Catalyst-free amination of 2-chloronicotinic acid in water under microwave irradiation

Article abstract of DOI:10.3184/174751911X13231642443092

A simple, efficient and environmental friendly method for the synthesis of 2-arylaminonicotinic acids derivatives by reacting 2-chloronicotinic acid with anilines with potassium carbonate as the base and water as the media under microwave irradiation is described. The synthesis of 2-arylaminonicotinic acids is important because they are nonsteroidal anti-inflammatory drugs.

Full text of DOI:10.3184/174751911X13231642443092

JOURNAL OF CHEMICAL RESEARCH 2011
RESEARCH PAPER 709
DECEMBER, 709–711
Catalyst-free amination of 2-chloronicotinic acid in water under
microwave irradiation
Zheng-hua Li, Zhi-ning Xia* and Gang Chen
College of Chemistry and Chemical Engineering, Chongqing University, Shazheng Street No.174, Shapingba District, Chongqing, 400030,
P. R. China
A simple, efficient and environmental friendly method for the synthesis of 2-arylaminonicotinic acids derivatives by
reacting 2-chloronicotinic acid with anilines with potassium carbonate as the base and water as the media under
microwave irradiation is described. The synthesis of 2-arylaminonicotinic acids is important because they are
nonsteroidal anti-inflammatory drugs.
Keywords: amination, 2-chloronicotinic acid, microwave irradiation, catalyst-free, water solvent
The synthesis of 2-arylaminonicotinic acids, such as niflumic
acid, has attracted considerable attention because of their
importance as nonsteroidal anti-inflammatory drugs.1–4
Furthermore, 2-arylaminonicotinic acids are also key interme-
diates for the preparation of substituted 1,8-naphthyridin-
2(1H)-ones with potential antibacterical, anti-inflammatory,
antiallergic and antisecretory activites5–7 and the synthesis of
substituted 2-aza-9-chloroacridine with potential as antitumor
agents.8–10
aromatic ring, and transformation of 2-chloronicotinic acid
into by-products such as nicotinic acid and 2,2′-binicotinic
acid.20,21 Later, the effect of temperature (100–150 °C) was
examined, the best yield is obtained at 120 °C (Table 1, entry
8). To study the effect of the proportion of reactants, and the
optimum yield of product was obtained when the ratio of 2-
chloronicotinic acid to aniline (1/2a) is 1:2 (Table 1, entry 8).
Therefore, the optimal conditions for obtaining 3a under
microwave irradiation have been established, which involve
using 2 equiv. aniline and heating the mixture at 120 °C for
1 hour. At the next stage, the scope of reaction for the synthesis
of 2-arylaminonicotinic acids from various aromatic amines
was investigated. The reactions conditions were further
optimised to adapt to the differences in amine reactivity. The
reaction temperature was raised to 150 °C or higher in order to
reduce the reaction time.
Under these conditions, the reactions of 2-chloronicotinic
acid with various substituted aromatic amines with electron-
donating or electron-withdrawing groups were performed to
produce a series of 2-arylaminonicotinic acids, and the results
are listed in Table 2. Electron-donating substituents on the
aromatic ring of aromatic amines improve the nucleophilic
aromatic substitution of 2-chloronicotinic acid and produce
higher yields (Table 2, entries 3–7). However, it was found that
incorporation of both ortho substituents to aniline has impeded
effective amination, so only a moderate yield was obtained in
the reactions of 2-chloronicotinic acid with 2,6-dimethylani-
line and 2,4,6-trimethylaniline (Table 2, entries 8–9). More-
over, electron-withdrawing substituents on the aromatic ring
of aromatic amines decrease the yield (Table 2, entries 10–13).
Note that the electron-withdrawing substituents on the
meta and para position have no obvious difference (Table 2,
entries 10, 11), but electron-withdrawing substituents on ortho
position significantly decrease the yield (Table 2, entries 12,
13).
Copper-mediated amination of 2-chloronicotinic acid is the
classical and still most widely used strategy for the synthesis
of 2-arylaminonicotinic acids.6,11–13 However, these procedures
require harsh conditions such as high temperature, non-green
solvent, amounts of copper or copper salts and a long reaction
time. More recently, Long and his coworkers14,15 reported
the preparation of 2-arylaminonicotinic acids by reacting 2-
chloronicotinic acid with anilines in water using p-toluenesul-
fonic acid as catalyst for more than 24 hours. Furthermore,
microwave irradiation has been applied to the reaction of
2-chloronicotinic acid and methoxyaniline with diisopropyle-
thylamine as the base at 200 °C for 2 hours in 83% yield.16
In recent years, the use of water as a solvent for microwave-
assisted organic synthesis reactions in the high-temperature
water region (<200 °C) has gained increased interest because
of its many advantages.17–19 For example, these reactions can
be completed very efficiently in a rapid manner and high yield
under microwave irradiation, the separation and purification
of the products is simple, and the process features simple
technology, low cost and a green solvent. Therefore, a simple,
efficient and environmental friendly method under microwave
irradiation for the amination of 2-chloronicotinic acid with
potassium carbonate as the base and water as the solvent is
described in present study.
Results and discussion
Table 1 The reaction of 2-chloronicotinic acid with aniline
The reaction of 2-chloronicotinic acid with aniline was chosen
for the optimisation of reaction conditions and the results were
listed in Table 1. Initially, the effect of catalyst was tested. It is
interesting that the highest yield was obtained without the
copper salt as catalyst (Table 1, entry 5). This could be due
to the copper(I)-catalysed substitution of chlorine atom at an
under different reaction conditionsa
Entry
Catalyst /mol % Ratio of 1/2a Temp/°C Yieldb /%
1
2
CuSO4 (8)
CuI (8)
CuI (16)
CuI (24)
None
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:1
1:3
150
150
150
150
150
140
130
120
110
100
120
120
66
70
65
58
75
73
75
76
68
30
69
77
3
4
5
6
None
7
None
8
None
9
None
10
11
12
None
None
None
a All the reactions were carried out with 2-chloronicotinic acid
(4 mmol) and aniline (8 mmol), potassium carbonate (2 mmol),
water (3 mL) for 1 hour under microwave irradiation.
Scheme 1
* Correspondent. E-mail: chem_lab_cqu@yahoo.com.cn

710 JOURNAL OF CHEMICAL RESEARCH 2011
Table 2 Synthesis of 2-arylaminonicotinic acids in water
2-[(4-Methylphenyl)amino]pyridine-3-carboxylic acid (3c): M.p.
203–204 °C (lit.22 203–207 °C); FT-IR (KBr) νmax: 3257, 3070, 3028,
2922, 2864, 1662, 1598, 1517, 1247 cm−1; 1H NMR (DMSO-d6, 500
MHz): δ = 2.26 (s, 3H, CH3), 6.82 (dd, J = 8.0 Hz, 4.5 Hz, 1H, ArH),
7.12 (d, J = 8.0 Hz, 2H, ArH), 7.58 (d, J = 8.5 Hz, 2H, ArH), 8.22 (dd,
J = 7.5 Hz, 1.5 Hz, 1H, ArH), 8.36 (dd, J = 4.5 Hz, 2.0 Hz, 2H, ArH),
10.35 (s, 1H, NH), 13.54 (s, 1H, COOH).
2-[(3-Methylphenyl)amino]pyridine-3-carboxylic acid (3d): M.p.
158 °C (lit.23 152 °C); FT-IR (KBr) νmax: 3264, 3070, 3028, 2922,
2856, 1681, 1585, 1527, 1242 cm−1; 1H NMR (DMSO-d6, 500 MHz):
δ = 2.31 (s, 3H, CH3), 6.83–6.87 (m, 2H, ArH), 7.20 (t, J = 8.0 Hz,
1H, ArH), 7.48 (s, 1H, ArH), 7.58 (d, J = 8.0 Hz, 1H, ArH), 8.25 (dd,
J = 7.5 Hz, 2.0 Hz, 1H, ArH), 8.39 (dd, J = 4.5 Hz, 2.0 Hz, 1H, ArH),
10.46 (s, 1H, NH), 13.62 (s, 1H, COOH).
2-[(2-Methylphenyl)amino]pyridine-3-carboxylic acid (3e): M.p.
165 °C (lit.7 165–167 °C); FT-IR (KBr) νmax: 3321, 3035, 2993, 2857,
1674, 1618, 1527, 1452, 1426, 1254 cm−1. 1H NMR (DMSO-d6,
500 MHz): δ = 2.29 (s, 3H, CH3), 6.84 (dd, J = 7.5 Hz, 4.5 Hz, 1H,
ArH), 6.97 (t, J = 7.5 Hz, 1H, ArH), 7.19 (t, J = 7.5 Hz, 1H, ArH),
7.22 (d, J = 7.0 Hz, 1H, ArH), 8.24–8.27 (m, 2H, ArH), 8.36 (dd,
J = 4.5 Hz, 1.5 Hz, 1H, ArH), 10.28 (s, 1H, NH), 13.56 (s, 1H,
COOH).
2-[(4-Ethoxyphenyl)amino]pyridine-3-carboxylic acid (3f): M.p.
195–197 °C (lit.7 202 °C); FT-IR (KBr) νmax: 3271, 3071, 2978, 2936,
2872, 1639, 1560, 1514, 1354, 1246, 1182 cm−1; 1H NMR (DMSO-d6,
500 MHz): δ = 1.32 (t, J = 7.0 Hz, 3H, CH3), 4.00 (q, J = 7.0 Hz,
7.0 Hz, 2H, CH2), 6.80 (dd, J = 7.5 Hz, 4.5 Hz, 1H, ArH), 6.89 (d,
J = 8.5 Hz, 2H, ArH), 7.56 (d, J = 9.0 Hz, 2H, ArH), 8.21 (dd, J =
8.0 Hz, 1.5Hz, 1H, ArH), 8.32 (dd, J = 4.5 Hz, 1.5 Hz, H, ArH), 10.23
(s, 1H, NH), 13.48 (s, 1H, COOH).
2-[(2,3-Dimethylphenyl)amino]pyridine-3-carboxylic acid (3g): M.p.
236–237 °C (lit.24 242–243 °C); FT-IR (KBr) νmax: 3258, 3065, 3036,
2914, 2850, 2772, 1678, 1580, 1508, 1454, 1300, 1242 cm−1; 1H NMR
(DMSO-d6, 500 MHz): δ = 2.15 (s, 3H, CH3), 2.27 (s, 3H, CH3), 6.79
(dd, J = 7.5 Hz, 5.0Hz, 1H, ArH), 6.92 (d, J = 7.0 Hz, 1H, ArH), 7.06
(t, J = 7.5 Hz, 1H, ArH), 7.81 (d, J = 8.0 Hz, 1H, ArH), 8.22 (dd,
J = 8.0 Hz, 1.5 Hz, 1H, ArH), 8.29 (dd, J = 4.5 Hz, 1.5Hz, 1H, ArH),
10.12 (s, 1H, NH), 13.49 (s, 1H, COOH).
2-[(2,6-Dimethylphenyl)amino]pyridine-3-carboxylic acid (3h): M.p.
209–211 °C (lit.7 209–211 °C); FT-IR (KBr) νmax: 3264, 3015, 2957,
2922, 1670, 1581, 1510, 1292, 1246, 1141 cm−1; 1H NMR (DMSO-d6,
500 MHz): δ = 2.11 (s, 6H, CH3), 6.70 (dd, J = 8.0 Hz,
4.5 Hz, 1H, ArH), 7.08–7.12 (m, 3H, ArH), 8.14 (dd, J = 4.5 Hz,
2.0 Hz, 1H, ArH), 8.18 (dd, J = 8.0 Hz, 1.5 Hz, 1H, ArH), 9.48 (s, 1H,
NH), 13.38 (s, 1H, COOH).
2-[(2,4,6-Trimethylphenyl)amino]pyridine-3-carboxylic acid (3i):
M.p. 257–258 °C; FT-IR (KBr) νmax: 3237, 2922, 2856, 1668, 1601,
1571, 1501, 1234, 1132 cm−1; 1H NMR (DMSO-d6, 500 MHz):
δ = 2.06 (s, 6H, CH3), 2.25 (s, 3H, CH3), 6.68 (dd, J = 7.5 Hz, 4.5 Hz,
1H, ArH), 6.91 (s, 2H, ArH), 8.13 (dd, J = 7.5 Hz, 1.5 Hz, 1H, ArH),
8.16 (dd, J = 7.5 Hz, 1.5 Hz, 1H, ArH), 9.36 (s, 1H, NH), 13.31 (s, 1H,
COOH). HRMS: found 256.1215; calcd. 256.1212 for C15H16N2O2.
2-[(4-Chlorophenyl)amino]pyridine-3-carboxylic acid (3j): M.p.
207–208 °C (lit.22 209–211 °C); FT-IR (KBr) νmax: 3057, 1647, 1556,
1492, 1220 cm−1; 1H NMR (DMSO-d6, 500 MHz): δ = 6.90 (dd,
J = 7.0 Hz, 5.0 Hz, 1H, ArH), 7.35 (d, J = 8.5 Hz, 2H, ArH), 7.77
(d, J = 8.0 Hz, 2H, ArH), 8.26 (d, J = 7.5 Hz, 1H, ArH), 8.40
(dd, J = 4.5 Hz, 1.5 Hz, 1H, ArH), 10.50 (s, 1H, NH), 13.69 (s, 1H,
COOH).
2-[(3-Chlorophenyl)amino]pyridine-3-carboxylic acid (3k): M.p.
196–197 °C (lit.7 199–201 °C); FT-IR (KBr) νmax: 3337, 3065, 2931,
1668, 1612, 1566, 1425, 1294, 1238 cm−1; 1H NMR (DMSO-d6,
500 MHz): δ = 6.94 (dd, J = 8.0 Hz, 4.5 Hz, 1H, ArH), 7.06 (dd,
J = 8.0 Hz, 1.5 Hz, 1H, ArH), 7.33 (t, J = 8.0 Hz, 1H, ArH), 7.49 (dd,
J = 8.0 Hz, 1.5 Hz, 1H, ArH), 8.11 (s, 1H, ArH), 8.28 (dd, J = 8.0 Hz,
1.5 Hz, 1H, ArH), 8.45 (dd, J = 4.5 Hz, 1.5 Hz,1H, ArH), 10.61 (s, 1H,
NH), 13.76 (s, 1H, COOH).
under microwave irradiation without catalyst
Entry
Ar
Temp/°C Time/h Products Yielda/%
1
2
C6H5
1-Naphthyl
4-CH3C6H4
150
150
150
150
150
150
150
170
170
150
150
170
170
1
3a
3b
3c
3d
3e
3f
75
65
81
85
93
86
80
33
42
78
72
35
13
2
3
1
4
3-CH3C6H4
1
5
2-CH3C6H4
1
6
4-C2H5OC6H4
2,3-diCH3C6H3
2,6-diCH3C6H3
2,4,6-triCH3C6H2
4-ClC6H4
1
7
1.5
2.5
2.5
1
3g
3h
3i
8
9
10
11
12
13
3j
3-ClC6H4
2-ClC6H4
2,4-diClC6H3
1.5
2
2.5
3k
3l
3m
a Yields refer to the isolated pure products.
Conclusions
In summary, we have developed a simple, efficient and
environmentally friendly method for the synthesis of 2-aryl-
aminonicotinic acids derivatives by reacting 2-chloronicotinic
acid with anilines with potassium carbonate as the base and
water as the solvent under microwave irradiation. Several
2-arylaminonicotinic acids derivatives were prepared in good
yields.
Experimental
Starting materials were purchased from commercial sources and used
without further purification. All reactions were carried out in the CEM
reactor. Melting points were measured using a micro melting point
X-4 apparatus and are uncorrected. IR spectra were recorded as KBr
discs on a Shimadzu IRAffinity-1 spectrometer. All 1H NMR spectra
were recorded on Bruker 500 MHz spectrometer in DMSO-d6 using
TMS as an internal standard. High-resolution mass spectra (HRMS)
were recorded on Micromass GCT-MS spectrometer with the EI
mode.
Amination of 2-chloronicotinic acid under microwave irradiation
A mixture of 2-chloronicotinic acid (4 mmol), aromatic amines
(8 mmol) anhydrous potassium carbonate (2 mmol) and distilled water
(3 mL) was placed into a 10 mL reaction vessel. After the vessel was
sealed, the sample was irradiated for the time and at the temperature
measured by the IR thermometer indicated in Table 2. The reaction
mixture was subsequently cooled to 50 °C by compressed air, and
the vessel was opened. Next, the reaction mixture was basified to
pH 13 with 10% NaOH solution and extracted with dichloromethane
(40×3 mL). The aqueous layer was acidified with aqueous HCl solu-
tion upon the careful pH adjustment. Meanwhile, if the precipitate
was observed, it can be collected by filtration and dried. If the
precipitate was not observed, the aqueous layer was extracted with
ethyl acetate (40×3 mL), dried over anhydrous MgSO4 and evaporated
the solvent under vacuum to get solid product. The residue was then
recrystallised with ethanol/water to give desired product with yields
listed in Table 2.
2-(Phenylamino)pyridine-3-carboxylic acid (3a): M.p. 149–150 °C
(lit.8 152–153 °C); FT-IR (KBr) νmax: 3261, 3049, 1660, 1591, 1514,
1454, 1385, 1240, 1140 cm−1; 1H NMR (DMSO-d6, 500 MHz):
δ = 6.86 (dd, J = 7.5 Hz, 5.0Hz, 1H, ArH), 7.01 (t, J = 7.5 Hz, 1H,
ArH), 7.32 (t, J = 7.5 Hz, 2H, ArH), 7.71 (d, J = 8.0 Hz, 2H, ArH),
8.25 (d, J = 7.5 Hz, 1H, ArH), 8.39 (dd, J = 4.5 Hz, 2.0 Hz, 1H, ArH),
10.44 (s, 1H, NH), 13.60 (s, 1H, COOH).
2-(1-Naphthalenylamino)-3-pyridinecarboxylic acid (3b): M.p.
193–194 °C; FT-IR (KBr) νmax: 3442, 3064, 3015, 1647, 1629, 1598,
1558, 1232, 1188 cm−1; 1H NMR (DMSO-d6, 500 MHz): δ = 6.89 (dd,
J = 8.0 Hz, 4.5 Hz, 1H, ArH), 7.57 (m, 3H, ArH), 7.68 (d, J = 8.5 Hz,
1H, ArH), 7.96 (d, J = 8.0 Hz, 1H, ArH), 8.08 (d, J = 8.5 Hz, 1H,
ArH), 8.31 (d, J = 8.0 Hz, H, ArH), 8.35–8.37 (m, 2H, ArH), 10.97
(s, 1H, NH), 13.73 (s, 1H, COOH). HRMS: found 264.0902; calcd
264.0899 for C16H12N2O2.
2-[(2-Chlorophenyl)amino]pyridine-3-carboxylic acid (3l): M.p.
212–214 °C; FT-IR (KBr) νmax: 3287, 3071, 2922, 1678, 1610, 1589,
1564, 1531, 1431, 1298, 1251 cm−1; 1H NMR (DMSO-d6, 500 MHz):
δ = 6.96 (dd, J = 8.0 Hz, 4.5 Hz, 1H, ArH), 7.02 (t, J = 7.5 Hz, 1H,
ArH), 7.34 (t, J = 7.5 Hz, 1H, ArH), 7.50 (dd, J = 8.0 Hz, 1.5 Hz, 1H,
ArH), 8.30 (dd, J = 8.0 Hz, 1.5 Hz, 1H, ArH), 8.42 (dd, J = 5.0 Hz,
1.5 Hz, 1H, ArH), 8.68 (dd, J = 8.5 Hz, 1.0 Hz, 1H, ArH), 10.97 (s,
1H, NH), 13.79 (s, 1H, COOH).

JOURNAL OF CHEMICAL RESEARCH 2011 711
5
6
7
H. Ban, M. Muraoka and N. Ohashi, Tetrahedron, 2005, 61, 10081.
H. Ban, M. Muraoka and N. Ohashi, Tetrahedron Lett., 2003, 44, 6021.
M.H. Sherlock, J.J. Kaminski, W.C. Tom, J.F. Lee, S. Wong, W. Kreutner,
R.W. Bryant and A.T. McPhail, J. Med. Chem., 1988, 31, 2108.
W.A. Denny, G.J. Atwell and B.F. Cain, J. Med. Chem., 1977, 20, 1242.
C. Afloroaei, M. Vlassa, A. Becze, P. Brouant and J. Barbe, Heterocycl.
Commun., 1999, 5, 249–252.
2-[(2,4-Dichlorophenyl)amino]pyridine-3-carboxylic acid (3m):
M.p. 242–244 °C; FT-IR (KBr) νmax: 3258, 3080, 1682, 1610, 1531,
1465, 1431, 1251 cm−1; 1H NMR (DMSO-d6, 500 MHz): δ = 7.00 (dd,
J = 7.5 Hz, 4.5 Hz, 1H, ArH), 7.43 (dd, J = 9.0 Hz, 2.5 Hz, 1H, ArH),
7.60 (d, J = 2.5 Hz, 1H, ArH), 8.32 (dd, J = 8.0 Hz, 1.5 Hz, 1H, ArH),
8.45 (dd, J = 4.5 Hz, 1.5 Hz, 1H, ArH), 8.75 (d, J = 9.0 Hz, 1H, ArH),
10.93 (s, 1H, NH), 13.79 (s, 1H, COOH). HRMS: found 281.9967;
calcd. 281.9963 for C12H8Cl2N2O2.
8
9
10 I. Sánchez, R. Reches, D.H. Caignard, P. Renard and M.D. Pujol, Eur. J.
Med. Chem., 2006, 41, 340–352.
11 H. Misbahi, P. Brouant and J. Barbe, Heterocycl. Commun., 2003, 9, 335.
12 N.B. Patel and S.N. Agravat, Chin. J. Chem., 2007, 25, 1363.
13 Y. Chen, R.S. Obach, J. Braselton, M.L. Corman, J. Forman, J. Freeman,
R.J. Gallaschun, R. Mansbach, A.W. Schmidt, J.S. Sprouse, F.D. Tingley
III, E. Winston and D.W. Schulz, J. Med. Chem., 2008, 51, 1385.
14 S. Long, S. Parkin, M.A. Siegler, A. Cammers and T. Li, Cryst. Growth
Des., 2008, 8, 4006.
15 S. Long and T. Li, Cryst. Growth Des., 2009, 9, 4993.
16 C.E. Quevedo, V. Bavetsias and E. McDonald, Tetrahedron Lett., 2009, 50,
2481.
This work was supported by the International Cooperation
Project of Ministry of Science and Technology (No.
2010DFA32680) which is gratefully acknowledged.
Received 23 October 2011; accepted 30 November 2011
Paper 1100949 doi: 10.3184/174751911X13231642443092
Published online: 27 December 2011
17 D. Dallinger and C.O. Kappe, Chem. Rev., 2007, 107, 2563.
18 V. Polshettiwar and R.S.Varma, Chem. Soc. Rev., 2008, 37, 1546.
19 L. Sun and Z.N. Xia, Chem. Res. Appl., 2009, 21, 1089. (in Chinese)
20 M. Saphier, A. Masarwa, H. Cohen, and D. Meyerstein, Eur. J. Inorg.
Chem., 2002, 5, 1226.
21 R. Csuk, A. Barthel and C. Raschke, Tetrahedron, 2004, 60, 5737.
22 V.P. Chesnokov, Nauch. Tr. Perm. Farmatsevt. In-t, 1975, 8, 29.
23 K.M.Ghoneim, Egypt. J. Pharm. Sci., 1987, 28, 9.
References
1
2
3
4
D. Jang, J. Park, H. Ko, J. Jee, J. Kim, S.T. Kim and C. Kim, Biomed.
Chromatogr., 2005, 19, 32.
M.T. Cocco, C. Congiu, V. Onnis, M. Morelli, V. Felipo and O. Cauli.
Bioorg. Med. Chem., 2004, 12, 4169.
P.C. Ting, J.J. Kaminski, M.H. Sherlock, W.C. Tom, J.F. Lee, R.W. Bryant,
A.S. Watnick and A.T. McPhail, J. Med. Chem., 1990, 33, 2697.
D.N. Criddle, A.V.P. Meireles, L.B. Macedo, J.H. Leal-Cardoso,
H.C. Scarparo and M. Jaffar, J. Pharm. Pharmacol., 2002, 54, 283.
24 M. Hussian, M. Zaman, M. Hanif, M. Altaf, S. Ali and H. Stoeckli-Evans,
J. Iran. Chem. Soc., 2009, 6, 769.

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