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1667
established intermediates in synthetic organic methodology as
formylating agents for the preparation of enamines.18 DMFDMA
is a potentially valuable reagent in heterocyclic synthesis19 and
we have used it for the preparation of enaminonitriles. The com-
pounds 3a–c were prepared by the reaction of arylethylidenemal-
ononitrile derivatives with an equimolar amount of DMFDMA at
room temperature for 2 h under solvent free conditions (Table 2).
The structure of the compounds 3a–c was confirmed by spectral
analysis. The IR spectra showed the appearance of a new band near
1600 cmÀ1 of C@C group. For all the compounds, the mass spectra
displayed molecular ion peaks in agreement with the expected
structures. NMR spectra of 3a–c were in accordance with the ex-
pected structure. Finally the X-ray crystallography of compound
3b has confirmed the structure of enaminonitrile that is com-
pletely planar.
imine anion and the double bond of the enamine. The reaction fin-
ished by an aromatization step.
3. Conclusions
In conclusion, we have reported a convenient and green
approach for the preparation of novel 4-substituted-3-cyano-
2-aminopyridines under solvent-free conditions under heating or
under MW activation. This methodology opens a new route for
the synthesis of various substituted nitrogen heterocycles because
of its ease in execution, rapid access and good yields.
Acknowledgement
The authors wish to thank financial support from the ‘Ministère
de l’Enseignement Supérieur et de la Recherche Scientifique Algé-
rien’ (MESRS) within the program PNR 2011.
The crystal packing of 3b is governed by intermolecular C–
H. . .N weak interactions (Fig. 2).
2.3. Synthesis of 2-aminopyridine derivatives
References and notes
In continuation of our current studies on the chemistry of ena-
minonitriles and particularly in the application of solvent-free syn-
thesis of nitrogen heterocycles, we have synthesized a new series
of substituted 2-aminopyridines 4–6 via the reaction of enamino-
nitriles 3a–c with various primary amines (Table 3). We report
herein an extension of our investigation on the synthesis of
2-aminopyridines15d under solvent-free conditions using both
thermal heating and MW irradiation methods and we have com-
pared our results which demonstrate the advantage of MW irradi-
ation method. Heating an equimolar mixture of precursors 3a–c
and different primary amines (methylamine, allylamine, butyl-
amine, isopropylamine and benzylamine) for 3 h provided the
compounds 4–6 in the yields of 48–79%a (Table 3). On the other
hand, compounds 4–6 were obtained in high yields 50–84%b from
precursors 3a–c and different amines using MW irradiation for
2 min. It is clear here that both solvent-free methods using conven-
tional heating and MW irradiation are efficient, but because of the
short reaction times (few minutes) and higher yields, MW irradia-
tion is preferred (Table 3). All structures are fully characterized by
standard spectroscopic methods (1H and 13C NMR, IR MS data).
The 2-aminopyridine structure was confirmed by single crystal
X-ray diffraction studies of the compound 5c (Fig. 3).
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Within the crystal, compound 5c is stabilized by one H-bond
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along the axis [101] (Fig. 3).
A possible mechanism for the formation of 4-substituted-3-cy-
ano-2-aminopyridines was described in Scheme 1. First, intermedi-
ate A was obtained by a condensation reaction between primary
amines and one of the nitrile groups of enaminonitrile 3. A then
underwent an intramolecular cyclization reaction between the
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H
R
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Benmeddah, A.; Hazimeh, H.; Ziani-Cherif, C. Lett. Org. Chem. 2006, 3, 558–559;
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R
N
N
NC
Ar
N
NC
Ar
NC
Ar
NH
N
NH
N
+
N
R NH2
A
3
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R
R
HN
N
NC
Ar
NC
Ar
H
N
N
17. General procedure 1 for the synthesis of arylethylidenemalononitriles 2a–c: A
mixture of substituted acetophenones 1a–c (10 mmol), malononitrile
Scheme 1. Formation of 4-substituted-3-cyano-2-aminopyridines 4–6.