144 J. Org. Chem., Vol. 71, No. 1, 2006

Cu-Catalyzed Amination of Chlorobenzoic Acids
CdO‚‚‚H-N hydrogen forces both anthranilic rings into the
same plane. The unit cell of the single crystal of 3 contains
eight molecules forming four centrosymmetric dimers (Figure
4
). Through a Cambridge Structural Database (CSD) search,
we found five additional N-phenylanthranilic acid derivatives
showing acid dimers with the same trans-anti arrangement in
2
1
the solid state.
The dihedral angle, R, between the 2-methylphenyl moiety
and the anthranilic ring of 3 was determined as 49.1° (Figure
5
). Changing the ortho substituent from methyl to iso-propyl,
tert-butyl, and phenyl did not affect the supramolecular archi-
tecture and molecular isomerism. However, the dihedral angle,
R, was found to change from 49.1° (3) to 62.5° (7), 62.8° (9),
and 77.1° (11) (Figure 5). Although the dihedral angle increases
with the bulkiness of the ortho substituent, the almost perpen-
dicular arrangement of the phenyl group is stabilized by
additional π-π interactions between adjacent dimers (Support-
ing Information).
FIGURE 2. Possible arrangements of dimers of 3.
Carboxylic acids are known to form centrosymmetric dimers
in solution and in the solid state to minimize the overall dipole
moment.18 In the case of substituted N-aryl anthranilic acids,
dimer formation could lead to two geometrical arrangements
isolable in the solid state, namely cis and probably favored trans
isomers exhibiting the N-aryl substituents on the same or
opposite sides. In addition, both trans and cis isomers could
exhibit either syn or anti orientation having substituted N-aryl
groups either pointing up or down relative to the anthranilic
plane, as shown for N-(2-methylphenyl)anthranilic acid, 3
The trans-anti dimers of 3, 7, 11, and 15 show one-
dimensional π-π interactions between the anthranilic aromatic
rings (Figure 6). Anthranilic acid 3 formed π-stacking rods with
a closest-contact distance of 3.46 Å. Anthranilic acids 7, 11,
and 15 have a similar packing arrangement, and the correspond-
ing closest-contact distance was determined as 3.50, 3.40, and
3
.46 Å, respectively. However, the bulky tert-butyl group of
anthranilic 9 impedes effective π-stacking which is replaced
by van der Waals interactions (Supporting Information).
(Figure 2).
Surprisingly, anthranilic acids 17 and 19 crystallized as
noncentrosymmetric trans-syn dimers (Figure 5). The confor-
mational isomerism is accompanied by a quite distinct crystal
architecture. In contrast to the formation of π-stacking rods
observed with anthranilic acids 3, 7, 11, and 15, the crystals of
17 and 19 show one-dimensional chains stabilized by π-π
interactions between the tert-butylphenyl and 3,5-dimethylbi-
phenyl rings, respectively. For example, the solid-state structure
of anthranilic acid 17 has a closest-contact distance between
the tert-butylphenyl rings of 3.48 Å (Figure 7). The π-stacking
of the trans-syn dimers results in infinite chains along the
b-axis. Empty space within one chain is filled with a comple-
mentary chain, thus providing one-dimensional intertwined rods.
The unexpected solid-state structures of the anthranilic acids
studied resemble supramolecular conformational isomerism.
Although the crystal structures of acids 3, 7, 9, 11, and 15 show
a previously reported packing motif exhibiting trans-anti
dimers, anthranilic acids 17 and 19 crystallized as dimeric
Supramolecular isomerism has been defined as the existence
of different types of crystal architectures produced from the same
molecular building blocks and is closely related to molecular
19
isomerism and polymorphism. The desire to understand and
rationally design solid-state structures has resulted in remarkable
20
advances in crystal engineering and supramolecular synthesis.
The possibility of four isomeric dimeric structures of anthranilic
acids has led us to the study of solid-state conformational
isomerism. We therefore employed appropriately substituted
anthranilic acids 3, 7, 9, 11, 15, 17, 19, 21, and 29 in
crystallization experiments. Through isothermal evaporation
from methylene chloride solutions, we were able to grow single
crystals of seven anthranilic acids (Figure 3). Anthranilic acids
3
and 11 formed monoclinic systems, and the others gave
triclinic crystals (Table 4). As expected, dimeric N-arylanthra-
nilic acid structures were obtained in all cases. The dimeric
arrangements of 3, 7, 9, 11, and 15 are of the centrosymmetric
trans-anti type. A pair of CdO‚‚‚H-O hydrogen bonds and
FIGURE 3. Structures of N-phenylanthranilic acid derivatives employed in single-crystal analysis.
J. Org. Chem, Vol. 71, No. 1, 2006 145

Mei et al.
FIGURE 4. ORTEP perspectives of anthranilic acid derivatives (a) N-(2-methylphenyl)anthranilic acid 3 and (b) N-(3-tert-butylphenyl)anthranilic
acid 17. Selected interatomic distances (Å) and angles (deg): (a) O(1)‚‚‚O(2) ) 2.224, N(1)‚‚‚O(1) ) 2.636, O(2)-H(2′)‚‚‚O(1) ) 172.79, N(1)-
H(1)‚‚‚O(1) ) 138.32 and (b) O(1)‚‚‚O(3) ) 2.643, O(2)‚‚‚O(4) ) 2.707, N(1)‚‚‚O(2) ) 2.733, N(2)‚‚‚O(3) ) 2.692, O(4)-H(4O)‚‚‚O(2) )
1
64.42, N(1)-H(1)‚‚‚O(2) ) 132.77.
TABLE 4. Crystallographic Parameters of Anthranilic Acid Derivatives
compound
name
3
7
9
11
15
17
19
formula
C14H13NO2
227.25
173
monoclinic
C2/c
11.7804(16)
7.4503(10)
26.627(3)
90
100.168(2)
90
2300.3(5)
8
C16H17NO2
255.31
183
triclinic
P1h
7.4585(10)
7.5891(10)
13.6653(19)
79.998(2)
85.875(2)
62.141(2)
673.42(16)
2
C17H19NO2
269.33
173
triclinic
P1h
7.4748(12)
9.3856(15)
11.0319(17)
106.582(3).
91.207(3)
99.212(3)
730.4(2)
2
C19H15NO2
289.32
183
monoclinic
P21/c
5.7231(8)
17.929(2)
14.4300(19)
90
101.064(2)
90
1453.2(3)
4
C14H13NO2
227.25
173
triclinic
P1h
4.6299(14)
8.332(2)
15.336(4)
98.466(4)
92.198(4)
101.337(4)
572.3(3)
2
C17H19NO2
269.33
163
triclinic
P1h
10.9634(7)
11.7048(7)
22.9688(14)
88.8990(10)
89.0970(10)
82.0050(10)
2918.0(3)
8
C21H19NO2
317.37
173
triclinic
P1h
10.5769(16)
11.4108(17)
14.162(2)
80.856(3)
82.334(3)
84.982(3)
1668.5(4)
4
mol wt
temp (K)
system
space group
a (Å)
b (Å)
c (Å)
R (deg)
â (deg)
γ (deg)
3
V (Å )
Z
3
F (g/cm )
1.312
1.55-27.99
-15 e h e 15
1.259
1.225
1.322
1.319
1.226
1.263
θ range (deg)
1.51-27.99
-9 e h e 9
-9 e k e 10
-17 e l e 18
6018
3054
0.0282
174
0.914
1.93-28.00
-9 e h e 9
-12 e k e 12
-14 e l e 14
6614
3338
0.0231
192
1.060
1.83-27.99
-7 e h e 7
-23 e k e 22
-18 e l e 19
12467
3401
0.0430
199
1.027
2.52-28.00
-76e h e 6
-10 e k e 11
-20 e l e 19
4861
2552
0.0211
155
0.980
1.76-28.00
-14 e h e 14
-15 e k e 15
-30 e l e 29
25329
13122
0.0345
733
1.045
1.95-27.99
-13 e h e 13
-14 e k e 14
-18 e l e 18
14927
7547
0.0309
445
1.032
index ranges
-
-
9 e k e 9
35 e l e 34
9959
reflns collected
unique reflns
R(int)
refined params
GOF on F
2714
0.0410
155
1.020
0.0483
0.1409
2
R1 [I > 2σ(I)]
wR2 (all data)
0.0462
0.1228
0.0414
0.1073
0.0463
0.1127
0.0442
0.1140
0.0618
0.2060
0.0460
0.1154
trans-syn conformers providing an unprecedented supramo-
mmol) in 3 mL of 2-ethoxyethanol was refluxed at 130°C under
inert atmosphere for 24 h. The cooled reaction mixture was poured
into 30 mL of water. Charcoal was then added, and the solution
was filtered through Celite. The crude product was obtained by
precipitation upon acidification of the filtrate with diluted HCl. The
lecular architecture.
Conclusion
We have developed a highly regioselective Cu/Cu2O-
catalyzed cross-coupling reaction for effective C-N bond
formation with 2-chlorobenzoic acids and aniline derivatives.
The reaction complements existing methods, tolerates a variety
of functional groups, and gives high to excellent yields with
both electron-deficient and electron-rich reagents. Crystal-
lographic analysis of seven substituted N-aryl anthranilic acids
showed two distinct supramolecular structures due to formation
of trans-anti and trans-syn dimers in the solid state.
2 3
residue was dissolved in 100 mL of 5% aqueous Na CO solution
and filtered through Celite, and the final product was isolated by
precipitation upon careful pH adjustment.
(18) Desiraju, G. R. Angew. Chem., Int. Ed. Engl. 1995, 34, 2311-2327.
(
19) (a) Moulton, B.; Zaworotko, M. J. Chem. ReV. 2001, 101, 1629-
1
658. (b) Swift, J. A.; Pivovar, A. M.; Reynolds, A. M.; Ward, M. D. J.
Am. Chem. Soc. 1998, 120, 5887-5894.
(20) (a) Desiraju, G. R. Crystal Engineering: The Design of Organic
Solids; Elsevier: Amsterdam, 1989. (b) Reddy, D. S.; Craig, D. C.; Desiraju,
G. R. J. Am. Chem. Soc. 1996, 118, 4090-4093. (c) Desiraju, G. R. Acc.
Chem. Res. 2002, 35, 565-573. (d) Gavezzotti, A. Acc. Chem. Res. 1994,
Experimental Section
2
7, 309-314.
(
21) N-(2-Methoxyphenyl)anthranilic acid, N-(2-carboxyphenyl)anthra-
General Procedure for the Cu-Catalyzed Amination of Aryl
Halides. A mixture of aniline (9.30 mmol), aryl halide (8.83 mmol),
nilic acid, N-(2′-carboxy-5′-chlorophenyl)-4-chloroanthranilic acid, N-(2-
methyl-3-chlorophenyl)anthranilic acid, and N-(3-methyl-2,6-dichlorophenyl)-
anthranilic acid.
2 3 2
K CO (8.83 mmol), Cu powder (0.78 mmol), and Cu O (0.35
146 J. Org. Chem., Vol. 71, No. 1, 2006

Cu-Catalyzed Amination of Chlorobenzoic Acids
FIGURE 5. X-ray crystal structures of anthranilic acids 3, 7, 9, 11, 15, 17, and 19 exhibiting trans-anti (left) and trans-syn (right) dimeric
conformations.
1
1
H), 9.18 (bs, 1H). 13C NMR (75 MHz, DMSO-d
16.9, 122.6, 124.0, 126.6, 130.9, 131.3, 134.0, 138.7, 148.6.
N-Phenylanthranilic Acid (5).22 Anthranilic acid 5 was obtained
6
) δ ) 17.6, 113.4,
from 2-chlorobenzoic acid, 1, and aniline, 4, as a white solid in
1
8
8
5
3
3% yield. H NMR (300 MHz, CDCl ) δ ) 6.75 (dd, J ) 7.9 Hz,
.3 Hz, 1H), 7.13 (dd, J ) 7.3 Hz, 8.6 Hz, 1H), 7.20-7.50 (m,
H), 8.05 (d, J ) 7.6 Hz, 1H), 9.33 (bs, 1H). 13C NMR (75 MHz,
CDCl ) δ ) 111.0, 114.7, 117.8, 123.8, 124.7, 130.0, 133.2, 135.8,
3
1
40.9, 149.5, 174.3.
N-(2-Isopropylphenyl)anthranilic Acid (7).12a Amination of
2
-chlorobenzoic acid, 1, and 2-isopropylaniline, 6, gave anthranilic
1
acid 7 as a white powder in 73% yield. H NMR (300 MHz, CDCl
3
)
δ ) 1.22 (d, J ) 6.9 Hz, 6H), 3.21 (sept, J ) 6.9 Hz, 1H), 4.68
bs, 1H), 6.68 (dd, J ) 7.2 Hz, 7.4 Hz, 1H), 6.81 (d, J ) 8.2 Hz,
H), 7.22-7.40 (m, 4H), 8.1 (dd, J ) 1.7 Hz, 8.2 Hz, 1H), 9.18
(
1
13
(bs, 1H). C NMR (75 MHz, DMSO-d
6
): δ ) 23.6, 28.4, 112.0,
1
1
13.6, 117.0, 125.7, 126.1, 127.1, 127.3, 132.5. 135.0, 137.9, 143.6,
49.8, 171.0.
N-(2-tert-Butylphenyl)anthranilic Acid (9).23 Anthranilic acid
9
was produced from 2-chlorobenzoic acid, 1, and 2-tert-butyla-
1
FIGURE 6. One-dimensional π-stacking of anthranilic acid 3 (top)
and schematic illustration of the trans-anti dimers and packing motif
niline, 8, as white crystals in 86% yield. H NMR (300 MHz,
CDCl
(d, J ) 8.6 Hz, 1H), 7.17-7.28 (m, 4H), 7.47-7.50 (m, 1H), 8.02
3
(d, J ) 8.1 Hz, 1H), 9.21 (bs, 1H). C NMR (75 MHz, CDCl ) δ
3
) δ ) 1.41 (s, 9H), 6.65 (dd, J ) 7.0 Hz, 7.9 Hz, 1H), 7.15
(bottom).
N-(2-Methylphenyl)anthranilic Acid (3).12a Compound 3 was
13
obtained from 2-chlorobenzoic acid, 1, and 2-methylaniline, 2, as
1
an off-white powder in 92% yield. H NMR (300 MHz, CDCl
2.29 (s, 3H), 6.72 (bs, 1H), 6.85 (d, J ) 8.2 Hz, 1H), 7.12 (dd,
J ) 7.2 Hz, 7.4 Hz, 1H), 7.20-7.34 (m, 5H), 8.05 (d, J ) 7.2 Hz,
3
) δ
(
22) Scherrer, R. A.; Beatty, H. R. J. Org. Chem. 1980, 45, 2127-2131.
)
(23) Denny, W. A.; Twigden, S. J.; Baguley, B. C. Anti-Cancer Drug
Des. 1986, 1, 125-132.
J. Org. Chem, Vol. 71, No. 1, 2006 147

Mei et al.
FIGURE 7. Formation of intertwined rods in the crystal structure of anthranilic acid 17 (top) and schematic illustration of the packing of the
trans-syn dimers (bottom).
1
)
31.3, 35.7, 110.0, 114.8, 116.7, 126.6, 127.6, 128.1, 129.8, 133.1,
20, as an off-white solid in 96% yield. H NMR (300 MHz, CDCl
3
)
1
35.9, 139.4, 147.1, 151.4, 173.7.
δ ) 6.73 (dd, J ) 7.3 Hz, 7.6 Hz, 1H), 6.85 (d, J ) 8.6 Hz, 1H),
N-(2-Biphenyl)anthranilic Acid (11).24 Acid 11 was obtained
7.23-7.29 (m, 1H), 7.46-7.51 (m, 4H), 7.75 (d, J ) 7.6 Hz, 1H),
13
from 2-chlorobenzoic acid, 1, and 2-aminobiphenyl, 10, as a white
7.89-7.92 (m, 1H), 8.08 (m, 2H), 9.60 (bs, 1H). C NMR (75
1
solid in 85% yield. H NMR (300 MHz, CDCl
H), 6.72 (dd, J ) 7.2 Hz, 7.7 Hz, 1H), 7.20-7.52 (m, 11H), 7.94
d, J ) 8.3 Hz, 1H), 9.18 (bs, 1H). 13C NMR (75 MHz, CDCl
) δ
111.4, 114.7, 117.7, 123.7, 124.8, 128.0, 128.6, 129.0, 129.7,
3
) δ ) 4.74 (bs,
3
MHz, CDCl ) δ )110.5, 114.2, 117.5, 122.8, 123.5, 126.5, 126.5,
1
(
127.1, 129.1, 130.8, 133.1, 135.5, 136.0, 136.9, 151.2, 174.2.
N-(1-Pyrenyl)anthranilic Acid (23). Amination of 2-chloroben-
zoic acid, 1, and 1-aminopyrene, 22, afforded anthranilic acid 23
3
)
1
1
31.7, 133.1, 135.6, 136.9, 138.2, 139.5, 149.3, 174.2.
as an off-white solid in 73% yield. H NMR (300 MHz, DMSO-
N-(2,6-Dimethylphenyl)anthranilic Acid (13).25 Amination of
d ) δ ) 6.94 (dd, J ) 7.4 Hz, 7.4 Hz, 1H), 7.14 (d, J ) 8.3 Hz,
6
2-chlorobenzoic acid, 1, and 2,6-dimethylaniline, 12, afforded acid
1H), 7.43 (dd, J ) 8.0 Hz, 7.4 Hz, 1H), 8.09-8.41 (m, 10H), 10.7
1
13
13 as a white powder in 65% yield. H NMR (300 MHz, CDCl
3
)
(bs, 1H). C NMR (75 MHz, DMSO-d ) δ ) 114.2, 118.1, 122.0,
6
δ ) 2.21 (s, 6H), 6.22 (d, J ) 8.5 Hz, 1H), 6.66 (dd, J ) 7.1 Hz,
122.1, 124.8, 124.9, 125.4, 125.7, 125.8, 126.4, 126.7, 127.2, 128.0,
128.2, 131.4, 131.7, 133.6, 134.6, 135.2, 148.8, 172.7. Anal. Calcd
for C H NO : C, 81.88; H, 4.48; N, 4.15. Found: C, 81.63; H,
7
1
.1 Hz, 1H), 7.10-7.20 (m, 3H), 7.24 (dd, J ) 7.6 Hz, 7.8 Hz,
H), 8.04 (d, J ) 7.6 Hz, 1H), 8.88 (bs, 1H). 13C NMR (75 MHz,
23
15
2
CD
35.9, 137.0, 149.9, 173.8.
N-(3-Methylphenyl)anthranilic Acid (15). Compound 15 was
obtained from 2-chlorobenzoic acid, 1, and 3-methylaniline, 14, as
3
OD) δ ) 18.5, 112.0, 115.7, 126.3, 128.3, 132.8, 134.1, 135.6,
4.74; N, 4.32.
1
N-(4-Methoxyphenyl)anthranilic Acid (25).16 Anthranilic acid
5 was obtained from 2-chlorobenzoic acid, 1, and 4-methoxya-
niline, 24, as a white powder in 84% yield. H NMR (300 MHz,
) δ ) 3.83 (s, 3H), 6.68 (dd, J ) 7.3 Hz, 7.3 Hz, 1H), 6.93
dd, J ) 8.6 Hz, 8.6 Hz, 3H), 7.18 (d, J ) 8.6 Hz, 2H), 7.26-7.32
m, 1H), 8.0 (d, J ) 8.6 Hz, 1H), 9.60 (bs, 1H). C NMR (75
) δ ) 55.2, 111.4, 112.8, 114.8, 116.3, 125.1, 131.9,
33.0, 134.2, 148.9, 156.1, 170.2.
N-(4-Nitrophenyl)anthranilic Acid (27).16 Anthranilic acid 27
was produced from 2-chlorobenzoic acid, 1, and 4-nitroaniline, 26,
25
2
1
1
a white solid in 80% yield. H NMR (300 MHz, CDCl
3
) δ ) 2.39
CDCl
3
(
s, 3H), 6.79 (bs, 1H), 6.97 (d, J ) 7.31 Hz, 1H), 7.00-7.15 (m,
(
(
2
1
1
H), 7.25-7.30 (m, 2H), 7.38 (m, 1H), 8.10 (m, 1H), 9.25 (bs,
13
H). 13C NMR (75 MHz, DMSO-d
22.0, 123.8, 129.2, 132.5, 134.0, 138.9, 140.5, 147.5.
6
) δ ) 21.0, 113.9, 117.3, 118.3,
MHz, DMSO-d
6
1
N-(3-tert-Butylphenyl)anthranilic Acid (17). Acid 17 was
produced by amination of 2-chlorobenzoic acid, 1, and 3-tert-
butylaniline, 16, as a white solid in 85% yield. H NMR (300 MHz,
CDCl
1
1
as a yellow solid in 87% yield. H NMR (300 MHz, CD
3
OD) δ )
3
) δ )1.34 (s, 9H), 6.74 (dd, J ) 0.7 Hz, 7.4 Hz, 1H), 7.10
7
2
.22 (dd, J ) 7.1 Hz, 7.8 Hz, 1H), 7.50 (m, 2H), 7.68-7.78 (m,
H), 8.26 (d, J ) 8.1 Hz, 1H), 8.36-8.36 (m, 2H). C NMR (75
OD) δ ) 118.1, 118.2, 118.8, 122.2, 127.1, 133.7, 135.3,
(
d, J ) 7.3 Hz, 1H), 7.16-7.37 (m, 5H), 8.05 (dd, J ) 1.5 Hz, 8.1
13
13
Hz, 1H), 9.29 (bs, 1H). C NMR (75 MHz, DMSO-d
3
1
6
) δ ) 31.0,
4.4, 112.4, 113.5, 117.2, 118.7, 118.9, 120.3, 129.0, 132.0, 134.1,
40.1, 147.4, 152.2, 170.1. Anal. Calcd for C17 20ClNO : C, 66.77;
MHz, CD
3
142.6, 145.4, 150.0, 171.5.
H
2
N-(3-Chlorophenyl)anthranilic Acid (29).28 Amination of
-chlorobenzoic acid, 1, and 3-chloroaniline, 28, gave anthranilic
acid, 29, as an off-white solid in 99% yield. H NMR (300 MHz,
H, 6.59; N, 4.58. Found: C, 67.27; H, 7.16; N, 4.93. (The HCl salt
was formed by addition of hydrogen chloride (diethyl ether, 2.0
M) for elemental analysis.)
2
1
CDCl ) δ ) 6.82 (dd, J ) 7.3 Hz, 7.6 Hz, 1H), 7.08 (d, J ) 7.8
3
N-[3-(3′,5′-Dimethylbiphenyl)]anthranilic Acid (19).26 Anthra-
nilic acid 19 was obtained from 2-chlorobenzoic acid, 1, and
Hz, 1H), 7.14 (d, J ) 7.8 Hz, 1H), 7.26-7.30 (m, 3H), 7.40 (dd,
J ) 7.6 Hz, 7.8 Hz, 1H), 8.06 (d, J ) 7.3 Hz, 1H), 9.32 (bs, 1H).
3-amino-3′,5′-dimethylbiphenyl, 18, as an off-white solid in 99%
13
C NMR (75 MHz, CDCl ) δ ) 114.2, 114.7, 118.5, 118.8, 119.9,
3
1
yield. H NMR (300 MHz, CDCl
3
) δ ) 2.39 (s, 6H), 4.43 (s, 2H),
1
22.1, 130.9, 132.0, 133.9, 134.0, 142.6, 145.8, 169.9.
6
8
2
1
.77 (dd, J ) 7.1 Hz, 7.6 Hz, 1H), 7.02 (s, 1H), 7.22-7.50 (m,
N-(4-Carboxyphenyl)anthranilic Acid (31).27 Anthranilic acid
1 was obtained from 2-chlorobenzoic acid, 1, and 4-aminobenzoic
H), 8.06 (d, J ) 8.0 Hz, 1H). 1 C NMR (75 MHz, CDCl
3
3
) δ )
3
1.7, 113.7, 114.4, 115.9, 117.5, 121.9, 122.1, 123.1, 125.2, 128.7,
29.3, 129.8, 133.9, 135.3, 138.5, 140.9, 143.0, 149.1. Anal. Calcd
acid, 30, using two equivalents of K
2
CO
OD) δ ) 7.00-7.06 (m, 1H), 7.37
d, J ) 8.8 Hz, 2H), 7.56-7.59 (m, 2H), 7.98 (d, J ) 8.8 Hz, 2H),
8.04 (d, J ) 8.3 Hz, 1H), 9.91 (bs, 1H).
OD) δ ) 115.3, 116.2, 117.9, 119.6, 123.5, 131.2, 132.0, 134.1,
3
as a white solid in 98%
1
yield. H NMR (300 MHz, CD
3
for C21
.23; N, 4.32.
N-(1-Naphthyl)anthranilic Acid (21).27 Anthranilic acid 21 was
obtained from 2-chlorobenzoic acid, 1, and 1-aminonaphthalene,
2
H19NO : C, 79.50; H, 5.99; N, 4.42. Found: C, 79.10; H,
(
6
13
3
C NMR (75 MHz, CD -
144.6, 145.6, 167.1, 169.7.
N-(4-Methoxyphenyl)-4-nitroanthranilic Acid (33).26 Anthra-
nilic acid 33 was obtained from 2-chloro-4-nitrobenzoic acid, 32,
and 4-methoxyaniline, 24, as a yellow solid in 99% yield. H NMR
OD) δ ) 3.98 (s, 3H), 5.07 (bs, 1H), 7.05-7.20
m, 3H), 7.32 (d, J ) 8.5 Hz, 2H), 7.40 (d, J ) 8.8 Hz, 1H), 8.05
(24) Graboyes, H.; Anderson, E. L.; Levinson, S. H.; Resnick, T. M. J.
Heterocycl. Chem. 1975, 12, 1225-1231.
1
(
25) Thilo, D.; Von Kaulla, K. N. J. Med. Chem. 1970, 13, 503-510.
(26) Dokorou, V.; Demertzis, M. A.; Jasinski, J. P.; Kovala-Demertzi,
(300 MHz, CD
3
D. J. Organomet. Chem. 2004, 689, 317-325.
(
(27) Szczepankiewicz, B. G.; Liu, G.; Hajduk, P. J.; Abad-Zapatero, C.;
Pei, Z.; Xin, Z.; Lubben, T. H.; Trevillyan, J. M.; Stashko, M. A.; Ballaron,
S. J.; Liang, H.; Huang, F.; Hutchins, C. W.; Fesik, S. W.; Jirousek, M. R.
J. Am. Chem. Soc. 2003, 125, 4087-4096.
(28) Dheyongera, J. P.; Geldenhuys, W. J.; Dekker, T. G.; Van der Schyf,
C. J. Bioorg. Med. Chem. 2005, 13, 689-698.
148 J. Org. Chem., Vol. 71, No. 1, 2006

Cu-Catalyzed Amination of Chlorobenzoic Acids
(
1
1
s, 1H). 13C NMR (75 MHz, CD
3
OD/DMSO-d
16.1, 116.2, 121.6, 126.7, 126.9, 132.5, 134.4, 135.3, 149.8, 158.6,
70.6.
N-(4-Methoxyphenyl)-4-chloroanthranilic Acid (35).26 Com-
6
) 10:1) δ ) 55.0,
DMSO-d
133.7, 134.2, 148.3, 157.0, 169.8. Anal. Calcd for C14
C, 52.20; H, 3.75; N, 4.35. Found: C, 52.08; H, 3.72; N, 4.78.
6
) δ ) 55.8, 113.5, 115.4, 120.1, 125.8, 131.4, 133.3,
H
12BrNO :
3
pound 35 was produced from 2,4-dichlorobenzoic acid, 34, and
Acknowledgment. Funding from the National Science
Foundation (CAREER Award, Grant CHE-0347368), the Na-
tional Institutes of Health (R01 AI060792), and the donors of
the Petroleum Research Fund, administered by the American
Chemical Society (Grant PRF40897-G4), are gratefully ac-
knowledged.
1
4
-methoxyaniline, 24, as an off-white powder in 86% yield. H
NMR (300 MHz, CDCl ) δ ) 3.83 (s, 3H), 6.87 (d, J ) 9.2 Hz,
H), 6.92 (d, J ) 8.9 Hz, 2H), 7.15 (d, J ) 8.9 Hz, 2H), 7.19-
3
1
7
13
.24 (m, 1H), 7.95 (d, J ) 2.5 Hz, 1H), 9.05 (bs, 1H). C NMR
3
(75 MHz, CDCl ) δ ) 56.2, 111.52, 115.4, 121.2, 126.9, 132.1,
133.1, 133.5, 135.5, 149.5, 157.7, 173.1.
N-(4-Methoxyphenyl)-4-bromoanthranilic Acid (37). Amina-
tion of 4-bromo-2-chlorobenzoic acid, 36, and 4-methoxyaniline,
4, afforded anthranilic acid 37 as an off-white solid in 85% yield.
Supporting Information Available: Single-crystal structures,
NMR spectra, and CIF files. This material is available free of charge
via the Internet at http://pubs.acs.org.
2
1
H NMR (300 MHz, CDCl
Hz, 1H), 6.92 (d, J ) 8.5 Hz, 2H), 7.15 (d, J ) 8.5 Hz, 2H), 7.30-
.35 (m, 1H), 8.10 (s, 1H), 9.10 (bs, 1H). C NMR (75 MHz,
3
) δ ) 3.83 (s, 3H), 6.82 (d, J ) 9.0
13
7
JO0518809
J. Org. Chem, Vol. 71, No. 1, 2006 149