Synthesis of N-substituted 4,6-dimethyl-3-cyano-2-pyridones under microwave irradiation

Article abstract of DOI:10.1080/00397910500334421

N-substituted 4,6-dimethyl-3-cyano-2-pyridones have been prepared from acetylacetone, N-substituted cyanoacetamide, and pyperidine as catalyst under microwave irradiation without solvent. The rapid and simple method produced pure products in high yields. Copyright Taylor & Francis LLC.

Full text of DOI:10.1080/00397910500334421

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Synthesis of N‐Substituted
4,6‐Dimethyl‐3‐cyano‐2‐pyridones Under
Microwave Irradiation
a
Dušan Mijin a & Aleksandar Marinković
a Department of Organic Chemistry, Faculty of Technology and Metallurgy,
University of Belgrade, Belgrade, Serbia and Montenegro
Published online: 15 Aug 2006.
To cite this article: Dušan Mijin & Aleksandar Marinković (2006): Synthesis of N‐Substituted
4,6‐Dimethyl‐3‐cyano‐2‐pyridones Under Microwave Irradiation, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 36:2, 193-198
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Synthetic Communicationsw, 36: 193–198, 2006
Copyright # Taylor & Francis LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500334421
Synthesis of N-Substituted
4,6-Dimethyl-3-cyano-2-pyridones
Under Microwave Irradiation
ˇ
´
Dusan Mijin and Aleksandar Marinkovic
Department of Organic Chemistry, Faculty of Technology and
Metallurgy, University of Belgrade, Belgrade, Serbia and Montenegro
Abstract: N-substituted 4,6-dimethyl-3-cyano-2-pyridones have been prepared from
acetylacetone, N-substituted cyanoacetamide, and pyperidine as catalyst under
microwave irradiation without solvent. The rapid and simple method produced pure
products in high yields.
Keywords: Synthesis, microwave, pyridone, cyanoacetamide, acetylacetone
Microwave irradiation has become an important method in organic synthesis
that can be applied to a wide range of reactions within short reaction times and
with high yields. Reactions in the absence of solvent (solvent-free synthesis)
under microwave irradiation also offer several advantages. The absence of
solvent reduces risk of explosion and simplifies the workup.[1]
Some studies have been published on synthesis of a wide variety of hetero-
cycles using microwave irradiation.[1,2] A few studies can be found about organic
synthesis under microwave irradiation of some 3-cyano-2-pyridones such as
synthesis of some derivatives of 6-hydroxy-3-cyano-2-pyridones[3] and lately
4,6-disubstituted 3-cyano-2-pyridones from chalkones and cyanoacetamide.[4]
Substituted 3-cyano-2-pyridones are important intermediates in the
pharmaceutical, dye, and photo industries. Their syntheses have been
Received in Poland May 23, 2005
ˇ
Address correspondence to Dusan Mijin, Department of Organic Chemistry,
Faculty of Technology and Metallurgy, University of Belgrade, Belgrade 11120,
Serbia and Montenegro. Tel.: þ381-11-33-03-671; Fax: þ381-11-33-70-671; E-mail:
kavur@tmf.bg.ac.yu
193

´
D. Mijin and A. Marinkovic
194
widely studied using conventional heating in the presence of various catalysts
and usually in polar solvents.[5,6]
In the study of condensation of various 1,3-diketones with cyanoacetamide
in our department, different reaction conditions, including phase-transfer
catalysis and enzymes, have been used.[6] Now, we report the synthesis of
N-substituted 4,6-dimethyl-3-cyano-2-pyridones using microwave irradiation.
A series of N-alkyl- and N-(4-substituted phenyl)-4,6-dimethyl-3-
cyano-2-pyridones were synthesized starting from acetylacetone
(2,4-pentanedione) and corresponding N-substituted cyanoacetamide using
microwave irradiation as well as conventional synthesis (Scheme 1).
Starting N-substituted cyanoacetamides were obtained by known
methods.[5,7] In both syntheses of pyridones, piperidine was used as the
catalyst. In conventional synthesis, a water/ethanol mixture was used as
the solvent and heating was performed at reflux temperature. Microwave
synthesis was performed in a domestic commercial microwave oven.
Unsubstituted pyridone was also obtained. Some of these compounds
have not been found in literature and to our knowledge were synthesized
for the first time. The obtained results are given in Table 1.
Except the 4,6-dimethyl-3-cyano-2-pyridone, which was obtained at
100 W and after 30 s (conventional synthesis 30 min, reflux), all other
N-substituted 4,6-dimethyl-3-cyano-2-pyridones were obtained at 200 W
after 7 min of irradiation. In comparison to the conventional, microwave
synthesis gives products in higher yields in almost all cases and in very
short reaction time (conventional synthesis 4 h, reflux). The obtained
1
products were characterized by melting point, IR, and H NMR data.
This simple and rapid microwave procedure, which gives the product in
high yield with high purity, can be used for the preparation of similar
heterocyclic substances that contain a 2-pyridone unit.
EXPERIMENTAL
IR spectra were obtained using FTIR BOMEM MB 100 in the form of
1
KBr pellets. H NMR spectra were recorded on a Varian-Gemini 200-MHz
spectrometer using DMSO-d6 or CF3COOD as solvent and TMS as internal
standard.
Scheme 1.

4,6-Dimethyl-3-cyano-2-pyridones
195
Table 1. N-substituted 4,6-dimethyl-3-cyano-2-pyridones obtained by microwave
and conventional synthesis
Conventional
synthesis
Microwave synthesis
Yield
(%)
Mp
(8C)
Yield
(%)
Mp
(8C)
No.
R
1
2
H
85
81
71
72
66
96
95
95
97
99
84
90
86
86
91
84
78
34
285–7
198–200
168–70
101–3
94–6
80
60
55
46
30
75
72
73
75
72
73
73
76
73
80
64
13
91
285–6
197–9
170–1
104–6
99–100
252–3
247–9
314–6
274–6
266–8
222–4
300–3
307–9
300–2
259–61
278–81
323 (dec.)
245–7
Me
Et
3
4
Pr
5
Bu
Ph
6
250–2
240–2
307–8
268–70
266–8
226–8
303–6
306–8
300–2
259–61
280–2
325 (dec.)
246–7
7
4-MeOC6H4
4-ClC6H4
4-MeC6H4
4-FC6H4
8
9
10
11
12
13
14
15
16
17
18
a
4-EtC6H4
a
4-NMe2C6H4
4-BrC6H4
4-IC6H4
4-AcC6H4
4-NO2C6H4
4-COOHC6H4
a
a
4-OHC6H4
aNew compounds.
General Procedure for the Preparation of Pyridones
Method A (Microwave)
A mixture of equimolar amounts of acetylacetone and corresponding
N-substituted cyanoacetamide (5 mmol) and piperidine (0.5 cm3) was placed
in a flask and irradiated at 200 W for 7 min in a domestic microwave oven.
Obtained product was purified by crystallization from ethanol.
Method B (Conventional)
Equimolar amounts of acetylacetone and corresponding N-substituted
cyanoacetamide (10 mmol) were heated under reflux in a water/ethanol
mixture (20 cm3) in the presence of a few drops of piperidine as catalyst for
4 h. Product was purified by crystallization from ethanol.

´
D. Mijin and A. Marinkovic
196
4,6-Dimethyl-3-cyano-2-pyridone (1): mp 290–18C,[8] IR nmax (cm21
(KBr): 2200, 1640, H NMR (d/ppm) (CF3COOD): 2.62 (3H, s, CH3); 2.68
(3H, s, CH3), 6.80 (1H, s, 5H).
)
1
N-Methyl-4,6-dimethyl-3-cyano-2-pyridone (2): 203–48C,[9] IR nmax
(cm21) (KBr): 2213, 1650, 1H NMR (d/ppm) (DMSO-d6): 2.30 (3H, s,
4-CH3), 2.42 (3H, s, 6-CH3), 3.44 (3H, s, 1-CH3), 6.32 (1H, s, 5H).
N-Ethyl-4,6-dimethyl-3-cyano-2-pyridone (3): 174–58C,[9]IR nmax(cm21
(KBr): 2213, 1644, H NMR (d/ppm) (DMSO-d6): 1.20 (3H, t, CH3–CH2),
2.30 (3H, s, 4-CH3), 2.45 (3H, s, 6-CH3), 4.00 (2H, q, CH2), 6.30 (1H, s, 5H).
)
1
N-n-Propyl-4,6-dimethyl-3-cyano-2-pyridone (4): 1148C,[9] IR nmax (cm21
(KBr): 2216, 1646, H NMR (d/ppm) (DMSO-d6): 0.90 (3H, t, CH3–CH2),
1.60 (2H, m, CH3–CH2), 2.30 (3H, s, 4-CH3), 2.44 (3H, s, 6-CH3), 3.90
(2H, q, CH2–N), 6.28 (1H, s, 5H).
)
1
N-n-Butyl-4,6-dimethyl-3-cyano-2-pyridone (5): 99–1008C,[9] IR nmax
(cm21) (KBr): 2214, 1653, 1H NMR (d/ppm) (DMSO-d6): 0.95 (3H, t,
CH3–CH2), 1.45 [4H, m, CH3–(CH2)2], 2.31 (3H, s, 4-CH3), 2.45 (3H, s,
6-CH3), 3.95 (2H, t, CH2–N), 6.30 (1H, s, 5H).
N-Phenyl-4,6-dimethyl-3-cyano-2-pyridone (6): 2558C,[10] IR nmax (cm21
)
(KBr): 2219, 1670, 1656, 1H NMR (d/ppm) (DMSO-d6): 1.960 (3H, s,
4-CH3); 2.388 (3H, s, 6-CH3) 6.459 (1H, s, 5H); 7.290–7.607 (5H, m, Ph).
N-(4-Methoxy phenyl)-4,6-dimethyl-3-cyano-2-pyridone (7): 247–98C,[5]
1
IR nmax (cm21) (KBr): 2217, 1658, H NMR (d/ppm) (DMSO-d6): 1.976
(3H, s, 4-CH3); 2.379 (3H, s, 6-CH3); 3.817 (3H, s, CH3O); 6.441 (1H, s,
5H); 7.053–7.252 (4H, dd, Ph).
N-(4-Chloro phenyl)-4,6-dimethyl-3-cyano-2-pyridone (8): 314–68C,[5] IR
1
nmax (cm21) (KBr): 2219, 1661, H NMR (d/ppm) (DMSO-d6): 1.975 (3H,
s, 4-CH3); 2.389 (3H, s, 6-CH3); 6.467 (1H, s, 5H); 7.366–7.649 (4H, dd, Ph).
N-(4-Methyl phenyl)-4,6-dimethyl-3-cyano-2-pyridone (9): 274–68C,[5] IR
1
nmax (cm21) (KBr): 2218, 1661, H NMR (d/ppm) (DMSO-d6): 1.962 (3H,
s, 4-CH3); 2.381 (6H, s, 6-CH3, and CH3Ph); 6.448 (1H, s, 5H); 7.157–
7.372 (4H, dd, Ph).
N-(4-Fluoro phenyl)-4,6-dimethyl-3-cyano-2-pyridone (10): 272–48C,[5] IR
1
nmax (cm21) (KBr): 2221, 1663, H NMR (d/ppm) (DMSO-d6): 1.975 (3H, s,
4-CH3); 2.388 (3H, s, 6-CH3); 6.462 (1H, s, 5H); 7.383–7.418 (4H, d, Ph).
N-(4-Ethyl phenyl)-4,6-dimethyl-3-cyano-2-pyridone (11): IR nmax (cm21
(KBr): 2218, 1659, H NMR (d/ppm) (DMSO-d6) 1.231 (3H, t, CH3–CH2);
1.961 (3H, s, 4-CH3); 2.382 (3H, s, 6-CH3); 2.680 (2H, q, CH3–CH2); 6.448
(1H, s, 5H); 7.181–7.406 (4H, dd, Ph).
)
1

4,6-Dimethyl-3-cyano-2-pyridones
197
N-(4-N,N-Dimethyl phenyl)-4,6-dimethyl-3-cyano-2-pyridone (12): IR
1
nmax (cm21) (KBr): 2215, 1658, H NMR (d/ppm) (DMSO-d6): 1.983 (3H,
s, 4-CH3); 2.366 (3H, s, 6-CH3); 2.957 [6H, s, N(CH3)2]; 6.408 (1H, s, 5H);
6.769–7.065 (4H, dd, Ph).
N-(4-Bromo phenyl)-4,6-dimethyl-3-cyano-2-pyridone (13): .3008C,[5] IR
n
max (cm21) (KBr): 2219, 1661, 1H NMR (d/ppm) (DMSO-d6): 1.974 (3H, s,
4-CH3); 2.387 (3H, s, 6-CH3); 6.465 (1H, s, 5H); 7.299–7.780 (4H, dd, Ph).
N-(4-Iodo phenyl)-4,6-dimethyl-3-cyano-2-pyridone (14): 300–28C,[5] IR
nmax (cm21) (KBr): 2218, 1659, 1H NMR (d/ppm) (DMSO-d6): 1.970
(3H, s, 4-CH3); 2.383 (3H, s, 6-CH3); 6.461 (1H, s, 5H); 7.133–7.938
(4H, dd, Ph).
N-(4-Acetyl phenyl)-4,6-dimethyl-3-cyano-2-pyridone (15): IR nmax
(cm21) (KBr): 2218, 1685, 1650, 1H NMR (d/ppm) (DMSO-d6): 1.975
(3H, s, 4-CH3); 2.404 (3H, s, 6-CH3); 2.649 (3H, s, CH3–CO); 6.501 (1H,
s, 5H); 7.497–8.143 (4H, dd, Ph).
N-(4-Nitro phenyl)-4,6-dimethyl-3-cyano-2-pyridone (16): 278–2818C,[5] IR
1
nmax (cm21) (KBr): 2220, 1660, H NMR (d/ppm) (DMSO-d6): 1.989 (3H,
s, 4-CH3); 2.412 (3H, s, 6-CH3); 6.517 (1H, s, 5H); 7.685–8.430 (4H, dd, Ph).
N-(4-Carboxy phenyl)-4,6-dimethyl-3-cyano-2-pyridone (17): IR nmax
(cm21) (KBr): 2222, 1730, 1718, 1643, 1H NMR (d/ppm) (DMSO-d6):
1.976 (3H, s, 4-CH3); 2.401 (3H, s, 6-CH3); 6.481 (1H, s, 5H); 7.461–8.124
(4H, dd, Ph); 13.238 (1H, s, COOH).
N-(4-Hydroxy phenyl)-4,6-dimethyl-3-cyano-2-pyridone (18): IR nmax
1
(cm21) (KBr): 2223, 1647, H NMR (d/ppm) (DMSO-d6): 1.972 (3H, s,
4-CH3); 2.366 (3H, s, 6-CH3); 6.409 (1H, s, 5H); 6.854–7.089 (4H, dd, Ph);
9.843 (1H, s, OH).
ACKNOWLEDGMENT
We are grateful to the Ministry of Science and Environmental Protection of
Serbia for the financial support (Project 1694).
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