Synthesis of 2-(arylamino)nicotinic acids in high-temperature water

Article abstract of DOI:10.1007/s11164-012-0494-0

In hydrothermal reactions at 150-180 °C, 2-(arylamino)nicotinic acids were synthesized by amination of 2-chloronicotinic acid with aromatic amine derivatives, with potassium carbonate as base. The procedure is efficient, environmentally friendly, and practical, with moderate to excellent yields (up to 98%). Springer Science+Business Media B.V. 2012.

Full text of DOI:10.1007/s11164-012-0494-0

Res Chem Intermed (2012) 38:1691–1697
DOI 10.1007/s11164-012-0494-0
Synthesis of 2-(arylamino)nicotinic acids
in high-temperature water
•
•
•
Zhenghua Li Shangyou Xiao Ronghui Liang
Zhining Xia
Received: 25 October 2011 / Accepted: 17 January 2012 / Published online: 3 February 2012
Ó Springer Science+Business Media B.V. 2012
Abstract In hydrothermal reactions at 150–180 °C, 2-(arylamino)nicotinic acids
were synthesized by amination of 2-chloronicotinic acid with aromatic amine
derivatives, with potassium carbonate as base. The procedure is efficient, environ-
mentally friendly, and practical, with moderate to excellent yields (up to 98%).
Keywords 2-(Arylamino)nicotinic acids Á High-temperature water Á
2-Chloronicotinic acid
Introduction
Organic reactions in high-temperature water were introduced because of a desire
for cleaner, safer, and more environmentally benign chemical processes. High-
temperature water has properties very different from those of ambient liquid water,
for example relatively high solubility of organic compounds, lower dielectric
constant, and fewer and less persistent hydrogen bonds [1]. These properties have
enabled use of high-temperature water in a variety of reactions involving hydrolysis
[2], hydration [3], reduction [4], catalytic oxidation [5], alkylation [6, 7], Heck
coupling [8], and Suzuki reaction [9].
2-(Arylamino)nicotinic acids have been studied as nonsteroidal anti-inflammatory
drugs [10, 11], crucial intermediates for the synthesis of substituted 1,8-naphthyridin-
2(1H)-ones with potential of antibacterical, anti-inflammatory, antiallergic, and
antisecretory activity [12–14], and the preparation of the substituted 2-aza-9-
chloroacridines with potential as antitumor agents [15, 16]. The Ullman reaction has
usually been used for synthesis of 2-arylaminonicotinic acids [13, 17–19], but these
Z. Li Á S. Xiao Á R. Liang Á Z. Xia (&)
College of Chemistry and Chemical Engineering, Chongqing University,
Chongqing 400030, People’s Republic of China
e-mail: chem_lab_cqu@yahoo.com.cn
123

1692
Z. Li et al.
procedures necessitate use of a stoichiometric amount of copper reagent, non-green
solvent, and long reaction period. In an alternative procedure reported by Long and
coworkers [20, 21], 2-(arylamino)nicotinic acids were synthesized by reacting
2-chloronicotinic acid with anilines in water at 100 °C in the presence of pyridine and
para-toluenesulfonic acid for a long reaction time. For example, aniline gave the
desired product 2-phenylamino-3-pyridinecarboxylic acid in 77% yield after 24 h
[20]. Microwave irradiation has also been used for synthesis of 2-(4-methoxyanili-
no)nicotinic acid with relatively expensive diisopropylethylamine as base [22].
Herein, we report an efficient, environmentally friendly, and practical procedure
for synthesis of 2-(arylamino)nicotinic acids, with potassium carbonate as base, in
high-temperature water in which the temperature reaches 150–180 °C (Scheme 1).
Scheme 1 Reaction of 2-chloronicotinic acid and anilines in high-temperature water
Results and discussion
Using 0.5 equiv potassium carbonate and 2 equiv aniline (2a) per mole
2-chloronicotinic acid, we initially evaluated CuI, Cu, CuSO4, and Cu(NO3)2 as
catalyst, and also investigated use of no catalyst; the highest yield was obtained
without use of a copper reagent as catalyst. Later, the effect of temperature (100,
110, 130, 150 °C) was examined, the best yield was obtained at 150 °C (Table 1,
entry 5). Therefore, the optimum conditions for obtaining 3a were established, and
involved heating the mixture without copper salt as catalyst at 150 °C for 2 h.
Table 1 The reaction of 2-chloronicotinic acid with aniline under different conditions
Entry
Catalyst (mol%)
Temperature (°C)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
CuI (10)
Cu (10)
CuSO4 (10)
Cu(NO3)2 (10)
None
150
150
150
150
150
130
110
100
2
2
80
74
72
77
85
56
34
83b
2
2
2
None
2
None
2
None
12
All the reactions were carried out with 2-chloronicotinic acid (4 mmol), aniline (8 mmol), potassium
carbonate (2 mmol), and water (3 mL) in a hydrothermal reactor
a
Yields refer to the isolated pure products
b
In the glass flask
123

Synthesis of 2-(arylamino)nicotinic acids
1693
Table 2 Synthesis of 2-(arylamino)nicotinic acids in high-temperature water
Entry
Ar
Temperature (°C)
Time (h)
Product
Yielda (%)
1
C6H5
150
150
150
150
150
150
180
180
150
150
150
180
180
150
2.0
2.5
1.5
2.5
1.5
2.5
4.0
4.0
3.0
3.0
3.0
4.0
4.0
3.0
3a
3b
3c
3d
3e
3f
85
2
4-CH3C6H4
3-CH3C6H4
2-CH3C6H4
4-C2H5OC6H4
2,3-diCH3C6H3
2,6-diCH3C6H3
2,4,6-triCH3C6H2
4-ClC6H4
96
91/93b
3
4
92
5
98
6
92
7
3g
3h
3i
36
8
45
9
92
10
11
12
13
14
a
3-ClC6H4
3j
94
4-IC6H4
3k
3l
90
2-ClC6H4
35
2,4-diClC6H3
1-Naphthyl
3m
3n
16
81
Reaction conditions: A mixture of 2-chloronicotinic acid (4 mmol), aniline derivative (8 mmol),
potassium carbonate (2 mmol), and water (3 mL) in a 10-mL sealed hydrothermal reactor
a
Yields refer to the isolated pure products
b
A mixture of 2-chloronicotinic acid (20 mmol), m-toluidine (40 mmol), potassium carbonate
(10 mmol), and water (15 mL) in a 50-mL sealed hydrothermal reactor
The optimized procedure was then applied to 2-chloronicotinic acid and a variety
of substituted aromatic amines; the results are listed in Table 2. To reduce the
reaction time, the temperature was raised to 180 °C for some reactions with anilines
of relatively low reactivity (Table 2, entries 7, 8, 11 and 12). We found that the
presence of one ortho substituent does not impede effect amination of 2-chloron-
icotinic acid. For example, m-toluidine and 2,3-dimethylaniline gave the desired
products 3d in 92% yield and 3f in 92% yield (Table 2, entries 4 and 6). However, it
was found that incorporation of two ortho substituents on the aniline reduced yields.
For example, 2,6-dimethylaniline and 2,4,6-trimethylaniline gave the corresponding
products 3g and 3h in 36 and 45% yield, respectively (Table 2, entries 7 and 8).
Moreover, there were no significant electronic effects in reactions of meta or para-
substituted anilines with 2-chloronicotinic acid, e.g., the desired product 3j was
obtained in 94% yield (Table 2, entry 10). But incorporation of an ortho electron-
withdrawing substituent on the aniline was found to reduce the yield substantially.
For example, o-chloroaniline gave the corresponding product 3l in 35% yield
(Table 2, entry 12). Reaction of 1-naphthylamine and 2-chloronicotinic acid gave
the desired product 3n in 81% yield (Table 2, entry 14).
Subsequently, we developed the procedure for preparation of 2-(arylamino)nic-
otinic acids in a large scale reaction. For instance, the reaction of 2-chloronicotinic
acid and m-toluidine at 150 °C for 1.5 h gave the desired product 3d in 93% isolated
yield (Table 2, entry 3).
Furthermore, the reactivity of alkylamines with 2-chloronicotinic acid was
explored at 180 °C for 4 h. n-Butylamine and laurylamine gave the expected
123

1694
Z. Li et al.
Fig. 1 The structures of the desired products 3o, 3p, and 3q
compounds 3o and 3p (Fig. 1) in 80 and 32% yields, respectively. Finally, we also
conducted a preliminary investigation of the reactivity of thiophenol with
2-chloronicotinic acid in the presence of 1 equiv potassium carbonate at 180 °C
for 2 h. This reaction proceeded smoothly and the desired product 3q (Fig. 1) was
obtained in 97% isolated yield.
Remarkably, this procedure affords moderate to excellent yields without stirring
of the hydrothermal reactor, indicating the anilines dissolve in the high-temperature
water and the reactions proceed in a homogenous phase. Moreover, this procedure
requires only inexpensive potassium carbonate as base and there is no need for a
copper reagent as catalyst. It is thus clear that this procedure has great potential as a
route for preparation of 2-(arylamino)nicotinic acids by the chemical industry.
Conclusions
In summary, an efficient, environmentally friendly, and practical procedure for the
synthesis of 2-(arylamino)nicotinic acids with potassium carbonate as base in high-
temperature water has been developed. This procedure gives moderate to excellent
yields with both electron-deficient and electron-rich aromatic amines. Moreover, the
procedure has good tolerance of alkylamines and thiophenols.
Experimental
All starting materials were purchased from commercial sources. All reactions were
carried out in a Teflon-lined hydrothermal synthesis 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
internal standard. High-resolution mass spectra (HRMS) of some compounds were
recorded on a Micromass GCT-MS spectrometer in EI mode.
General procedure for synthesis of 2-(arylamino)nicotinic aids in high-
temperature water
A mixture of 2-chloronicotinic acid (4 mmol), aromatic amine (8 mmol), anhydrous
potassium carbonate (2 mmol), and distilled water (3 mL) was placed in a
hydrothermal reactor with a Teflon inner wall having an inner volume of 10 mL.
123

Synthesis of 2-(arylamino)nicotinic acids
1695
The sample was heated in a constant-temperature electric desiccator for the time and
at the temperature indicated in Table 2. After the reactor had cooled to room
temperature, the reaction mixture was adjusted to pH 12 with 10% NaOH solution
and extracted with dichloromethane (40 9 3 mL). The aqueous layer was acidified
with aqueous HCl solution by careful pH adjustment and extracted with ethyl
acetate (40 9 3 mL). The organic layers were combined, and dried over anhydrous
MgSO4. The solvent was evaporated under vacuum to furnish a solid residue which
was recrystallized from ethanol–water to give the desired product at the yield given
in Table 2.
Spectroscopic data for representative products
2-(Phenylamino)nicotinic acid (3a)
m.p. 149–150 °C (lit. [15]:152–153 °C); FT-IR (KBr) mmax: 3261, 3049, 1660, 1591,
1514, 1454, 1385, 1240, 1140 cm-1; 1H NMR (DMSO-d6, 500 MHz): d = 6.86(dd,
J = 7.5, 5.0 Hz, 1H, Ar–H), 7.01(t, J = 7.5 Hz, 1H, Ar–H), 7.32(t, J = 7.5 Hz,
2H, Ar–H), 7.71(d, J = 8.0 Hz, 2H, Ar–H), 8.25(d, J = 7.5 Hz, 1H, Ar–H),
8.39(dd, J = 4.5, 2.0 Hz, 1H, Ar–H), 10.44(s, 1H, NH), 13.60(s, 1H, COOH).
2-[(3-Methylphenyl)amino]nicotinic acid (3c)
m.p. 158 °C (lit. [23]: 152 °C); FT-IR (KBr) mmax: 3264, 3070, 3028, 2922, 2856,
1
1681, 1585, 1527, 1242 cm-1; H NMR (DMSO-d6, 500 MHz): d = 2.31(s, 3H,
CH3), 6.83–6.87(m, 2H, Ar–H), 7.20(t, J = 8.0 Hz, 1H, Ar–H), 7.48(s, 1H, Ar–H),
7.58(d, J = 8.0 Hz,1H, Ar–H), 8.25(dd, J = 7.5 Hz, 2.0 Hz, 1H, Ar–H), 8.39(dd,
J = 4.5 Hz, 2.0 Hz, 1H, Ar–H), 10.46(s, 1H, NH), 13.62(s, 1H, COOH).
2-[(4-Ethoxyphenyl)amino]nicotinic acid (3e)
m.p. 195–197 °C (lit. [14]: 202 °C); FT-IR (KBr) mmax: 3271, 3071, 2978, 2936,
2872, 1639, 1560, 1514, 1354, 1246, 1182 cm-1; 1H NMR (DMSO-d6, 500 MHz):
d = 1.32(t, J = 7.0 Hz, 3H, CH3), 4.00(q, J = 7.0 Hz, 2H, CH2), 6.80(dd, J = 7.5,
4.5 Hz, 1H, Ar–H), 6.89(d, J = 8.5 Hz, 2H, Ar–H), 7.56(d, J = 9.0 Hz, 2H, Ar–H),
8.21(dd, J = 8.0, 1.5 Hz, 1H, Ar–H), 8.32(dd, J = 4.5, 1.5 Hz, H, Ar–H), 10.23(s,
1H, NH), 13.48(s, 1H, COOH).
2-[(2,4,6-Trimethylphenyl)amino]nicotinic acid (3h)
m.p. 257–258 °C; FT-IR (KBr) mmax: 3237, 2922, 2856, 1668, 1601, 1571, 1501,
1
1234, 1132 cm-1; H NMR (DMSO-d6, 500 MHz): d = 2.06(s, 6H, CH3), 2.25(s,
3H, CH3), 6.68(dd, J = 7.5, 4.5 Hz, 1H, Ar–H), 6.91(s, 2H, Ar–H), 8.13(dd,
J = 7.5, 1.5 Hz, 1H, Ar–H), 8.16(dd, J = 7.5, 1.5 Hz, 1H, Ar–H), 9.36(s, 1H, NH),
13.31(s, 1H, COOH). HRMS: calcd. for C15H16N2O2 256.1212, obs. 256.1215.
123

1696
Z. Li et al.
2-[(3-Chlorophenyl)amino]nicotinic acid (3j)
m.p. 196–197 °C (lit. [14]: 199–201 °C); FT-IR (KBr) mmax: 3337, 3065, 2931,
1668, 1612, 1566, 1425, 1294, 1238 cm-1 1H NMR (DMSO-d6, 500 MHz):
;
d = 6.94(dd, J = 8.0, 4.5 Hz, 1H, Ar–H), 7.06(dd, J = 8.0, 1.5 Hz, 1H, Ar–H),
7.33(t, J = 8.0 Hz, 1H, Ar–H), 7.49(dd, J = 8.0, 1.5 Hz, 1H, Ar–H), 8.11(s, 1H,
Ar–H), 8.28(dd, J = 8.0, 1.5 Hz, 1H, Ar–H), 8.45(dd, J = 4.5, 1.5 Hz,1H, Ar–H),
10.61(s, 1H, NH), 13.76(s, 1H, COOH).
2-[(2, 4-Dichlorophenyl)amino]nicotinic acid (3m)
m.p. 242–244 °C; FT-IR (KBr) mmax: 3258, 3080, 1682, 1610, 1531, 1465, 1431,
1
1251 cm-1; H NMR (DMSO-d6, 500 MHz): d = 7.00(dd, J = 7.5, 4.5 Hz, 1H,
Ar–H), 7.43(dd, J = 9.0, 2.5 Hz, 1H, Ar–H), 7.60(d, J = 2.5 Hz, 1H, Ar–H),
8.32(dd, J = 8.0, 1.5 Hz, 1H, Ar–H), 8.45(dd, J = 4.5, 1.5 Hz, 1H, Ar–H), 8.75(d,
J = 9.0 Hz, 1H, Ar–H), 10.93(s, 1H, NH), 13.79(s, 1H, COOH). HRMS: calcd. for
C12H8Cl2N2O2 281.9963, obs. 281.9967.
2-(1-Naphthalenylamino)nicotinic acid (3n)
m.p. 193–194 °C; FT-IR (KBr) mmax: 3442, 3064, 3015, 1647, 1629, 1598, 1558,
1
1232, 1188 cm-1; H NMR (DMSO-d6, 500 MHz): d = 6.89(dd, J = 8.0, 4.5 Hz,
1H, Ar–H), 7.57(m, 3H, Ar–H), 7.68(d, J = 8.5 Hz, 1H, Ar–H), 7.96(d,
J = 8.0 Hz, 1H, Ar–H), 8.08(d, J = 8.5 Hz, 1H, Ar–H), 8.31(d, J = 8.0 Hz, H,
Ar–H), 8.35–8.37(m, 2H, Ar–H), 10.97(s, 1H, NH), 13.73(s, 1H, COOH). HRMS:
calcd. for C16H12N2O2 264.0899, obs. 264.0902.
2-(Butylamino)nicotinic acid (3o)
m.p. 159–161 °C (lit. [12]: 160–161 °C); FT-IR (KBr) mmax: 3074, 3018, 2958,
2926, 1647, 1554, 1344, 1238, 1192 cm-1 1H NMR (DMSO-d6, 500 MHz):
;
d = 0.90(t, J = 7.5 Hz, 3H, CH3), 1.35(quint, J = 7.5 Hz, 2H, CH2), 1.54(sext,
J = 7.5 Hz, 2H, CH2), 3.43(t, J = 7.0 Hz, 2H, CH2), 6.56(dd, J = 8.0, 5.0 Hz, 1H,
Ar–H), 8.03–8.05(dd, J = 8.0, 1.5 Hz, 1H, Ar–H), 8.09(s, 1H, Ar–H), 8.24(dd,
J = 5.0, 1.5 Hz, 1H, NH), 13.00(s, 1H, COOH).
2-(Dodecylamino)nicotinic acid (3p)
m.p. 142–144 °C; FT-IR (KBr) mmax: 3086, 3026, 2920, 2850, 1641, 1556, 1338,
1
1242, 1042 cm-1; H NMR (DMSO-d6, 500 MHz): d = 0.84(t, J = 7.0 Hz, 3H,
CH3), 1.23(m, 18H, CH2), 1.53(quint, J = 7.0 Hz, 2H, CH2), 3.41(t, J = 7.0 Hz,
2H, CH2), 6.56(dd, J = 7.5, 4.5 Hz, 1H, Ar–H), 8.03–8.05(dd, J = 7.5, 2.0 Hz, 1H,
Ar–H), 8.09(s, 1H, Ar–H), 8.23(dd, J = 4.5, 2.0 Hz, 1H, NH), 12.98(s, 1H, COOH).
HRMS: calcd. for C18H30N2O2 306.2307, obs. 306.2311.
123

Synthesis of 2-(arylamino)nicotinic acids
1697
2-(Phenylthio)nicotinic acid (3q)
m.p. 171–172 °C (lit. [24]: 171–171.5 °C); FT-IR (KBr) mmax: 3076, 3046, 3016,
2972, 2885, 2810, 1674, 1558, 1553, 1418, 1308, 1250 cm-1; 1H NMR (DMSO-d6,
500 MHz): d = 7.22(dd, J = 7.5, 4.5 Hz, 1H, Ar–H), 7.42–7.46(m, 3H, Ar–H),
7.48–7.50(m, 2H, Ar–H), 8.23(dd, J = 8.0, 1.5 Hz, 1H, Ar–H), 8.39(dd, J = 5.0,
1.5 Hz, 1H, Ar–H), 13.59(s, 1H, COOH).
Acknowledgment We thank the Ministry of Science and Technology of China (no. 2010DFA32680)
for their generous financial support.
References
1. N. Akiya, P.E. Savage, Chem. Rev. 102, 2725–2750 (2002)
2. M. Sasaki, B. Kabyemela, R. Malaluan, S. Hirose, N. Takeda, T. Adschiri, K. Arai, J. Supercrit.
Fluids 13, 261–268 (1998)
3. N.A. Rebacz, P.E. Savage, Ind. Eng. Chem. Res. 49, 535–540 (2010)
4. Z. Shen, Y. Zhang, F. Jin, X. Zhou, A. Kishita, K. Ind, Eng. Chem. Res. 49, 6255–6259 (2010)
5. J. Fraga-Dubreuil, J. Garcia-Serna, E. Garcia-Verdugo, L.M. Dudd, G.R. Aird, W.B. Thomas,
M. Poliakoff, J. Supercrit. Fluids 39, 220–227 (2006)
6. T. Hirashita, S. Kuwahara, S. Okochi, M. Tsuji, S. Araki, Tetrahedron Lett. 51, 1847–1851 (2010)
7. K. Chandler, F. Deng, A.K. Dillow, C.L. Liotta, C.A. Eckert, Ind. Eng. Chem. Res. 36, 5175–5179
(1997)
8. L.U. Gron, A.S. Tinsley, Tetrahedron Lett. 40, 227–230 (1999)
9. C.J. Li, Angew. Chem. Int. Ed. 42, 4856–4858 (2003)
10. D.J. Jang, J.S. Park, H.R. Ko, J.P. Jee, J.K. Kim, S.T. Kim, C.K. Kim, Biomed. Chromatogr. 19,
32–35 (2005)
11. M.T. Cocco, C. Congiu, V. Onnis, M. Morelli, V. Felipo, O. Cauli, Bioorg. Med. Chem. 12,
4169–4177 (2004)
12. H. Ban, M. Muraoka, N. Ohashi, Tetrahedron 61, 10081–10092 (2005)
13. H. Ban, M. Muraoka, N. Ohashi, Tetrahedron Lett. 44, 6021–6023 (2003)
14. M.H. Sherlock, J.J. Kaminski, W.C. Tom, J.F. Lee, S.C. Wong, W. Kreutner, R.W. Bryant,
A.T. McPhail, J. Med. Chem. 31, 2108–2121 (1988)
15. W.A. Denny, G.J. Atwell, B.F. Cain, J. Med. Chem. 20, 1242–1246 (1977)
16. C. Afloroaei, M. Vlassa, A. Becze, P. Brouant, J. Barbe, Heterocycl. Commun. 5, 249–252 (1999)
17. H. Misbahi, P. Brouant, J. Barbe, Heterocycl. Commun. 9, 335–336 (2003)
18. N.B. Patel, S.N. Agravat, Chin. J. Chem. 25, 1363–1369 (2007)
19. Y.L. 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, D.W. Schulz, J. Med. Chem.
51, 1385–1392 (2008)
20. S. Long, S. Parkin, M.A. Siegler, A. Cammers, T. Li, Cryst. Growth Des. 8, 4006–4013 (2008)
21. S. Long, T. Li, Cryst. Growth Des. 9, 4993–4997 (2009)
22. C.E. Quevedo, V. Bavetsias, E. McDonald, Tetrahedron Lett. 50, 2481–2483 (2009)
23. K.M. Ghoneim, Egypt J. Pharm. Sci. 28, 9–16 (1987)
24. F.G. Mann, J. Chem. Soc. 2057–2062 (1952)
123