Electroorganic synthesis of 6-aminonicotinic acid from 2-amino-5-chloropyridine

Article abstract of DOI:10.1016/S0040-4039(03)00816-5

A synthesis of 6-aminonicotinic acid by electrochemical hydrogenation of 5-chloro-2-nitropyridine and electrochemical carboxylation of 2-amino-5-chloropyridine at a cathode surface in the presence of sulphuric acid and carbon dioxide in a dimethylformamide (DMF) solution at an apparent current density of 10 mA/cm² using an undivided cell with good yields is reported.

Full text of DOI:10.1016/S0040-4039(03)00816-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4133–4135
Electroorganic synthesis of 6-aminonicotinic acid from
2-amino-5-chloropyridine
R. Ramesh Raju, S. Krishna Mohan and S. Jayarama Reddy*
Electrochemical Research Laboratories, Department of Chemistry, Sri Venkateswara University, Tirupati 517502, India
Received 6 January 2003; revised 13 March 2003; accepted 21 March 2003
Abstract—A synthesis of 6-aminonicotinic acid by electrochemical hydrogenation of 5-chloro-2-nitropyridine and electrochemical
carboxylation of 2-amino-5-chloropyridine at a cathode surface in the presence of sulphuric acid and carbon dioxide in a
dimethylformamide (DMF) solution at an apparent current density of 10 mA/cm2 using an undivided cell with good yields is
reported. © 2003 Elsevier Science Ltd. All rights reserved.
6-Aminonicotinic acid, a main constituent of the ‘B3’
vitamin, is used to cure pellagra disease.1 The conven-
tional synthesis of 6-aminonicotinic acid reported2–4 in
the literature has certain drawbacks such as the forma-
tion of hazardous chemicals including cyanide and
ammonia gas and low yields due to the high tempera-
tures required. Electrochemical hydrogenation and car-
boxylation are used for the synthesis of many organic
compounds5–8 and include hydrogenation of nitro
compounds9 and carboxylation of halogenated deriva-
tives.10–12 In this paper, we wish to report a new
method for the synthesis of 6-aminonicotinic acid,
which involves the combination of electrochemical
hydrogenation and carboxylation.
The six-electron reduction of a nitro group to the
corresponding amine is well known13 and the electro-
chemical conversion of 5-chloro-2-nitropyridine 1 to
2-amino-5-chloropyridine 2 at a nickel cathode and
copper anode in the presence of acid proceeded in up to
84% yield.14–16 Reductive-carboxylation of this then
gave 6-aminonicotinic acid 3 in 78% yield.
Scheme 1.
Keywords: 6-aminonicotinic acid; 5-chloro-2-nitropyridine; 2-amino-5-chloropyridine; electroorganic synthesis.
* Corresponding author. Fax: +91-877-2248592; e-mail: jreddy s@yahoo.com
–
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00816-5

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R. Ramesh Raju et al. / Tetrahedron Letters 44 (2003) 4133–4135
Table 1. Electrochemical hydrogenation of 5-chloro-2-nitropyridinea,b
Experiment no.
1
Temperature (°C)
Substrate concentration (g/dm3)
Yield of 2-amino-5-chloropyridine (%)
25
30
40
60
40
60
40
60
40
60
2.0
84
83
81
80
78
74
68
65
64
60
2
3
4
4.0
6.0
8.0
a At current density of 100 A/m2.
b Charged passed 2F.
Table 2. Electrochemical carboxylation of 2-amino-5-chloropyridinea,b,c
Experiment no.
Temperature (°C)
Substrate concentration (g/dm3)
Yield of 6-aminonicotinic acid (%)
1
2
3
4
5
5
5
5
2.0
4.0
6.0
8.0
78
77
76
73
a PCO =1 atm.
2
b Current density=10 mA/cm2.
c Charge passed=2F.
The mechanism of reductive-carboxylation is outlined
in Scheme 1. The two-electron reduction of 2-amino-5-
chloropyridine produced an intermediate carbanion
which attacks carbon dioxide to give a carboxylate
anion. Capture of the anion by metal ions generated by
the dissolution of the anodic metal, gives a metal
carboxylate. Finally, treatment of the metal carboxylate
with acid gives 6-aminonicotinic acid.17
trolytic procedure is an alternative route for the synthe-
sis of 6-aminonicotinic acid which needs only a current
generator and is especially easy to work-up.
References
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Chem. Lett. 1997, 917–918.
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Synthesis 1997, 1143–1145.
To optimise the electroreductive reactions (hydrogena-
tion and carboxylation) of 5-chloro-2-nitropyridine and
2-amino-5-chloropyridine they were carried out at dif-
ferent electrodes in the presence of supporting elec-
trolytes with different substrate concentrations and
reaction temperatures. The experimental results pre-
sented in Tables 1 and 2, demonstrate the variation in
the yields of product due to changes in the initial
concentrations of the substrates which were reduced at
fixed current densities, and also from changes in tem-
perature at a given substrate concentration. The condi-
tions that favoured the formation of good yields of the
products were low concentrations of substrate, low
temperatures and proper selection of the electrode
material. The yields were strongly dependent on the
electrolysis conditions and the selectivity for the desired
product was found to be sensitive to the nature of the
cathode material and solvent. Electrolyses with plat-
inum and nickel cathodes and dimethylformamide
(DMF) as solvent gave good yields of the reductive
carboxylation.
12. Damodar, J.; Krishna Mohan, S.; Jayarama Reddy, S.
Electrochem. Commun. 2001, 3, 762–766.
13. Cyr, A.; Hout, P.; Belot, G.; Lessard, J. Electrochim.
Acta 1990, 35, 147–152.
14. Chichibabin, A. E. Chem. Abstr. 1929, 23, 2182–2183.
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In conclusion, the electroorganic synthesis of 6-amino-
nicotinic acid from 2-amino-5-chloropyridine can be
achieved at a cathode surface in good yield. This elec-

R. Ramesh Raju et al. / Tetrahedron Letters 44 (2003) 4133–4135
4135
16. Experimental procedure for 2-amino-5-chloropyridine:
The electrochemical hydrogenation was carried out by
dissolving 5-chloro-2-nitropyridine (5.0 g) in ethanol (50
mL) containing 10% sulphuric acid (15 mL) at a constant
current density of 100 A/m2 in an undivided cell equipped
with a nickel cathode (3×4 cm2) and a copper anode (3×4
cm2). These electrodes were connected to a dc power
supply and 2F of charge passed. The cell was then kept
under an atmosphere of nitrogen and the contents were
stirred using a magnetic stirrer. At the end of the reac-
tion, the electrolyte solution was diluted with water, the
product was extracted into ether, washed with water,
dried over anhydrous magnesium sulphate and the evapo-
ration of the solvent gave 4.1 g of 2-amino-5-chloropy-
ridine in 82% isolated yield; mp 136–138°C; 1H NMR
(CDCl3): l 8.21 (d, 1H, J=2.1 Hz), 7.45 (dd, 1H, J=8.3
electrochemical carboxylation was carried out in an undi-
vided cell equipped with a platinum cathode (20 cm2) and
magnesium anode (20 cm2). The cell was charged with a
dimethylformamide (50 mL) solution containing Bu4NI
(0.04 mol/dm3) and 2-amino-5-chloropyridine (20 mmol)
was added to the cell. Then, the cell was immersed in cold
water to dissipate the heat evolved during the electrolysis
and to keep the temperature near 5°C. Before electrolysis,
the oxygen in the system was removed by passing nitro-
gen gas through the solution. After that, the stirred
mixture was saturated by bubbling carbon dioxide gas. In
this saturated state, the system was electrolysed by sup-
plying regulated dc power at 10 mA/cm2 until 2F had
been passed through the cell at 5°C. The usual work-up
of the electrolysed solution afforded 3.2 g of 6-aminoni-
cotinic acid in 78% isolated yield; mp 244–246°C; 1H
NMR (CDCl3): l 8.79 (d, 1H, J=2.1 Hz), 8.0 (dd, 1H,
J=8.3 Hz), 6.26 (d, 1H, J=8.4 Hz), 7.36 (brs, 2H), 11.64
Hz), 6.48 (d, 1H, J=8.4 Hz), 6.2–7.8 (brs, 2H, NH2
(neat): w 3226, 3130, 1713, 1635, 795 cm−1
17. Experimental procedure for 6-aminonicotinic acid: The
6 ); IR
.
(brs, 1H); IR (neat): w 3250, 3130, 1724, 1638, 1540 cm−1
.