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
[1] Gmiza, T.; Khiari, J. E.; Hadj Ayed, M. A.; Ben Hassine, B.
Synth Commun 2007, 37, 1053.
[2] (a) Khiari, J. E.; Gmiza, T.; Hadj Ayed, M. A.; Ben Hassine,
B. Synth Commun 2007, 37, 3939; (b) Xue, H. Z.; Wu, Z. L.; Song, L.
Chin Chem Lett 2009, 20, 771.
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