Preparation of 2,6-dimethyl-4-arylpyridine-3,5-dicarbonitrile: A paired electrosynthesis

Article abstract of DOI:10.1021/jo016065h

Electrolysis of benzylthiocyanate, benzyl chloride, p-methylbenzyl chloride, p-methoxybenzyl chloride, or toluene in acetonitrile, at platinum electrodes in a two compartments cell divided by a glass-frit diaphragm, affords 2,6-dimethyl-4-arylpyridine-3,5

Full text of DOI:10.1021/jo016065h

J . Org. Chem. 2002, 67, 2369-2371
2369
both compartments show a cooperative action to lead
simultaneously to interesting products.7
P r ep a r a tion of 2,6-Dim eth yl-4-a r ylp yr id in e-
3,5-d ica r bon itr ile: A P a ir ed
Electr osyn th esis†
Resu lts a n d Discu ssion
Bele´n Batanero and Fructuoso Barba*
The anodic oxidation of benzylthiocyanate (5 mmol) at
platinum net anode and a platinum plate as cathode, in
dry acetonitrile-Bu4NBF4 or LiClO4 (0.05 M), using a
two-compartment cell separated by a glass-frit dia-
phragm (D3), at constant temperature of 15 °C and under
controlled potential of +2.5V (vs SCE), determined by
voltammetry, afforded in good yield (70%) a crystalline
product (1). The same reaction carried out in a one-
compartment cell led to a mixture of products and the
yield in our crystalline product was poor.
Department of Organic Chemistry, University of Alcala´,
28871 Alcala´ de Henares, Madrid, Spain
Avelino Mart´ın
Department of Inorganic Chemistry, University of Alcala´,
28871 Alcala´ de Henares, Madrid, Spain
fructuoso.barba@uah.es
Received August 28, 2001
The solid presented a melting point of 174 °C. In its
IR spectrum the band at 2156 cm-1 corresponding to the
SCN group of the starting molecule had disappeared, and
simultaneously, another band appeared at 2230 cm-1 that
could be assigned to a CN group joined to an aromatic
ring. In the proton NMR spectrum, a singlet assigned to
two equivalent methyl groups, which integrated for 6
hydrogen atoms, appeared at 2.87 ppm and also showed
a multiplet centered at 7.57 ppm corresponding to the,
almost equivalent, five aromatic protons. The 13C NMR
confirms the previous data and shows the presence of
carbon-nitrogen double bond. Moreover, the elemental
analysis together with the molecular weight obtained by
mass spectrometry led to the molecular formula C15H11N3.
With these data and having in mind the nature of the
starting material, it was not possible to establish the
structure of the final compound, as it was necessary to
apply an X-ray analysis. The molecular structure of 1 can
be described as a central pyridine ring with two methyl
and two cyanide groups located in a symmetrical fashion,
and a tilted phenyl ring (torsion angle C2-C1-C7-C8
124.8(3)°) as substituents.8 The X-ray study was in
agreement with the compound 2,6-dimethyl-4-phenyl-3,5-
pyridinedicarbonitrile (1), a known compound9 whose
formation was very surprising.
Abstr a ct: Electrolysis of benzylthiocyanate, benzyl chlo-
ride, p-methylbenzyl chloride, p-methoxybenzyl chloride, or
toluene in acetonitrile, at platinum electrodes in a two
compartments cell divided by a glass-frit diaphragm, affords
2,6-dimethyl-4-arylpyridine-3,5-dicarbonitrile as major prod-
uct.
The synthesis of polysubstituted pyridines,1 particu-
larly the 3,5-dicarbonitrile, has received considerable
attention due to its chemistry1 and photochemistry,2 but
also to its antibacterial activity as nifedipine analogue,3
as intermediate in thrombin inhibition,4 or its use to
avoid the prion replication through structure-based drugs
design.5 On the other hand, polysubstituted 1,4-dihydro-
pyridines are interesting as pharmacologically active
substances, antioxidants, and NADH coenzyme ana-
logues that mediate the hydrogen transfer in biological
systems.6
The highest electric current efficiency is one of the aims
of the organic electrochemists. It is known that the
number of electrons added at the cathode (for reduction)
must simultaneously be removed at the anode (for
oxidation). For instance, to obtain a product into the
anodic compartment it is necessary for another to be
formed into the cathode. Unfortunately, in most of the
processes the product in one of the compartments is
undesirable. Herein, we describe the paired electrosyn-
thesis of the 2,6-dimethyl-4-arylpyridine-3,5-dicarbo-
nitrile. There are few examples in the literature where
The cathodic reduction of acetonitrile in absence of
water leads to 3-aminocrotonitrile anion (i), as proposed
by Pons et al.10 (see Scheme 1).
IR spectroscopy of i showed a band at 2151 cm-1
corresponding to the CN group in the anion. This CN
band appears at 2181 cm-1 in 3-aminocrotonitrile. It is
noticeable that we observed both bands in the IR spec-
(7) Lund, H.; Baizer, M. M. In Organic Electrochemistry, 3rd ed.;
Lund, H., Baizer, M. M., Eds.; Marcel Dekker Inc.: New York, 1991;
Chapter 35, pp 1421-1430.
* To whom correspondence should be addressed. Fax: 34 91
8854686.
(8) X-ray data for C15H11N3: colorless crystals, orthorhombic, Pnab,
a ) 8.165(2) Å, b ) 11.075(2) Å, c ) 13.999(3) Å, V ) 1265.9(5) Å3,
Z ) 4, Fcalcd ) 1.224 Mg/m3. All data were collected on an Enraf Nonius
CAD4 diffractometer at room temperature, KR Mo ) 0.710 73 Å. The
structure was solved, using the WINGX package (Farrugia, L. J . J .
Appl. Crystallogr. 1999, 32, 837), by direct methods (SHELXS-97) and
refined by least-squares against F2 (SHELXL-97). Intensity measure-
ments were performed by ω - 2θ scans in the range 3° < 2θ < 46°, of
the 1093 measured reflections, 883 were independent; R1 ) 0.058 and
wR2 ) 0.161 (for 717 reflections with F >4σ(F)). The values of R1 and
† In Memory of Prof. Lennart Eberson.
(1) (a) Kanomata, N.; Nagahara, H.; Tada, M. J . Heterocycl. Chem.
1992, 29, 1567. (b) Kambe, S.; Saito, K.; Sakurai, A.; Midorikaua, H.
Synthesis 1981, 531. (c) Fuentes, L.; Vaquero, J . J .; Ardid, M. I.;
Lorente, A. Heterocycles 1988, 9, 27.
(2) Caronna, T.; Vittimberga, B.; Cornn, M. E.; McGimpsey, W. G.
J . Photochem. Photobiol., A 1995, 90, 137.
(3) Gorlitzer, K.; Klanck, S. Pharmazie 1999, 54, 814.
(4) Sanderson, P. E.; Lyle, T.; Dorsey, B.; Stanton, M. G.; Naylor-
Olsen, A. M. (Merck & Co., Inc.) U.S. Patent PCT Int. Appl. WO 00
26,210 (Cl C07D403/12) 1998.
(5) Perrier, V.; Wallace, A. C.; Kaneko, K.; Safar, J .; Prusiner, S.
B.; Cohen, F. E. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 6073.
(6) (a) Eisner, V.; Kuthan, J . Chem. Rev. 1972, 72, 1. (b) Kuthan,
J .; Kurfuerst, A. Ind. Eng. Chem. Prod. Res. Dev. 1982, 21, 191. (c)
Stout, D. M.; Meyers, A. J . Chem. Rev. 1982, 82, 223.
wR are defined R1 ) ∑||Fo| - |Fc||/[∑|Fo|]; wR2 ) [[∑w(Fo - Fc2)2]/
2
[∑w(Fo2)2]]1/2. Largest difference: peak and hole 0.274 and -0.210
e‚Å-3. All non-hydrogen atoms were anisotropically refined.
(9) Paleccek, J .; Vondra, K.; Kuthan, J . Collect. Czech. Chem.
Commun. 1969, 34, 2991.
(10) Foley, J . K.; Korzeniewski, C.; Pons, S. Can. J . Chem. 1988,
66, 201.
10.1021/jo016065h CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/14/2002

2370 J . Org. Chem., Vol. 67, No. 7, 2002
Sch em e 1. Ca th od ic F or m a tion of 3-Am in ocr oton itr ile An ion
Notes
Sch em e 2. P r op osed Rou te for th e P a ir ed Rea ction
trum of the catholyte. If we assume that the anion i goes
through the glass-frit diaphragm to the anodic compart-
ment, it can be explained the formation of 1 in agreement
with the route proposed in Scheme 2.
SCE. This value is again less positive than that of the
substrate.
To confirm the proposed routes, an electrolysis using
a cationic Nafion 450 membrane, instead of the glass-
frit diaphragm, was carried out. Under the same experi-
mental conditions, 1 was not obtained and i was isolated
into the catholyte. In the anodic compartment, all of the
substrate was converted into benzaldehyde. This fact
supports the formation of ii, which affords benzaldehyde
in the presence of water during the workup.
Despite benzylthiocyanate is consumed after 2e- per
substrate molecule passed over the solution, the reaction
proceeds until 4e- per substrate molecule are circulated.
At the end of the reaction, in the cathodic compartment
there is an excess of i (precipitated solid when lithium
perchlorate is used as electrolyte or in solution when
Bu4NBF4 is employed). It has to be mentioned that when
4e- per substrate molecule have been circulated, the
current does not go down to zero, because molecules of i
going through the diaphragm are oxidized into the anodic
compartment.
When benzyl chloride is oxidized instead of benzyl-
thiocyanate, under the same experimental conditions,
the yield in 1 was 74%.
To make the reaction more general other substrates
(p-methylbenzyl chloride and p-methoxybenzyl chloride)
have been employed. In both cases, the corresponding
pyridines and their 1,4-dihydro derivatives were ob-
tained.
Two concurrent routes are proposed to explain the
formation of 1. In both cases, intermediates have been
isolated. The only difference between these routes is
whether the oxidation step takes place before or after the
substitution reaction. In the first case the cation ii does
not react with acetonitrile, and only a small trace of
PhCH(SCN)NHCOCH3, formed by a Ritter reaction with
the acetonitrile (acetamidation reaction), was detected
by mass spectrometry EI: 206 (M+, 6), 148(100), 121 (46),
91 (55).
On the other hand 3-amino-2-benzylcrotonitrile (iii)
has been prepared by addition of i (obtained by treatment
of 3-aminocrotonitrile with NaH in hexane) to a solution
of substrate, MS m/e (relative intensity) EI: 172 (M+, 47),
171 (23), 157 (8), 145 (10), 103 (10), 91(100), 65 (26), 51
(19), IR showed bands at 3478, 3380, and 2185 cm-1. The
oxidation potential of iii was +1.15V (vs SCE) deter-
mined by voltammetry in CH3CN/LiClO4. This value is
less positive than that of the substrate, and it is im-
mediately oxidized under the applied potential. A small
amount of 1,4-dihydropyridine, was obtained when the
reaction was stopped before its conclusion. Mp: 209-211
°C (lit.11 mp 211-212 °C). MS m/e (relative intensity)
EI: 235 (M+, 10), 158 (100), 91 (13), 77 (15). 1HNMR
(CDCl3) δ: 2.1 (s, 6H), 4.35 (s, 1H), 5.9 (bs, 1H), 7.2-7.5
(m, 5H). The oxidation potential of the 1,4-dihydropyri-
dine, determined by voltammetry12 with a rotated plati-
num electrode in acetonitrile/TBAHFP, was +1.34V vs
2,6-Dim et h yl-4-(4-m et h ylp h en yl)p yr id in e-3,5-d i-
ca r bon itr ile (67% yield). Mp: 232-234 °C. IR (KBr) ν
) 3039, 2925, 2223, 1611, 1573, 1552, 1540, 1513, 822,
1
774, 518 cm-1. H NMR (300 MHz, CDCl3) δ: 7.35-7.43
(11) Zandersons, A.; Lusis, V.; Muceniece, D.; Duburs, G. Khim.
Geterotsikl. Soedin. 1987, 81.
(m, 4H), 2.85 (s, 6H), 2.44 (s, 3H). 13C NMR (75.4 MHz,
(12) Ludvik, J .; Volke, J .; Klima, J . Electrochim. Acta 1987, 32, 1063.
CDCl3) δ: 21.7, 24.9, 107.5, 115.6, 128.8, 130.1, 130.2,

Notes
J . Org. Chem., Vol. 67, No. 7, 2002 2371
Sch em e 3. P r op osed Alter n a tive Rou te to 1 in th e An od ic Oxid a tion of Tolu en e
141.8, 157.1, 165.3. MS m/e (relative intensity) EI: 248
(M+ + 1, 18), 247 (M+, 100), 246 (27), 232 (9), 219 (9),
205 (15), 151 (9), 140 (9), 91 (8).
acetonitrile, via a Ritter reaction, to give N-benzyl-
acetamide or with the anion i affording iii, which is
immediately oxidized at the applied working potential
to the corresponding cation, as has been previously
demonstrated. Subsequent attack of i leads to the di-
hydropyridine. Since i is a stronger nucleophile than
acetonitrile one would expect the benzyl cation to react
faster with i than with acetonitrile; however, the aceta-
mide is the main product. This effect was observed by
Eberson13 and by Nyberg.14 They postulated that “as the
cation becomes more stable, the selectivity is toward the
weaker nucleophile”.
2,6-Dim eth yl-4-(4-m eth oxyp h en yl)p yr id in e-3,5-d i-
ca r bon itr ile (62% yield). Mp: 182 °C (Lit.11 mp 181-
183 °C). IR (KBr) ν ) 3070, 2945, 2845, 2225, 1610, 1578,
1
1540, 1520, 1271, 1189, 1027, 835 cm-1. H NMR (300
MHz, CDCl3) δ: 7.5 (d, 2H, J ) 8.9 Hz), 7.1(d, 2H, J )
8.9 Hz), 3.9 (s, 3H), 2.9 (s, 6H). 13C NMR (75.4 MHz,
CDCl3) δ: 24.9, 55.7, 107.4, 114.8, 115.8, 125.1, 130.7,
156.8, 162.0, 165.3. MS m/e (relative intensity) EI: 264
(M+ + 1, 19), 263 (M+, 100), 262 (11), 248 (7), 232 (8),
220 (13), 205 (10), 192 (13), 152 (12), 114 (13), 76 (10).
2,6-Dim eth yl-4-(4-m eth ylp h en yl)-1,4-d ih yd r op yr i-
d in e-3,5-d ica r b on it r ile. Mp: 218-222 °C. IR (KBr)
ν ) 3313, 3123, 2856, 2192, 1668, 1504, 1273, 1021, 787
On the other hand, by linear free energy relatioship15
+
has been determined that PhCH2 is more stable than
PhCH+SCN or PhCH+Cl. In both cases JI value is higher
than the JR value. For this reason and due to the fact
that both cations are harder acids than the benzyl cation,
they react preferently with the harder base i.
The radical route is not discarded, as a side pathway,
in the oxidation of these compounds. Having in mind
that i can be oxidized to radical in the anodic compart-
ment, subsequent coupling with electrogenerated benzyl
radicals can take place.
1
cm-1. H NMR (300 MHz, CDCl3) δ: 6.9-7.2 (m, 4H),
6.3 (s, 1H), 4.3 (s, 1H), 2.35 (s, 3H), 2.0 (s, 6H). 13C NMR
(75.4 MHz, CDCl3) δ: 18.4, 21.4, 41.8, 84.8, 119.1, 127.6,
129.8, 137.9, 139.9, 145.7. MS m/e (relative intensity)
EI: 249 (M+, 9), 248 (5), 234 (4), 159 (11), 158 (100), 91
(9), 65 (13).
2,6-Dim eth yl-4-(4-m eth oxyp h en yl)-1,4-d ih yd r op y-
r id in e-3,5-d ica r bon itr ile. Mp: 216-217 °C. IR (KBr)
ν ) 3317, 3128, 2924, 2204, 1668, 1509, 1244, 1023, 849
cm-1. 1H NMR (300 MHz, CDCl3) δ: 7.17 (d, 2H, J ) 8.6
Hz), 6.89 (d, 2H, J ) 8.6 Hz), 6.1 (s, 1H), 4.3 (s, 1H), 3.8
(s, 3H), 2.1 (s, 6H). 13C NMR (75.4 MHz, CDCl3) δ: 18.8,
41.5, 55.5, 85.9, 114.6, 118.8, 129.0, 135.0, 144.7, 159.6.
MS m/e (relative intensity) EI: 265 (M+, 13), 264 (10),
250 (4), 234 (5), 159 (10), 158 (100), 108 (19).
As conclusion, all substrates able to be oxidized to a
benzyl cation will lead under the described experimental
conditions to 2,6-dimethyl-4-arylpyridine-3,5-dicarbo-
nitrile.
Ack n ow led gm en t. This study was financed by the
Spanish Ministry of Science and Technology (BQU2001-
1083) and by the University of Alcala´ (E029/2001).
On the other hand, it is well-known that the anodic
oxidation of toluene in acetonitrile in a one-compartment
cell affords N-benzylacetamide as major product.13 When
this reaction is carried out under our experimental
conditions, again N-benzylacetamide (54%) is the major
product, but 1 (38%) is also obtained. In this case, the
electrogenerated benzyl cation can react either with
Su p p or t in g In for m a t ion Ava ila b le: Crystal data and
structure refinement for 1. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O016065H
(14) Nyberg, K. Chem. Commun. 1969, 774.
(15) Isaacs, N. S. Physical Organic Chemistry; Longman Scientific
and Technical: Essex, U.K., 1987; p 134.
(13) Eberson, L.; Olofsson, B. Acta Chem. Scand. 1969, 23, 2355.