Electrosynthesis of pyridines from 'only acetonitrile'

Article abstract of DOI:10.1016/j.tetlet.2005.10.059

2,4,6-Trimethylpyridine-3,5-dicarbonitrile has been obtained as the main product after the electrolysis of acetonitrile in the presence of tetrabutylammonium bisulfate as supporting electrolyte using a divided cell with a medium porosity diaphragm. 2,6-Dimethylpyridine-3,5-dicarbonitrile and 2,6-dimethylpyridine-3,4,5-tricarbonitrile have also been obtained in minor quantity. This process, which takes place with participation of both electrodes, is an example of a paired electrosynthesis.

Full text of DOI:10.1016/j.tetlet.2005.10.059

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8681–8683
Electrosynthesis of pyridines from ‘only acetonitrile’
M. Dolores Otero, Belen Batanero and Fructuoso Barba*
Department of Organic Chemistry, University of Alcala´, 28871 Alcala´ de Henares, Madrid, Spain
Received 9 September 2005; revised 11 October 2005; accepted 14 October 2005
Abstract—2,4,6-Trimethylpyridine-3,5-dicarbonitrile has been obtained as the main product after the electrolysis of acetonitrile in
the presence of tetrabutylammonium bisulfate as supporting electrolyte using a divided cell with a medium porosity diaphragm. 2,6-
Dimethylpyridine-3,5-dicarbonitrile and 2,6-dimethylpyridine-3,4,5-tricarbonitrile have also been obtained in minor quantity. This
process, which takes place with participation of both electrodes, is an example of a paired electrosynthesis.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Polysubstituted pyridines-3,5-dicarbonitrile have recei-
ved considerable attention due to their pharmacological
and biological activity.1,2
As higher current density is applied and larger amount
of charge is circulated through the cell, higher yield of
pyridines is achieved (Table 2).
On the other hand, the cathodic reduction of acetonitrile
in the absence of water leads to 3-aminocrotonitrile
anion,3 while the positive potential limit of acetonitrile
solutions is fixed by the anodic oxidation of the support-
ing electrolyte anion.
The proposed mechanism to explain these results is as
follows: 3-aminocrotonitrile anion, formed into the
cathodic compartment, can react with acetonitrile either
before or after the migration through the diaphragm to
the anodic site. This reaction in the cathodic compart-
ment is displaced to the left side, for this reason, experi-
mentally no traces of imine i, neither its hydrolysis
products, were found in this compartment. However,
in the anodic compartment, the attack of 3-aminocroto-
nitrile anion to the solvent becomes irreversible as a
result of the subsequent in situ protonation of the
anionic intermediate to give imine i (Scheme 1). It is
supported by the fact that no pyridines were obtained
into the cathodic compartment.
In the present letter, a paired electrosynthesis of
substituted pyridines: 2,4,6-trimethylpyridine-3,5-dicar-
bonitrile (1a) (as main product), 2,6-dimethylpyridine-
3,5-dicarbonitrile (1b) and 2,6-dimethylpyridine-3,4,5-
tricarbonitrile (1c) is described.
Constant current electrolyses of acetonitrile-electrolyte
solutions, in a divided cell with a medium porosity dia-
phragm, afforded pyridines 1a–c in the anodic compart-
ment. It is important to notice that no pyridines were
found in the cathodic side, and that if the reaction is
performed in an undivided cell, under the same experi-
mental conditions, pyridines were not obtained.
The protons source is generated by anodic oxidation of
the electrolyte anion and further reaction with aceto-
nitrile.4
ꢀeꢀ
CH3CN
Å
HSOꢀ4 ! HSO4 ! H2SO4 þ CH2CN
Å
In Table 1 the improvement on the yield of pyridine
mixture with the current density is observed, after
4000 C circulated through the cell.
Table 1. Increase of the pyridines yield with the current density
Circulated
charge
(C)
I
Current
(mA) density
(mA/cm2) (mg)
Pyridine Yield
mixture (%) 1a (%) 1b (%) 1c
Yield
Yield
Keywords: 2,4,6-Trimethylpyridine-3,5-dicarbonitrile; Paired electro-
chemical reaction; Acetonitrile; Constant current.
4000
4000
4000
300 22.5
900 67.6
1200 90.2
273
380
537
50
54
57
28
311
33
22
10
5
*
Corresponding author. Tel.: +34 918854617; fax: +34 918854686;
e-mail: fructuoso.barba@uah.es
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.059

8682
M. D. Otero et al. / Tetrahedron Letters 46 (2005) 8681–8683
Table 2. Increase of the pyridines yield with the circulated charge
postulated as intermediates in the synthesis of substi-
tuted pyridines5 and polysubstituted pyrimidines.6 The
reaction of iii with 3-aminocrotonitrile allows the obten-
tion of pyridines 1b and 1c, as indicated in Scheme 2.
Circulated
charge
(C)
I
Current
(mA) density
(mA/cm2) (mg)
Pyridine Yield
mixture (%) 1a (%) 1b (%) 1c
Yield
Yield
10000
20000
40000
1200 90.2
1200 90.2
1200 90.2
1440
2570
4710
71
79
84
22
17
13
7
4
3
The obtained yield of each pyridine is directly related to
the theoretical charge consumption postulated for their
formation.
When the electrolysis is performed using a low porosity
diaphragm (D4), the migration of 3-aminocrotonitrile
anion to the anode is hindered, and a large amount of
this compound is found into the catholyte. In this case,
only traces of pyridines are obtained in the anodic com-
partment while 2,4,6-trimethylpyrimidine-5-carbonitrile
(2) is isolated as the main product. The regioselective
formation of 2 can be rationalized (Scheme 3) as a reac-
tion between acetonitrile and the intermediate i, already
postulated in the formation of pyridine 1a. This reaction
only takes place when the concentration of 3-aminocro-
tonitrile anion into the anolyte is too low, due to the low
porosity of the diaphragm employed.
Reaction of i with 3-aminocrotonitrile leads, after loss of
two ammonia molecules, to 2,4,6-trimethylpyridine-3,5-
dicarbonitrile (1a).
The formation of the secondary products, pyridines 1b
and 1c, can be rationalized as follows: some 3-aminocro-
tonitrile anion molecules arrive to the anode surface
where they are oxidized to the corresponding radicals,
which are further coupled with the acetonitrile radicals
ÅCH2CN, whose formation is described above and well
known in the literature.4 This coupling affords enamine
ii, which is immediately oxidized to the a,b-unsaturated
imine iii. a,b-Unsaturated imines have already been
NC
NC
NC
CH3CN
NH2
NH
NH2
+ H+
NH
N
CN
-
NH
NH2
(i)
NH2
NH2
H+
CN
CN
-
NH2
NH2
NC
CN
NH2
NC
CN
NC
CN
-NH3
-NH3
N
N
N
H
H
(1a)
Scheme 1.
CN
NH2
NH2
NC
.
CH2CN
CN
CN
-2e-
-2H+
CN
.
(ii)
(iii)
NH
NH2
NH2
H+
CN
CN
NC
CN
-
- HCN
CN
CN
N
NC
CN
NH2
NC
CN
1b
-NH3
N
H
N
H
CN
-2e-
NC
CN
-2H+
N
1c
Scheme 2.

M. D. Otero et al. / Tetrahedron Letters 46 (2005) 8681–8683
8683
C10H6N4: C, 65.93; H, 3.30; N, 30.77. Found: C,
65.81; H, 3.39, N, 30.67.
NC
NC
NC
CH3
NH
NH2
N
NH
- NH3
2,4,6-Trimethylpyrimidine-5-carbonitrile (2): Mp 134–135
ꢁC (hexane). IR (KBr) m = 2926, 2226, 1562, 1434, 1137,
N
N
H2N
N
(i)
Scheme 3.
2
1
1102 cmꢀ1. H NMR (300 MHz, CDCl3) d: 2.65 (s, 6H,
2Me), 2.68 (s, 3H, Me). 13C NMR (75.4 MHz, CDCl3)
d: 23.6, 26.6, 105.3, 115.4, 169.4, 170.0. MS m/e (relative
intensity) EI: 148 (M++1, 11), 147 (M+, 100), 120 (54),
119 (92), 105 (20), 90 (9), 78 (16), 66 (14), 51 (12). Anal.
Calcd for C8H9N3: C, 65.31; H, 6.12, N, 28.57. Found:
C, 65.13; H, 6.17, N, 28.71.
The anodic obtention of pyrimidine 2 supports the pos-
tulated mechanism (Scheme 1) to explain the formation
of pyridine 1a.
Experimental: Electrolyses of dry acetonitrile were car-
ried out under constant current conditions at a platinum
mesh anode (13.3 cm2) and a platinum plate cathode,
using Bu4NHSO4 (0.05 M) as electrolyte, which is the
Acknowledgements
This study was financed by the Spanish Ministry of Sci-
ence and Education CTQ2004-05394/BQU. B.B. thanks
the Spanish Ministry of Science and Technology for the
ÔRamon y CajalÕ financial support.
cheapest tetraalkylammonium salt.
A refrigerated
(15 ꢁC) two-compartment cell with a medium porosity
glass-frit diaphragm (D2) was employed. After the de-
sired charge was circulated through the cell, the solvent
in the anodic solution was removed under reduced pres-
sure, the residue was extracted with ether/water and the
organic phase dried over Na2SO4 and concentrated by
evaporation. The resulting solid was chromatographed
on silica gel (18 · 3 cm) column, using CH2Cl2–hexane
(9:1) as eluent. A mixture of 1a, 1b and 1c was obtained.
Spectroscopical and physical description of the obtained
pyridines 1a (mp 115–117 ꢁC [lit.7 116–118 ꢁC]) and 1b
(mp 116–118 ꢁC [lit.8 117–118 ꢁC]) coincided with those
from the literature.
References and notes
1. Attias, A. J.; Cavalli, C.; Donnio, B., et al. J. Polym. Sci.,
Part A: Polym. Chem. 2005, 43, 493.
2. Beukers, M. W.; Chang, L. C. W.; Kunzel, J. K. V. D.,
et al. J. Med. Chem. 2004, 47, 3707–3709.
3. Foley, J. K.; Korzeniewski, C.; Pons, S. Can. J. Chem.
1988, 66, 201; Abbot, E. M.; Bellamy, A. J.; Kerr, J. Chem.
Ind. 1974, 828; Kistenbrugger, L.; Mischke, P.; Voss, J.;
Wiegand, G. Justus Liebigs Ann. Chem. 1980, 461.
´
´
4. Batanero, B.; Barba, F.; Sanchez-Sanchez, C. M.; Aldaz, A.
2,6-Dimethylpyridine-3,4,5-tricarbonitrile (1c): Mp 100
ꢁC (hexane). IR (KBr) m = 2921, 2233, 1569, 1412,
J. Org. Chem. 2004, 69, 2423–2426.
5. Kiselyov, A. S. Tetrahedron Lett. 1995, 36, 9297–9300.
6. Kiselyov, A. S. Tetrahedron Lett. 2005, 46, 1663–1665.
7. Al-Omran, F.; El-Khair, A. A. Indian J. Chem. 2001, 40,
608–611.
8. Biellmann, J. F.; Callot, H. J.; Goeldner, M. P. Tetrahedron
1970, 26, 4655–4666.
1
1222, 1021, 916 cmꢀ1. H NMR (300 MHz, CDCl3) d:
2.87 (s, 2Me). 13C NMR (75.4 MHz, CDCl3) d: 24.9,
109.3, 111.6, 112.7, 127.5, 166.28. MS m/e (relative
intensity) EI: 183 (M++1, 12), 182 (M+, 100), 167 (2),
155 (5), 141 (7), 114 (4), 88 (5). Anal. Calcd for