The application of vinamidinium salts to the synthesis of 2-amino-5-aryl or formylpyridine-3-carbonitriles

Article abstract of DOI:10.1002/jhet.911

The symmetrical vinamidinium salts were allowed to react with malononitrile in refluxing ethanol in the presence of ammonium acetate for 12 h to afford the 2-amino-5-aryl or formylpyridine-3-carbonitriles.

Full text of DOI:10.1002/jhet.911

Month 2013
The Application of Vinamidinium Salts to the Synthesis of
2‐Amino‐5‐aryl or Formylpyridine‐3‐carbonitriles
*
Fayçel Jemmezi, Samar Chtiba, and Jameleddine Khiari
Laboratoire de Chimie Organique et Analytique. Institut Supérieur de l’Education et de la
Formation Continue, Bardo, Tunisia
*
E-mail: jamelkhiari@yahoo.fr
Received January 11, 2011
DOI 10.1002/jhet.911
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
The symmetrical vinamidinium salts were allowed to react with malononitrile in refluxing ethanol in the
presence of ammonium acetate for 12 h to afford the 2‐amino‐5‐aryl or formylpyridine‐3‐carbonitriles.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
procedure by condensation of symmetrical vinamidinium
salts with malononitrile and ammonium acetate.
In our quest to utilise vinamidinium salts as three‐carbon
synthons in the formation of heterocyclic compounds, we
have reported the preparation of pyridine‐2‐ones [1, 2]
and pyrimidines [3]. The pyridine ring is one of the most
well‐known systems among the naturally occurring hetero-
cycles [4]. Classical methods for the formation of pyridines
have been used extensively. Such methods include the
Friedländer condensation of enaminoketones of β‐ketoesters
with 1,3‐diketones [5], the Hantzsch pyridine synthesis from
β‐dicarbonyl compounds in the presence of an aldehyde and
ammonia [6] and the related Knovenagel cyclisation of
β‐aminoacrylates with α,β‐unsaturated carbonyl compounds
[7]. The synthesis of trisubstitued pyridines has been
reported [8, 9] from the reaction of deoxybenzoin,
vinamidinium species and ammonia in good yields and
act as Cox‐2 inhibitors. 2‐Aminopyridine are promising
substituted pyridines which have been shown to be biologi-
cally active molecules [10]. Additionally, because of their
chelating abilities, 2‐aminopyridines are commonly used as
ligands in inorganic and organometallic chemistry [11]. This
class of compounds and their derivatives are valuable
synthetic target compounds and their synthesis has been
extensively reviewed [12–17].
The vinamidinium salts (1a–g) used in this study were
prepared by the standard Vilsmeir–Haack reaction of the
appropriate aryl acetic [18]. During the course of our
studies on the synthetic application of vinamidinium
salts, we succeeded in a very simple access to 2‐
dimethylaminomethylene‐1,3‐bis(dimethylimonio)propane
diperchlorate 1h from malonic acid [19]. All of these salts,
were isolated as the perchlorate and were used without
further purification for the synthesis of 3,5‐disubstituted
2‐aminopyridines. As shown in Scheme 1, the symmetrical
vinamidinium salts (1a–h) were allowed to react with
malononitrile in refluxing ethanol in the presence of
ammonium acetate for 12 h to afford the 2‐amino‐5‐aryl
or formylpyridine‐3‐carbonitriles (2a–h). For the most part
the reactions were rather clean and proceed in excellent
yields (Table 1).
Additionally, as shown in Table 1, the phenylsulfonyl at
the C5‐substituent (2g) affected the cyclocondensation
reaction. This may be the result of the “push–pull” relation-
ship between the strong electron‐withdrawing sulfonyl
group at C2 position and enamine group, in the correspond-
ing vinamidinium salts allowing the imino group to behave
like an isolated moiety.
The proposed mechanism delineated in Scheme 2
involves addition of malononitrile to vinamidinium salts
(1) and should lead to the formation of enamine (3). Alter-
natively, intramolecular cyclisation of this intermediate
induced by ammonium acetate with elimination of
RESULTS AND DISCUSION
We report here a simple method for the synthesis of 2‐
amino‐5‐aryl or formylpyridine‐3‐carbonitriles in one‐step
© 2013 HeteroCorporation

J. Fayçel, C. Samar, and K. Jameleddine
Vol 000
Scheme 1
Scheme 2. Proposed reaction mechanism.
dimethylamine would give the 5‐substituted 2‐aminopyridine‐
3‐carbonitrile (2).
organic layers were dried over sodium sulphate. The drying
agent was removed by filtration and the solvents were removed
in vacuo to give the crude material. The crude product was
purified by a column chromatography (10% EtOAc in hexane)
to give product 2a–g. However, for trisubstituted pyridine 2h,
after evaporation of the solvent, 6 mL of THF and 6 mL of 1 N
HCl are added. The mixture is allowed to stir at room
temperature for 2 h, then neutralized with satured aqueous
NaHCO3 and extracted with three portions of methylene chloride.
CONCLUSION
In summary, we have demonstrated that malononitrile
react with vinamidinium salts in the presence of ammo-
nium acetate to give in one‐step the corresponding 2‐
amino‐5‐aryl or formylpyridine‐3‐carbonitriles in fair to
excellent yields. Therefore, the aldehyde group becomes
a convenient vehicle for functional group interconversion.
Representative spectral data of selected compounds.
2‐Amino‐5‐phenylpyridine‐3‐carbonitrile (2a). Yield: 96%;
1
yellow solid; mp = 132–134°C; H‐NMR (300 MHz, CDCl3): δ
= 5.72 (s, 2H), 7.40–7.60 (m, 5H), 7.83–7.7.84 (d, 1H, J = 2.6
Hz), 8.41–8.42 (d, 1H, J = 2.6 Hz); Anal. calcd. for C12H9N3: C,
73.83; H, 4.65; N, 21.52%. Found: C, 73.79; H, 4.60; N,
21.48%. Mass m/z (EI, 30 eV): m/z = 195 (M+).
2‐Amino‐5‐(4‐methoxyphenyl)pyridine‐3‐carbonitrile (2b).
Yield: 97%; yellow solid; mp = 137–139°C; 1H‐NMR (300
MHz, CDCl3): δ = 3.42 (s, 3H), 5.81 (s, 2H), 6.91–6.96 (m, 2H),
7.11–7.16 (m, 2H), 7.49–7.50 (m, 2H, J = 2.4 Hz), 7.94–7.95 (d,
1H, J = 2.4 Hz); 13C‐NMR (CDCl3) δ = 55.8, 107.6, 113.9,
128.8, 132.6, 132.8, 135.8, 136.2, 137.1, 145.7, and 159.9. Anal.
calcd. for C13H11N3O: C, 69.32; H, 4.92; N, 18.65%. Found: C,
69.28; H, 4.89; N, 18.62%. Mass m/z (EI, 30 eV): m/z = 225 (M+)
EXPERIMENTAL
Melting points were determined in a capillary tube and are
uncorrected. The H‐NMR spectra were recorded on a Brucker
1
AC 300 MHz spectrometer in CDCl3 containing tetramethylsilane
as an internal standard. Elemental analyses were determined by
using Perkin‐Elmer 240c elemental analyzer. Thin layer chroma-
tography (TLC) was performed on precoated silica gel plates
(0.25 mm, Merck). Column chromatography was performed on
Merck silica gel having size 0.063–0.200 mm.
General procedure for the heteroannulation. A mixture
of vinamidinium salt 1 (0.48 mmol), malononitrile (1 mmol),
ammonium acetate (3.36 mmol), and anhydrous ethanol (8 mL)
were combined in a reaction flask and allowed to reflux
overnight at which time the reaction mixture was allowed to
cool at room temperature and the solvent was removed by
rotary evaporation. The resulting residue was partitioned
between methylene chloride and water. The aqueous layer was
extracted with fresh methylene chloride and the combined
2‐Amino‐5‐(1‐naphtyl)pyridine‐3‐carbonitrile (2f).
Yield:
92%; yellow solid; mp = 148–150°C; 1H‐NMR (300 MHz,
CDCl3): δ = 6.51 (s, 2H), 7.40–7.87 (m, 5H), 7.83–7.84 (d, 1H,
J = 2.4 Hz), 8.41–8.42 (d, 1H, J = 2.4 Hz); 13C‐NMR (CDCl3)
δ = 125.53, 126.157, 127.45, 128.45, 129.189, 130.30, 130.95,
132.8, 135.8, 136.2, 137.1, 145.7, and 159.9. Anal. calcd. for
C16H11N3: C, 78.35; H, 4.52; N, 17.13%. Found: C, 78.31; H,
4.49; N, 17.11%. Mass m/z (EI, 30 eV): m/z = 245 (M+).
2‐Amino‐5‐formylpyridine‐3‐carbonitrile (2h). Yield: 78%;
yello‐white solid; mp = 127–129°C; 1H‐NMR (300 MHz,
CDCl3): δ = 5.06 (s, 2H), 8.18 (d, H, J = 2.3 Hz), 9.21(d, H, J =
2.3 Hz), 9.95 (s, 1H). 13C‐NMR (CDCl3) δ = 97.31, 115.38,
123.24, 142.19, 154.92, 168.84, and 192.45. Anal. calcd. for
C7H5N3O: C, 57.14; H, 3.43; N, 28.56%. Found: C,57.11; H,
3.41; N, 28.53%. Mass m/z (EI, 30 eV): m/z = 147 (M+).
Table 1
Synthesis of 2‐amino‐5‐aryl or formylpyridine‐3‐carbonitriles 2a–h.
Compounda
R
R′
Yield (%)
2a
2b
2c
2d
2e
2f
Ph
Ph
96
97
95
91
94
92
82
78
4‐CH3OPh
4‐CH3Ph
4‐BrPh
4‐ClPh
Naphtyl
SO2Ph⊕
HC ¼ NðMeÞ2
4‐CH3OPh
4‐CH3Ph
4‐BrPh
4‐ClPh
Naphtyl
SO2Ph
REFERENCES AND NOTES
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[2] (a) Khiari, J. E.; Gmiza, T.; Hadj Ayed, M. A.; Ben Hassine,
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2g
2h
CHO
aAll products were characterized from their 1H NMR, 13C NMR, and mass
spectroscopic data.
[3] Hadj Ayed, M. A.; Khiari, J. E.; Ben Hassine, B. Mol Divers
2008, 12, 61.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
The Application of Vinamidinium Salts to the Synthesis of 2-Amino-5-aryl or
Formylpyridine-3-carbonitriles
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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