Design and synthesis of some new N-phenylanthranilic acids from highly sterically hindered anilines

Article abstract of DOI:10.1080/00397911.2011.631074

Some new N-phenylanthranilic acids were designed and synthesized from highly sterically hindered anilines in an efficient and convenient method using CuI as catalyst with microwave irradiation and conventional heating.

Full text of DOI:10.1080/00397911.2011.631074

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Design and Synthesis of Some New N-
Phenylanthranilic Acids from Highly
Sterically Hindered Anilines
Zhenghua Li a , Gang Chen a , Shu Qiao b , Ronghui Liang a , Cong Lan
a & Zhining Xia a
a College of Chemistry and Chemical Engineering, Chongqing
University, Chongqing, China
b College of Chemistry and Environmental Engineering, Chongqing
Three Gorges University, Wanzhou, Chongqing, China
Accepted author version posted online: 29 Feb 2012.Version of
record first published: 21 Feb 2013.
To cite this article: Zhenghua Li , Gang Chen , Shu Qiao , Ronghui Liang , Cong Lan & Zhining Xia
(2013): Design and Synthesis of Some New N-Phenylanthranilic Acids from Highly Sterically Hindered
Anilines, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 43:9, 1270-1279
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Synthetic Communications1, 43: 1270–1279, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.631074
DESIGN AND SYNTHESIS OF SOME NEW
N-PHENYLANTHRANILIC ACIDS FROM HIGHLY
STERICALLY HINDERED ANILINES
Zhenghua Li,1 Gang Chen,1 Shu Qiao,2 Ronghui Liang,1
Cong Lan,1 and Zhining Xia1
1College of Chemistry and Chemical Engineering, Chongqing University,
Chongqing, China
2College of Chemistry and Environmental Engineering, Chongqing Three
Gorges University, Wanzhou, Chongqing, China
GRAPHICAL ABSTRACT
Abstract Some new N-phenylanthranilic acids were designed and synthesized from highly
sterically hindered anilines in an efficient and convenient method using CuI as catalyst with
microwave irradiation and conventional heating.
Keywords Copper(I) iodide; highly sterically hindered anilines; microwave irradiation;
N-phenylanthranilic acids
INTRODUCTION
N-Phenylanthranilic acids, such as mefenamic acid, are important nonsteroidal
anti-inflammatory drugs (NSAIDs)[1] and crucial intermediates for the synthesis of
acridones and acridines, which possess bioactivity such as antimalarial and
anticancer properties.[2–4] Ullmann first reported the synthesis of N-phenyanthranilic
acids from 2-chlorobenzoic acid in 1903.[5] Since then, chemists have improved
the efficiency of this reaction by use of various copper catalysts, such as copper
powder,[6–9] copper acetate,[10] anhydrous copper sulfate,[11,12] copper=cuprous
Received May 17, 2011.
Address correspondence to Zhining Xia, College of Chemistry and Chemical Engineering,
Chongqing University, Shazheng Street No. 174, Shapingba District, Chongqing 400030, China.
E-mail: chem_lab_cqu@yahoo.com.cn
1270

NEW N-PHENYLANTHRANILIC ACIDS
1271
Scheme 1. Coupling reaction of o-chlorobenzoic acid with anilines using CuI as catalyst.
oxide,[13,14] and so on. Palladium-catalyzed C-N coupling reactions exhibiting free
carboxylic acids groups in the meta or para position have been reported.[15] More-
over, besides conventional heating, ultrasound-assisted[8] or microwave-assisted[11,12]
methods have been applied to enhance reaction rates for synthesis of
N-phenylanthranilic acids.
Quantitative structure–activity relationship on NSAIDs indicated that the sub-
stituents at the 20- and 30-positions of mefenamic acid exert a steric effect to favor a
nonplanar arrangement between the benzene ring and anthranilic acid, which is
important in the effective interaction of mefenamic acid at its inhibitory site.[16,17]
It is presumed that N-phenylanthranilic acids that have a nonplanar arrangement,
such as mefenamic acid, would possess anti-inflammatory activity. However, to our
knowledge, there are few relevant studies on the synthesis of N-phenylanthranilic
acids from highly sterically hindered anilines at present, such as 2-((2,6-
dimethylphenyl)amino)benzoic acid (3a)[13,14,18] and 2-((2,3-dimethylphenyl)amino)
benzoic acid (3b).[7]
In this article, we report an efficient and convenient method for the synthesis of
N-phenylanthranilic acids from highly sterically hindered anilines using CuI as cata-
lyst under microwave irradiation and conventional heating, respectively (Scheme 1).
Some of the target compounds are reported for the first time and expected to possess
anti-inflammatory activity.
RESULTS AND DISCUSSION
At first, the synthesis of N-phenylanthranilic acids from the coupling reaction
of o-chlorobenzoic acid (1a) and 2,6-dimethylaniline (2a) was studied to optimize the
reaction conditions under microwave irradiation. In the solvents tested for this reac-
tion, it was found that the best result was obtained in dimethylformanide (DMF).
Later, the effect of catalyst amount was examined, and the optimal yield of product
was obtained when 8 mol% of CuI was used. To study the effect of temperature, the
model reactions were performed at three different temperatures (110, 140, and

1272
Z. LI ET AL.
Table 1. Optimization of the reaction conditionsa
Entry
CuI (mol%)
Solvent
T (ꢀC)
Time (min)
Yield (%)b
1
2
3
4
5
6
7
8
8
8
Water
Water
Water
DMF
DMF
DMF
DMF
DMF
100
120
140
140
140
140
110
150
90
30
30
10
10
10
30
10
25
32
40
63
55
46
22
61
8
8
12
4
8
8
aAll the reactions were carried out with o-chlorobenzoic acid (4 mmol), 2,6-dimethylaniline (8 mmol),
potassium carbonate (2 mmol), and solvent (3 mL) under microwave irradiation.
bYields refer to the isolated pure prouducts.
150 ꢀC). The best yield has been obtained at 140 ꢀC. The results are summarized in
Table 1.
Under the optimized conditions, the reactions of o-chlorobenzoic acids with a
variety of highly sterically hindered anilines were performed to produce a series of
N-phenylanthranilic acids, and the results are listed in Table 2. Incorporation of
the ortho substituents to aniline has impeded effective amination, so only moderate
yield was obtained in all the reactions. It was found the presence of more bulky ortho
substituents for anilines causes lower yields. For example, 2,6-dimethylaniline, 2a,
and 2,6-diisopropylaniline, 2f, gave 2-((2,6-dimethylphenyl)amino)benzoic acid, 3a,
in 63% yield and 2-((2,6-diisopropylphenyl)amino)benzoic acid, 3f, in 48% yield
(Table 2, entries 1 and 6). It is noteworthy that Dokorou et al.[18] reported the for-
mation of 3a in only 24% yield by copper(II) acetate–promoted amination of 2-bro-
mobenzoic acid (145 ꢀC, 3 h), and Mei et al.[13] also reported the formation of 3a in
65% yield by copper=cuprous oxide–promoted amination of 2-chlorobenzoic acid
(130 ꢀC, 24 h). It is thus clear that copper(I) iodide is a good catalyst for amination
of o-chlorobenzoic acids with highly sterically hindered anilines with moderate yields
in a short reaction time.
The high regio- and chemoselectivity was found in the reactions of 2,4-dichlor-
obenzoic acid (1a) with different anilines (Table 2, entries 8–13). Amination only
occurred when the halide was located in the ortho position of the carboxylic acid
moiety, which suggested the carboxylic acid moiety may direct the amination
through coordination with the Cu catalyst.[19] The same phenomena had been
reported by Mei.[13] Moreover, it was found that the presence of chlorine atoms at
the para position of 1b could improve amination. For example, coupling of 2,4,6-tri-
methylaniline with 2-chlorobenzoic acid or 2,4-dichlorobenzoic acid gave the corre-
sponding products 3c and 3j in 64% and 79% yield (Table 2, entries 3 and 10).
To investigate the difference between the microwave irradiation and conven-
tional heating, all the reactions were processed at the same conditions under conven-
tional heating. The results are shown in Table 2. There was shorter reaction time and
fewer by-products under microwave irradiation than with conventional heating,
which indicated the actual temperature on the catalyst should be greater than the
bulk solution.[20]

1273

1274

NEW N-PHENYLANTHRANILIC ACIDS
1275
CONCLUSION
In conclusion, some new N-phenylanthranilic acids were synthesized from
highly sterically hindered anilines in an efficient and convenient method using CuI
as catalyst under microwave irradiation and conventional heating. Preliminary inves-
tigations on the anti-inflammatory activity of the new N-phenylanthranilic acids 3
will be reported elsewhere.
EXPERIMENTAL
Staring materials were purchased from commercial sources and used without
further purification. Microwave experiments were carried out in the CEM reactor.
The course of the reactions was monitored by thin-layer chromatography (TLC)
on GF254 silica-gel chromatoplates using a mixture of chloroform and methanol
as developing solvent system and visualization with ultraviolet (UV) irradiation at
254 nm. Melting points were measured using a micro-melting-point apparatus and
are uncorrected. Infrared (IR) spectra were recorded on a Shimadzu IR Affinity-1
spectrometer. All 1H NMR and 13C NMR spectra were recorded on a Bruker
500-MHz spectrometer with dimethylsulfoxide (DMSO-d6) as the solvent. Chemicals
shifts were reported in values (ppm) relative to internal tetramethylsilane (TMS).
High-resolution mass spectra (HRMS) were recorded on a Micromass GCT-MS
spectrometer with the electron ionization (EI) mode.
General Procedure
N-phenylanthranic acids were synthesized from highly sterically hindered
anilines under microwave irradiation and conventional heating.
A mixture of 2-chlorbenzoic acid (4 mmol), aniline derivatives (8 mmol), anhy-
drous potassium carbonate (2 mmol), 8 mol% copper (I) iodide, and dimethylforma-
mide (DMF) (3 mL) was placed into a 10-mL reaction vessel. After the vessel was
sealed, the sample was irradiated for the time at the temperature measured by the
IR radiation thermometer indicated in Table 2. The reaction mixture was subse-
quently cooled to 50 ꢀC by compressed air, the vessel was opened, and the TLC
was used to monitor the progress of the reaction until the starting material disap-
peared. The mixture was acidified with aqueous HCl solution upon the careful pH
adjustment and then left to stand overnight in cold storage. The solid was filtered
off and dried under vacuum conditions. The crude product was purified by flash
columm chromatography on silica gel (eluent: gradient CHCl3=CH3OH, 100:0 to
20:1) to provide the desired product. The yields are listed in Table 2. All the reactions
were processed at the same conditions under conventional heating.
Spectroscopic Data and Melting Points for Compounds in Table 2
2-((2,6-Dimethylphenyl)amino)benzoic acid (3a). Mp 205–206 ꢀC (lit.[18]
1
209–210 ꢀC); FT-IR (KBr): nN-H 3346, nC¼O 1654, 1577 cmꢁ1; H NMR (DMSO-
d6, 500 MHz): d ¼ 2.12 (s, 6H, CH3), 6.08 (d, J ¼ 8.00 Hz, 1H, ArH), 6.64 (t,
J ¼ 7.50 Hz, 1H, Ar-H), 7.13–7.19 (m, 3H, Ar-H), 7.25 (t, J ¼ 7.50 Hz, 1H, Ar-H),

1276
Z. LI ET AL.
8.75 (d, J ¼ 7.50 Hz, 1H, Ar-H), 9.17 (s, 1H, NH), 12.94 (1H, COOH) ppm. HRMS:
found 241.1102; calcd. 241.1103 for C15H15NO2.
2-((2,3-Dimethylphenyl)amino)benzoic acid (3b). Mp 226–228 ꢀC (lit.[7]
1
228–230 ꢀC); FT-IR (KBr): nN-H 3314, nC¼O 1653, 1577 cmꢁ1; H NMR (DMSO-
d6, 500 MHz): d ¼ 2.10 (s, 3H, CH3), 2.29 (s, 3H, CH3), 6.70 (t, J ¼ 8.00 Hz, 2H,
Ar-H), 7.02–7.13 (m, 3H, Ar-H), 7.30 (t, J ¼ 8.00 Hz, 1H, Ar-H), 7.80 (dd,
J ¼ 8.00 Hz, 1.50 Hz, 1H, Ar-H), 9.46 (s, 1H, NH), 13.01 (s, 1H, COOH) ppm.
HRMS: found 241.1106; calcd. 241.1103 for C15H15NO2.
2-(Mesitylamino)benzoic acid (3c). Mp 229–230 ꢀC; FT-IR (KBr): nN-H
3350, nC¼O 1653, 1573 cmꢁ1
;
1H NMR (DMSO-d6, 500 MHz): d ¼ 2.07 (s, 6H,
CH3), 2.27 (s, 3H, CH3), 6.06 (d, J ¼ 8.00 Hz, 1H, Ar-H), 6.62 (t, J ¼ 7.50 Hz, 1H,
Ar-H), 6.99 (s, 2H, Ar-H), 7.23 (t, J ¼ 8.00 Hz, 1H, Ar-H), 7.86 (dd, J ¼ 8.00 Hz,
1.50 Hz, 1H, Ar-H), 9.07 (s, 1H, NH), 12.87 (s, 1H, COOH) ppm. HRMS: found
255.1265; calcd. 255.1259 for C16H17NO2.
2-((2-Ethyl-6-methylphenyl)amino)benzoic acid (3d). Mp 153–155 ꢀC;
1
FT-IR (KBr): nN-H 3343, nC¼O 1653, 1573 cmꢁ1; H NMR (DMSO-d6, 500 MHz):
d ¼ 1.06 (t, J ¼ 7.50 Hz, 3H, CH3), 2.10 (s, 3H, CH3), 2.47 (t, J ¼ 7.50 Hz, 2H,
CH2), 6.08 (d, J ¼ 8.50 Hz, 1H, Ar-H), 6.63 (t, J ¼ 7.50 Hz, 1H, Ar-H), 7.18–7.21
(m, 3H, Ar-H), 7.25 (t, J ¼ 8.00 Hz, 1H, Ar-H), 7.87 (dd, J ¼ 8.00 Hz, 1.50 Hz, 1H,
Ar-H), 9.22 (s, 1H, NH), 12.92 (s, 1H, COOH) ppm. 13C NMR (DMSO-d6,
500 MHz): d170.43, 149.88, 141.99, 136.41, 136.36, 134.57, 131.83, 128.67, 127.10,
127.00, 115.73, 112.07, 110.35, 24.61, 18.02, 15.09. HRMS: found 255.1262; calcd.
255.1259 for C16H17NO2.
2-((2,6-Diethylphenyl)amino)benzoic acid (3e). Mp 177–178 ꢀC; FT-IR
(KBr): nN-H 3350, nC¼O 1657, 1577 cmꢁ1
;
1H NMR (DMSO-d6, 500 MHz):
d ¼ 1.06 (t, J ¼ 7.50 Hz, 6H, CH3), 2.43–2.48 (m, 4H, CH2), 6.09 (d, J ¼ 8.50 Hz,
1H, Ar-H), 6.62 (t, J ¼ 7.50 Hz, 1H, Ar-H), 7.20–7.26 (m, 4H, Ar-H), 7.86 (dd,
J ¼ 8.00 Hz, 1.50 Hz, 1H, Ar-H), 9.24 (s, 1H, NH), 12.92 (s, 1H, COOH) ppm. 13C
NMR (DMSO-d6, 500 MHz): d 170.30, 150.16, 142.08, 135.58, 134.32, 131.61,
127.15, 126.88, 115.45, 111.95, 110.07, 24.34, 14.81. HRMS: found 269.1418; calcd.
269.1416 for C17H19NO2.
2-((2,6-Diisopropylphenyl)amino)benzoic acid (3f). Mp 217–219 ꢀC;
1
FT-IR (KBr): nN-H 3340, nC¼O 1661, 1574 cmꢁ1; H NMR (DMSO-d6, 500 MHz):
d ¼ 1.07 (d, J ¼ 7.00 Hz, 6H, CH3), 1.10 (d, J ¼ 6.50 Hz, 6H, CH3), 2.97–3.03 (m,
2H, CH), 6.07 (d, J ¼ 8.50 Hz, 1H, Ar-H), 6.61 (t, J ¼ 7.50 Hz, 1H, Ar-H),
7.23–7.27 (m, 3H, Ar-H), 7.33 (t, J ¼ 8.00 Hz, 1H, Ar-H), 7.85 (dd, J ¼ 8.00 Hz,
1.50 Hz, 1H, ArH), 9.12 (s, 1H, NH), 12.92 (s, 1H, COOH) ppm. 13C NMR
(DMSO-d6, 500 MHz): d 170.30, 150.86, 146.78, 134.29, 133.96, 131.61, 127.68,
123.82, 115.37, 112.10, 109.85, 27.98, 24.33, 22.67. HRMS: found 297.1736; calcd.
297.1729 for C19H23NO2.
2-((2,4,6-Trichlorophenyl)amino)benzoic acid (3g). Mp 238–240 ꢀC;
1
FT-IR (KBr): nN-H 3300, nC¼O 1662, 1580 cmꢁ1; H NMR (DMSO-d6, 500 MHz):
d ¼ 6.24 (d, J ¼ 8.50 Hz, 1H, ArH), 6.80 (t, J ¼ 7.50 Hz, 1H, ArH), 7.32 (t,
J ¼ 8.00 Hz, 1H, ArH), 7.88 (s, 1H, ArH), 7.90 (dd, J ¼ 8.00 Hz, 1.50 Hz, 2H,

NEW N-PHENYLANTHRANILIC ACIDS
1277
ArH), 9.50 (s, 1H, NH), 13.23 (s, 1H, COOH)ppm.13C NMR (DMSO-d6, 500 MHz):
d 170.36, 147.03, 134.55, 131.90, 131.72, 129.19, 118.21, 113.39, 112.50. HRMS:
found 314.9615; calcd. 314.9621 for C13H8NO2Cl3.
4-Chloro-2-((2,6-dimethylphenyl)amino)benzoic
acid
(3h). Mp
245–246 ꢀC; FT-IR (KBr): nN-H 3337, nC¼O 1659, 1562 cmꢁ1; H NMR (DMSO-
d6, 500 MHz): d ¼ 2.12 (s, 6H, CH3), 5.97 (d, J ¼ 1.50 Hz, 1H, Ar-H), 6.69 (dd,
J ¼ 8.50 Hz, 2.00 Hz, 1H, Ar-H), 7.19–7.23 (m, 3H, Ar-H), 7.87 (d, J ¼ 8.50 Hz,
1H, ArH), 9.30 (s, 1H, NH), 13.21 (s, 1H, COOH) ppm. 13C NMR (DMSO-d6,
500 MHz): d 169.43, 150.22, 139.18, 136.13, 135.93, 133.65, 128.61, 127.00, 115.60,
110.74, 109.46, 17.71. HRMS: found 275.0714; calcd. 275.0713 for C15H14NO2Cl.
1
4-Chloro-2-((2,3-dimethylphenyl)amino)benzoic
acid
(3i). Mp
239–240 ꢀC; FT-IR (KBr): nN-H 3345, nC¼O 1661, 1564 cmꢁ1; H NMR (DMSO-
d6, 500 MHz): d ¼ 2.09 (s, 3H, CH3), 2.30 (s, 3H, CH3), 6.50 (d, J ¼ 2.50 Hz, 1H,
Ar-H), 6.71 (dd, J ¼ 8.50 Hz, 2.00 Hz, 1H, Ar-H), 7.10–7.19 (m, 3H, Ar-H), 7.88
(d, J ¼ 8.50 Hz, 1H, A-rH), 9.55 (s, 1H, NH), 13.26 (s, 1H, COOH) ppm. 13C
NMR (DMSO-d6, 500 MHz): d 169.50, 150.00, 138.98, 138.18, 137.38, 133.59,
132.09, 127.37, 126.28, 123.23, 115.97, 111.73, 109.88, 20.15, 13.62. HRMS: found
275.0715; calcd. 275.0713 for C15H14NO2Cl.
1
4-Chloro-2-(mesitylamino)benzoic acid (3j). Mp 263–264 ꢀC; FT-IR
(KBr): nN-H 3342, nC¼O 1666, 1564 cmꢁ1
;
1H NMR (DMSO-d6, 500 MHz):
d ¼ 2.07 (s, 6H, CH3), 2.28 (s, 3H, CH3), 5.97 (s, 1H, Ar-H), 6.61–6.68 (m, 1H,
Ar-H), 7.01 (s, 2H, Ar-H), 7.86 (d, J ¼ 7.50 Hz, 1H, Ar-H), 9.20 (s, 1H, NH),
12.65 (s, 1H, COOH) ppm. HRMS: found 289.0878; calcd. 289.0870 for
C16H16NO2Cl.
4-Chloro-2-((2-ethyl-6-methylphenyl)amino)benzoic
acid
(3k). Mp
193–195 ꢀC; FT-IR (KBr): nN-H 3339, nC¼O 1670, 1564 cmꢁ1; H NMR (DMSO-
d6, 500 MHz): d ¼ 1.07 (t, J ¼ 7.00 Hz, 3H, CH3), 2.11 (s, 3H, CH3), 2.50 (s, 2H,
CH2), 5.97 (s, 1H, Ar-H), 6.75 (d, J ¼ 8.00 Hz, 1H, Ar-H), 7.23 (s, 3H, Ar-H),
7.87 (d, J ¼ 8.50 Hz, 1H, Ar-H), 9.34 (s, 1H, NH), 13.20 (s, 1H, COOH) ppm. 13C
NMR (DMSO-d6, 500 MHz): d 169.69, 150.77, 141.98, 139.35, 136.27, 135.57,
133.81, 128.86, 127.53, 127.29, 115.73, 110.98, 109.45, 24.51, 17.90, 15.03. HRMS:
found 289.0874; calcd. 289.0870 for C16H16NO2Cl.
1
4-Chloro-2-((2,6-diethylphenyl)amino)benzoic acid (3 l). Mp 212–214 ꢀC;
1
FT-IR (KBr): nN-H 3314, nC¼O 1653, 1568 cmꢁ1; H NMR (DMSO-d6, 500 MHz):
d ¼ 1.07 (t, J ¼ 7.50, 6H, CH3), 2.45–2.49 (m, 4H, CH2), 5.98 (s, 1H, Ar-H), 6.72
(d, J ¼ 8.00 Hz, 1H, Ar-H), 7.24–7.31 (m, 3H, Ar-H), 7.87 (d, J ¼ 8.50 Hz, 1H,
Ar-H), 9.36 (s, 1H, NH), 12.96 (s, 1H, COOH) ppm. 13C NMR (DMSO-d6,
500 MHz): d 169.57, 151.04, 141.98, 139.10, 134.75, 133.60, 127.67, 127.10, 115.49,
110.91, 109.18, 24.28, 14.77. HRMS: found 303.1022; calcd. 303.1026 for
C17H18NO2Cl.
4-Chloro-2-((2,6-diisopropylphenyl)amino)benzoic
acid
(3m). Mp
1
249–251 ꢀC; FT-IR (KBr): nN-H 3333, nC¼O 1663, 1566 cmꢁ1; H NMR (DMSO-
d6, 500 MHz): d ¼ 1.08–1.15 (m, 12H, CH3), 2.94–2.99 (m, 2H, CH), 6.00 (s, 1H,
Ar-H), 6.67 (d, J ¼ 8.50 Hz, 1H, Ar-H), 7.29–7.39 (m, 3H, Ar-H), 7.87 (d,

1278
Z. LI ET AL.
J ¼ 8.50 Hz, 1H, Ar-H), 9.17 (s, 1H, NH), 12.94 (s, 1H, COOH) ppm. 13C NMR
(DMSO-d6, 500 MHz): d 169.57, 151.60, 146.52, 139.00, 133.59, 133.10, 128.15,
124.10, 115.41, 111.18, 109.04, 28.06, 24.24, 22.69. HRMS: found 331.1342; calcd.
331.1339 for C19H22NO2Cl.
ACKNOWLEDGMENTS
Funding from the Ministry of Science and Technology of China (No.
2010DFA32680) and the Fundamental Research Funds for the Central Universities
(CDJRC10220010, CDJXS11232242) are gratefully acknowledged.
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