Improved Synthesis of 2-Amino-3-cyanopyridines in Solvent Free Conditions under Microwave Irradiation

Article abstract of DOI:10.1039/a708521d

A simple and efficient method is developed for the rapid synthesis of 2-amino-3-cyanopyridines 3-5 from arylidenemalanonitriles 1 and ketones 2 or 4 in presence of ammonium acetate without solvent/containing traces of solvent under microwave irradiation:

Full text of DOI:10.1039/a708521d

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330 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
1998, 330±331$
Improved Synthesis of 2-Amino-3-cyanopyridines
in Solvent Free Conditions under Microwave
Irradiation$
Satya Paul,a Rajive Gupta*a and Andre Loupyb
aDepartment of Chemistry, University of Jammu, Jammu 180006, India
bLaboratoire des Reactions Selectives sur Supports ICMO, UA 478 Batiment 410,
Universite de Paris - Sud, 91405 ORSAY, Cedex, France
A simple and efficient method is developed for the rapid synthesis of 2-amino-3-cyanopyridines 3±5 from arylidenemala-
nonitriles 1 and ketones 2 or 4 in presence of ammonium acetate without solvent/containing traces of solvent under
microwave irradiation : reaction times are considerably reduced with improved yields as compared to those obtained
under classical heating.
Organic synthesis under microwave irradiation is now
widely used.1±3 Dry media techniques by microwave heating
have attracted much attention4±6 and o€ers several advan-
tages: solvents are often expensive, toxic, dicult to remove
in case of aprotic dipolar solvents with high boiling points,
and are agents that pollute the environment. Liquid±liquid
extraction is avoided for the isolation of the reaction pro-
ducts. The absence of solvent also reduces the risk of
hazardous explosions when the reaction takes place in a
closed vessel in the microwave oven.
The preparation of 2-amino-3-cyanopyridines continues
to be the subject of numerous papers as these are versatile
intermediates for the synthesis of variety of heterocyclic
compounds.7±9 Many of the standard procedures10±12
require either longer reaction times or in some cases lead to
mixtures of products and proceed in low yields.
Keeping in view the importance of 2-amino-3-cyano-
pyridines and recent trends of phasing out the use of
organic solvents and devising environmentally-friendly tech-
niques, we report the synthesis of 2-amino-3-cyanopyridines
3±5 from arylidenemalanonitriles 1 and ketones 2 or 4 in the
presence of ammonium acetate using microwaves without
solvent or containing traces of solvent.
In the classical approach, the synthesis of 3 or 5 requires
Scheme 1
The amount of ammonium acetate and power output
was adjusted to get the maximum yield of the products
3 or 5. By carrying out reactions with di€erent amounts
of ammonium acetate at di€erent power outputs, it has
been found that 8 mmol of the ammonium acetate furnished
the maximum yield for 1 mmol of the reactants, when
5±8 h re¯uxing in benzene. In contrast, the same reaction
when performed under microwave irradiation required
3±5 min and improvement in yields was also observed. The
work-up is simply reduced to treatment with ethanol, which
on standing gave 2-amino-3-cyanopyridines as crystalline
products.
Table 1 Analytical and spectral data of compounds 5
1
b
dH
Compound
Mp (8C)
Ma
umax/cm
m/z (%)
5a
169±170
C20H15N3
3420, 3350, 3175, 2210
3450, 3350, 3150, 2220
2.55±2.95 [m, 4 H, (CH2)2], 5.20±5.50 (br s, 297 (100)
2 H, NH2) 7.00±7.80 (m, 9 H, aryl H)
5b
5c
164±165
215±216
C21H17N3O
C22H19N3O2
2.60±3.0 [m, 4 H, (CH2)2], 3.85±3.95 (s,
3 H, OCH3), 5.25±5.35 (br s, 2 H, NH2),
6.95±7.60 (m, 8 H, aryl H)
327 (100)
3450, 3310, 3180, 2210
3430, 3330, 3150, 2200
1.50±1.57 (t, 3 H, CH3), 3.60±3.66 (s, 2 H, 357 (100)
CH2), 3.90±3.98 (s, 3 H, OCH3), 4.20±
4.28 (q, 2 H, OCH2), 5.25±5.32 (br s, 2 H,
NH2), 6.98±7.60 (m, 7 H, aryl H)
5d
208±209
C23H21N3O3
1.50±1.60 (t, 3 H, CH3), 3.60±3.65 (s, 2 H,
CH2), 3.90±4.0 (s, 6 H, 2 Â OCH3), 4.20±
4.30 (q, 2 H, OCH2), 5.30±5.38 (br s, 2 H,
NH2), 6.95±7.55 (m, 6 H, aryl H)
387 (100)
aAll the compounds gave C, H and N analyses within 20.5%. bThe 1H NMR spectra were recorded in CDCl3.
irradiated at a power output of 275 W. Furthermore, it
has been found that if o-dichlorobenzene (0.5 ml) was added
to the reactants (3 mmol), the yields increase considerably
e.g. in 5b it increases from 50 to 78%. The addition of
*To receive any correspondence.
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [J. Chem. Research (S), 1998, Issue 1]; there is therefore
no corresponding material in J. Chem. Research (M).

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J. CHEM. RESEARCH (S), 1998 331
Table 2 Comparison of reaction times and yields for compounds 3 and 5 using microwave and classical methods
Reaction time
Yield (%)
Microwave (min)
Without solvent
Microwave
Classical reflux
with benzene (h)
Compound
Trace solvent
Without solvent
Trace solvent
Classical
3a
3b
3c
3d
5a
5b
5c
5d
4.0
4.0
4.5
3.5
4.0
4.5
4.0
4.5
3.0
3.5
3
3.5
4.0
4.0
3.5
3.5
5
6
5.5
6
5.5
6
52
43
58
52
51
50
42
52
72
75
78
69
70
78
72
70
49
46
69
46
52
55
46
48
6
5.5
obtained was ®ltered, washed with ethanol and recrystallised from
the appropriate solvent (benzene, light petroleum (bp 40±60 8C)±
ethanol or tetrahydrofuran). The analytical and spectral data of
5a±5d are given in Table 1 while 3a±3d were characterised by their
literature melting points.12
o-dichlorobenzene as an energy-transfer medium is to permit
a higher temperature and better homogeneity in the reaction
medium.
In order to study the possible existence of a speci®c
microwave e€ect, we have carried out all the reactions using
the conventional heating mode (oil bath) at the same ®nal
temperatures and reaction times as measured in the micro-
wave experiments. In all cases no reactions were detected as
determined by TLC. Lower yields were obtained with the
conventional heating mode, even after 4 h of reaction, indi-
cating that the e€ect of microwave irradiation is not purely
thermal.
In conclusion, we have developed
a simple, ecient and
environmentally friendly method for the synthesis of 2-amino-3-
cyanopyridines using an unmodi®ed domestic microwave oven.
Yields were enhanced by addition of a small amount of solvent,
here o-dichlorobenzene.
One of us (S. P.) thanks the CSIR, New Delhi for the
award of a senior research fellowship.
The title compounds were characterised on the basis of
analytical, spectral data and by comparison with authentic
samples prepared by known methods12 (Table 1). The reac-
tion pathway is shown in Scheme 1. The reaction times and
yields using microwave and conventional methods have been
compared (Table 2).
Received, 25th November 1997; Accepted, 25th February 1998
Paper E/7/08521D
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The mass spectra were performed on a Delsi/Nermag spectral 30
spectrometer. Reactions were carried out in a BMO-700 T domestic
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General procedure for the synthesis of 2-amino-3-cyanopyridines.
ÐA mixture of arylidenemalanonitrile 1 (3 mmol), ketone 2 or 4
(3 mmol), ammonium acetate (24 mmol) and o-dichlorobenzene
a
(0.5 ml) was placed in
a borosil beaker (100 ml) and mixed
thoroughly with the help of a glass rod. The mixture was then sub-
jected to microwave irradiation for an optimized time (Table 2) at
a power output of 275 W. After completion of the reaction (moni-
tored by TLC), ethanol (4 ml) was added to the reaction mixture
and kept at room temperature for 5±10 min, the crystalline product
12 S. Kambe, K. Saito, A. Sakurai and H. Midorikawa, Synthesis,
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