An Efficient Method for the Synthesis of 3-Cyano-6-hydroxy-2(1H)- pyridinones under Microwave Irradiation and Solvent-free Conditions

Article abstract of DOI:10.1007/s00706-002-0551-2

Three component condensation of alkylacetoacetates, primary amines, and alkyl cyanoacetates catalyzed by solid supports under microwave irradiation gave N-alkyl 3-cyano-6-hydroxy-2(1H)-pyridinones with high yields. Upon carrying out the reaction under the same condition on acidic alumina, zeolite HY, silica gel, and montmorillonite K-10, the best yields were achieved by silica gel.

Full text of DOI:10.1007/s00706-002-0551-2

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Monatshefte f€ur Chemie 134, 453–456 (2003)
DOI 10.1007/s00706-002-0551-2
An Efficient Method for the Synthesis
of 3-Cyano-6-hydroxy-2(1H)-pyridinones
under Microwave Irradiation
and Solvent-free Conditions
Saeed Balalaie1;ꢀ, Elahe Kowsari1, and Mehri S. Hashtroudi2
1
Chemistry Department, K. N. Toosi University of Technology, P.O. Box 15875-4416 Tehran, Iran
2
Energy and Environment Department, Material and Energy Research Center, Tehran, Iran
Received August 28, 2002; accepted September 3, 2002
Published online February 3, 2003 # Springer-Verlag 2003
Summary. Three component condensation of alkylacetoacetates, primary amines, and alkyl cyano-
acetates catalyzed by solid supports under microwave irradiation gave N-alkyl 3-cyano-6-hydroxy-
2(1H)-pyridinones with high yields. Upon carrying out the reaction under the same condition on acidic
alumina, zeolite HY, silica gel, and montmorillonite K-10, the best yields were achieved by silica gel.
Keywords. Solvent-free organic synthesis; Microwave chemistry; Cyclocondensation; 2-pyridinones.
Introduction
1,2-Dihydro-6-hydroxy-4-methyl-2-oxo-3-pyridinecarbonitrile (3-cyano-6-hydroxy-
4-methyl-2(1H)-pyridinone) and other 1-substituted derivatives have found wide
application in the preparation of azo dyes, especially as disperse dyes for polymeric
materials [1–15].
There are many methods for the synthesis of 3-cyano-6-hydroxy-2(1H)-pyr-
idinones. Condensation of methyl acetoacetate with appropriate amines and methyl
cyanoacetate is a common method [1a, 16, 17]. Condensation of N-alkylcyano-
acetamides with ꢀ-ketoesters under pressure or in the presence of base [17] and
also basic condensation of N-alkylacetoacetamide with enamino-ꢀ-ketoesters lead
to 2(1H)-pyridinones [18]. Another efficient method is heating of cyanoacetamide
and methylacetoacetate in a microwave oven [19].
Following our research on the combination of solid supports and microwave for
the synthesis of many heterocyclic compounds [20], we report an efficient three
component condensation of alkylcyanoacetates, primary amines, and ꢀ-ketoesters
ꢀ
Corresponding author. E-mail: balalaie@yahoo.com

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454
S. Balalaie et al.
on the surface of silica gel, montmorillonite K-10, zeolite Hy, and acidic alumina
under microwave irradiation.
Results and Discussion
We introduce a one-pot three component condensation for the synthesis of 3-
cyano-6-hydroxy-2(1H)-pyridinones under microwave irradiation and solvent-free
condition. (Scheme 1)
In order to select the best solid support, we carried out the reaction of methyl
acetoacetate, methyl cyanoacetate, and methyl amine on the surface of silica gel,
acidic alumina, montmorillonite K-10, and zeolite HY under microwave irradia-
tion. Under all conditions, 4a was produced with good yields (93, 65, 60, 55%).
The best yield was obtained with silica gel as the solid support (Table 1). In all
experiments the optimized time of irradiation was two minutes. The products were
1
identified by their IR and H NMR spectroscopic data and melting points. These
compounds have two tautomeric forms, and in solution there is a very fast equili-
bration between them [21].
Yields of products under microwave irradiation and in the abscence of solid
supports under neat conditions were low and the reactants and products adhered to
the reaction vessel and led to irreproducible results. It seems that in-situ reaction of
ꢀ-ketoesters and primary amines leads to enamino-ꢀ-ketoester and reaction with
Scheme 1
Table 1. Solvent-free synthesis of 3-cyano-6-hydroxy-2(1H)-pyridinones under microwave
irradiation
R1
R2
R3
Product
Yielda
a
b
c
d
e
f
Me
Et
Me
Et
Me
4a
4a
4a
4a
4b
4b
4b
4b
4c
4d
93
91
91
91
93
93
94
94
77
87
Me
Et
Me
Et
Me
Me
Me
Et
Me
Me
Et
Et
Et
g
h
i
Et
Me
Et
Et
Me
Me
Me
Et
Me
Me
n-Pr
j
–CH2CH2OH
a
In all experiments, the optimized time of irradiation was 2 minutes

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Synthesis of 3-Cyano-6-hydroxy-2(1H)-pyridinones
455
alkylcyanoesters gives N-substituted 3-cyano-6-hydroxy-2(1H)-pyridinones in
high yield.
In conclusion, the one-pot nature of the present procedure makes it an accept-
able alternative to multistep approaches. It also simplifies the laborious procedures
and offers considerable advantages, such as elimination of solvents, high yields,
short reaction times, application of reusable solid catalysts, and environmentally
friendly character over the existing methodologies.
Experimental
Melting points were obtained on an Electrothermal 9100 apparatus and are uncorrected. The 1H NMR
spectra were determined in DMSO-d6 with TMS as internal reference on a Bruker AC-80 and DRX-500
AVANCE spectrometer. IR spectra were recorded on a Shimadzu IR-408 spectrometer in KBr disks. A
domestic microwave oven (Moulinex 2735 A) at 2450 MHz (100% power corresponding to 850 W)
was used in all experiments.
General Procedure
Alkylacetoacetic ester (3mmol), alkylcyanoacetic ester (3 mmol), primary amines (4mmol) and 2 g
silica gel were mixed thoroughly in a mortar, then the reaction mixture was irradiated under microwave
irradiation for 2 min. The reaction progress was monitored by TLC. The mixture was extracted with
2 ꢁ 30cm3 of methanol, filtered, and the solvent was removed under reduced pressure. For purification
of the products 10cm3 of hot H2O was added, then acidified with 6N HCl to pH 1–2. The precipitate
was collected, washed with H2O and dried to give the pure product. The yields are shown in Table 1.
3-Cyano-6-hydroxy-1,4-dimethyl-2(1H)-pyridinone (4a, C8H8N2O2): Mp 285ꢂC (ethanol [17a] 285ꢂC);
1
IR (KBr): ꢁꢀ ¼ 1665 (C¼O), 2200 (CN)cmꢃ 1; H NMR (DMSO-d6): ꢂ ¼ 2.25 (s, 3H, CH3), 3.40 (s,
3H, NCH3), 5.70 (s, 1H, ¼CH) ppm.
1-Ethyl-3-cyano-6-hydroxy-4-methyl-2(1H)-pyridinone (4b, C9H10N2O2): Mp 245ꢂC (ethanol [17a]
244–5ꢂC), IR (KBr): ꢁꢀ ¼ 1660 (C¼O), 2210 (CN)cmꢃ 1
;
1H NMR (DMSO-d6): ꢂ ¼ 1.0 (t, 3H,
J ¼ 7 Hz, CH3), 2.20 (s, 3H, CH3), 3.90 (q, 2H, J ¼ 7 Hz, CH2), 5.70 (s, 1H, ¼ CH) ppm.
3-Cyano-6-hydroxy-4-methyl-1-propyl-2(1H)-pyridinone (4c, C10H12N2O2): Mp 239–242ꢂC (ethanol
[17a] 239–240ꢂC), IR (KBr): ꢁꢀ ¼ 1660 (C¼O), 2210 (CN)cmꢃ 1; H NMR (DMSO-d6): ꢂ ¼ 0.9
1
(t, 3H, J ¼ 7 Hz, CH3), 1.50 (m, 2H, CH2), 2.20 (s, 3H, CH3), 3.90 (t, 2H, J ¼ 7 Hz, CH2), 5.60
(s, 1H, ¼CH) ppm.
3-Cyano-6-hydroxy-1-(2-hydroxyethyl)-4-methyl-2(1H)-pyridinone (4d, C9H10N2O3): Mp 171–2ꢂC
(ethanol [22] 171–2ꢂC), IR (KBr): ꢁꢀ ¼ 1660 (C¼O), 2220 (CN) cmꢃ 1
;
1H NMR (DMSO-d6):
ꢂ ¼ 2.30 (s, 3H, CH3), 4.18 (t, 2H, J ¼ 8.7Hz, NCH2), 4.81 (t, 2H, J ¼ 8.7Hz, OCH2), 5.90 (s, 1H,
¼CH) ppm.
Acknowledgment
We are grateful to the research council of K. N. Toosi University of Technology for financial support.
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