A three component one-pot synthesis of N-amino-2-pyridone derivatives catalyzed by KF-Al2O3

Article abstract of DOI:10.1080/00397911.2018.1468467

Synthesis of 1,6-diamino-4-phenyl-3,5-dicyano-2-pyridone derivatives via a one-pot, three-component reaction of aryl aldehydes, malononitrile, and cyanoacetic hydrazide at room temperature using KF-Al₂O₃ as a recyclable catalyst have been developed. The reaction proceeds through the initial Knoevenagel condensation between aldehyde and malononitrile in the presence of KF-Al₂O₃ to form the benzylidene derivative which then undergoes Michael addition with cyanoacetic hydrazide followed by intramolecular cyclization of the resulting intermediate to produce the N-amino-2-pyridones in good to excellent yields. The structure of the synthesized compounds were characterized and established on the basis of their spectral data analysis and single-crystal XRD analysis.

Full text of DOI:10.1080/00397911.2018.1468467

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
A three component one-pot synthesis of N-
amino-2-pyridone derivatives catalyzed by KF-
Al2O3
B. Kshiar, O. R. Shangpliang & B. Myrboh
To cite this article: B. Kshiar, O. R. Shangpliang & B. Myrboh (2018) A three component one-pot
synthesis of N-amino-2-pyridone derivatives catalyzed by KF-Al2O3, Synthetic Communications,
48:14, 1816-1827, DOI: 10.1080/00397911.2018.1468467
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SYNTHETIC COMMUNICATIONSV
2018, VOL. 48, NO. 14, 1816–1827
https://doi.org/10.1080/00397911.2018.1468467
A three component one-pot synthesis of N-amino-2-pyridone
derivatives catalyzed by KF-Al2O3
B. Kshiar , O. R. Shangpliang , and B. Myrboh
Department of Chemistry, North-Eastern Hill University, Shillong, Meghalaya, India
ABSTRACT
ARTICLE HISTORY
Received 19 March 2018
Synthesis of 1,6-diamino-4-phenyl-3,5-dicyano-2-pyridone derivatives
via a one-pot, three-component reaction of aryl aldehydes, malononi-
trile, and cyanoacetic hydrazide at room temperature using KF-Al2O3
as a recyclable catalyst have been developed. The reaction proceeds
through the initial Knoevenagel condensation between aldehyde and
malononitrile in the presence of KF-Al2O3 to form the benzylidene
derivative which then undergoes Michael addition with cyanoacetic
hydrazide followed by intramolecular cyclization of the resulting
intermediate to produce the N-amino-2-pyridones in good to excel-
lent yields. The structure of the synthesized compounds were charac-
terized and established on the basis of their spectral data analysis
and single-crystal XRD analysis.
KEYWORDS
KF-Al2O3; multi-component
reactions; N-amino-
2-pyridones
GRAPHICAL ABSTRACT
Introduction
Multi-component reactions (MCRs) have become a powerful synthetic strategy in syn-
thetic organic chemistry due to their flexibility, atomic economy, and convergence. They
are usually favoured for development of environmentally benign synthetic methods in
organic syntheses.[1] MCRs have also been successfully employed for the synthesis of
diverse range of heterocyclic compounds having wide application in pharmaceutical
industry and material science.[2,3] In recent years, MCRs have been used for the synthe-
sis of N-heterocycles having structural diversity. The synthesis of 2-pyridone derivatives
has attracted much attention as they are valuable building blocks in natural products
synthesis. They are also known to possess pharmacological, antibacterial,[4] antifungal,[5]
anti-inflammatory,[6] and anti-tumour[7,8] properties. Furthermore, 3,5-dicyanopyridine
CONTACT Bekington Myrboh
bmyrboh@nehu.ac.in
Department of Chemistry, North-Eastern Hill University,
Shillong 792022, Meghalaya, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2018 Taylor & Francis

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Scheme 1. Synthesis of N-amino-2-pyridone derivatives.
derivatives have been reported to possess a number of pharmacological properties and
have been considered as useful anti-prion[9,10] and anticancer agents.[11] Likewise mole-
cules bearing N-amino-2-pyridone moieties are also used as building blocks for the syn-
thesis of biologically active natural products[12] and as well as a versatile synthon for the
construction of biologically important heterocycles.[5,13–15]
A number of methods have been reported for the synthesis of N-substituted 2-pyri-
done derivatives. Generally, these methods employed heterogeneous catalysts such as
Zirconium pyrophosphates (ZrP2O7) nano particles,[16,17] ZnO nanoparticles and magne-
sium oxide (MgO),[18] while bismuth (III) nitrate pentahydrate (Bi(NO3)3ꢀ5H2O)[18] and
piperidine[19] have also been used for synthesis of the N-amino-2-pyridones. These
methods, however, suffer from limitations such as long reaction time, harsh reaction
conditions, use of toxic solvents and non-reusable catalysts. The development of an
alternative protocol for an efficient, clean, and environmentally benign method for the
synthesis of N-diamino-2-pyridone derivatives would therefore be of considerable inter-
est. The use of solid heterogeneous catalysts in organic synthesis has been of great inter-
est due to operational simplicity, high selectivity, and clean separation of the
products.[20–22] Potassium fluoride impregnated over alumina (KF-Al2O3) has been
recognized as an efficiently recyclable and useful green heterogeneous catalyst to
promote a wide range of organic reactions.[23–29]
As part of our ongoing interest in the synthesis of some important heterocyclic com-
pounds through MCRs,[30–32] we herein wish to report a rapid and green approach for
the synthesis of highly substituted N-amino-2-pyridones via a three-component conden-
sation of aromatic aldehydes 1, active methylene compound 2, and 2-cyanoacetohydra-
zide 3 in the presence of catalytic amount of KF-Al2O3 at room temperature to afford
the required products 4 in excellent yields (Scheme 1).
Results and discussion
Optimization of reaction conditions
The reaction of 4-methoxybenzaldehyde 1b (2 mmol) malononitrile 2a (2.1 mmol) and
cyanoacetic hydrazide 3 (2.1 mmol) was selected as model reaction to establish the best
reaction conditions. The reaction was first performed without any catalyst at room tem-
perature, and even after more than 3 h only trace amount of the product (<5%)
was obtained. The reaction was then carried out in the presence of the prepared
catalyst (KF-Al2O3) and the effect of different solvent systems for the synthesis of
1,6-diamino-4-(4-methoxyphenyl)-3,5-dicyano-2-pyridone 4b was studied (summarized

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B. KSHIAR ET AL.
Table 1. Synthesis of 1,6-diamino-4-(4-methoxyphenyl)-3,5-dicyano-
2-pyridone 4b: Effect of solvent and catalyst loading.
t
Catalyst (mol%)
Solvent
Time (min)
Yield (%)a
1
2
3
4
5
6
7
8
No catalyst
EtOH
EtOH
CH3CN
H2O
EtOH-H2O (1:1)
EtOH-H2O (1:1)
EtOH-H2O (1:1)
EtOH-H2O (1:1)
180
45
45
45
45
40
30
30
<5 (trace)
10
10
10
5
10
15
20
89
90
65
78
89
96
96
aIsolated yield.
in Table 1). The reaction carried out using water, EtOH, EtOH-H2O (1:1), and aceto-
nitrile. From a greener approach in synthesis, 50% EtOH was chosen as a suitable solv-
ent for the reaction. The model reaction was also optimized in terms of catalyst loading
and addition of 5 mol% catalyst resulted in a sharp increase of yield within a short
period of time. And the use of 15 mol% of catalyst was found to be most sufficient for
good yield of the product. Further increase in addition of catalyst up to 20 mol% did
not show any effective increase in the product yield.
Under the optimized conditions, sets of controlled reactions in 50% ethanol of
aromatic aldehydes, malononitrile or methyl cyanoacetate or ethyl cyanoacetate, and
2-cyanoacetohydrazide in the presence of catalytic amount of KF-Al2O3 (15 mol%) via a
three component reaction generates the desired N-amino-2-pyridone derivatives in
good yields. Substituted aldehydes with electron-withdrawing and electron-donating
groups under the same reaction condition also resulted in excellent yield of the
products (Table 2). Disubstituted aldehydes such as 2,3-dimethoxy benzaldehyde (1c) and
4,5-dimethoxy benzaldehyde (1d) with malononitrile 2a and 2-cyanoacetohydrazide 3
gave 4c and 4d in 84–87% yields (Table 2, entry 3–4). This method also gave good yield
of fluorinated N-amino-2-pyridone derivatives both at -meta, and -para positions (Table
2, entry 8,12–14). The present method was also carried out with aliphatic aldehydes under
the optimized condition but failed to give the desired N-amino-2-pyridones.
The plausible mechanism is depicted in Scheme 2, which involves Knoevenagel con-
densation, Michael addition, and cyclization to form N-amino-2-pyridone derivatives.
The reaction presumably proceeds through the initial Knoevenagel condensation
between aldehyde 1 and malononitrile 2a in the presence of KF-Al2O3 to form the inter-
mediate 5. The intermediate 5 then undergoes Michael addition with activated cyano-
acetic hydrazide 3 followed by intramolecular cyclization of the resulting intermediate 6
which undergoes dehydration to produce N-amino-2-pyridones.
Recyclability of catalysts
After first use, the catalyst was separated by filtration, washed with ethanol, ethyl acetate
and then dried. The recovered catalyst was further used for the same reaction to check
the catalytic activity and it was found out that the catalyst can be recycle and reused
effectively up to five times, after which the yield start to decrease gradually (Fig. 1).
A comparative study of the catalytic activity of KF-Al2O3 with reported catalysts was
given in Table 3.

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Table 2. Three-component one-pot synthesis of N-amino-2-pyridone derivatives.
Entry
Substrate 1
Substrate 2 (R1)
Time (min)
Product
Yielda (%)
1
CN
35
95
2
3
CN
CN
30
35
96
84b
4
CN
40
87
5
6
CN
CN
40
30
87b
93
7
8
CN
CN
30
35
96
92
9
COOMe
COOMe
45
45
93
10
82b
11
COOMe
40
89
(continued)

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B. KSHIAR ET AL.
Table 2. Continued
Entry
Substrate 1
Substrate 2 (R1)
Time (min)
Product
Yielda (%)
12
13
COOMe
COOEt
40
35
91
87
14
15
COOEt
COOEt
40
40
88
85b
16
COOEt
35
89
aIsolated yield.
bPurified by column chromatography.
Experimental section
Materials and methods
All commercially available chemicals and reagents were purchased from Sigma Aldrich,
Merck (St. Louis, MO) and were used without further purification. The synthesized com-
1
pounds were characterized by FT-IR, H NMR, 13C NMR and mass spectrometry analy-
ses. Melting points were recorded with open capillary tube method and are uncorrected.

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Scheme 2. Mechanism for the synthesis of N-amino- 2- pyridine derivatives.
Table 3. Comparative study of catalytic activity of KF-Al2O3 with reported catalysts for the
synthesis of N-amino-2-pyridones.
Catalyst
Reaction time Solvent
Temperature Yield (%) References
[16]
ZrP2O7 NPs
CdZr4(PO4)6 NPs
MgO
Bi(NO3)3ꢀ5H2O
Piperidine
KF-Al2O3
35
45
40
EtOH
EtOH
EtOH
Reflux
Reflux
Reflux
Reflux
Reflux
84
82
82
90
42
96
[17]
[18]
[18]
[33]
10
5hrs
30
EtOH
Dioxane
EtOH-H2O (1:1) Rt
This work
Figure 1. Recyclability results of KF-Al2O3 (15 mol%) with 4b.

1822
B. KSHIAR ET AL.
FT-IR spectra were recorded with KBr pellets using a Perkin-Elmer 400 Series FT-IR
1
spectrometer (Waltham, MA). H and 13C NMR spectra were recorded on a Bruker
Avance II-400 instrument operating at 400 MHz for protons, 100 MHz for carbon in
dimethylsulphoxide (DMSO-d6) as solvent (chemical shifts in d) with tetramethylsilane
(TMS) as internal standard. Electrospray ionization (ESI) mass spectra were recorded on
a Waters ZQ-4000 LC-MS spectrometer. The progress of the reaction was monitored by
thin-layer chromatography (TLC) analysis on pre-coated silica gel 60 F254 aluminum
sheets (Merck), visualized under UV light.
X-ray crystallography
The X-ray crystallography data of 4g and 4i (Table 4) was collected at 292.6(6) K with a
Agilent Xcalibur (Eos, Gemini) diffractometer using graphite monochromated Mo-Ka
radiation (k ¼ 0.71073 Å). The data was collected and refined in CrysAlis PRO (Rigaku,
2015) software[34] and data reduction was performed using the CrysAlisPro (Rigaku,
2015) software which corrects for Lorentz polarisation. A multi-scan absorption correc-
tion was performed using CrysAlisPro (Rigaku, 2015). Empirical absorption correction
using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. Using
Olex2,[35] the structure was solved with the ShelXS[36] structure solution program using
Direct Methods and refined with ShelXL-2018[37] using full matrix least squares on F2
minimisation. All non-hydrogen atoms were refined anisotropically. Hydrogen atom
positions were calculated geometrically and refined using the riding model. An ORTEP
view of 4g and 4i are illustrated by ORTEP-3[38] as shown in Figure 2. The crystal
Figure 2. Ortep image of (a) 4g (CCDC 1824530) and (b) 4i (CCDC 1824529) showing thermal
ellipsoids at 50% probability level.

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Table 4. X-ray crystallography data for compound 4g (CCDC 1824530) and 4i (CCDC 1824529).
Empirical formula
C13H8ClN5O (4g)
C15H14N4O4 (4i)
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
285.69
292.6 (6)
0.71073
Monoclinic
314.30
295.7 (6)
0.71073
Monoclinic
P21/n
Space group
P21/c
a (Å)
b (Å)
9.1112 (11)
7.8131 (11)
17.807 (2)
90
94.076 (11)
90
1264.4 (3)
4
1.501
0.305
584
6.638 to 52.73
9.3961 (7)
14.2120 (9)
11.5460 (9)
90
99.299 (7)
90
1521.56 (19)
4
1.372
c (Å)
a (ꢁ)
b (ꢁ)
c (ꢁ)
Volume (Å3)
Z
q (calc.) (g/cm3)
Absorption coefficient (l) (mmꢂ1
F(000)
)
0.102
656
6.738 to 52.74
2h range for data collection (ꢁ)
Index ranges
ꢂ5 ꢃ h ꢃ 11, ꢂ9 ꢃ k ꢃ 8, ꢂ22 ꢃ l
ꢂ11 ꢃ h ꢃ 10, ꢂ17 ꢃ k ꢃ 16, ꢂ14 ꢃ
ꢃ 21
l ꢃ 14
Reflections collected
4883
5888
Independent reflections
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I ꢄ 2r(I)]
R indices (all data)
2562 [Rint ¼ 0.0305]
3109 [Rint ¼ 0.0294]
2562/0/182
3109/0/211
1.014
1.028
R1 ¼ 0.0532, wR2 ¼ 0.1334
R1 ¼ 0.0482, wR2 ¼ 0.1048
R1 ¼ 0.0823, wR2 ¼ 0.1526
R1 ¼ 0.0749, wR2 ¼ 0.1189
structural data can be obtained free of charge on request from the Cambridge
Crystallographic Data Center (https://www.ccdc.cam.ac.uk/structures/?).
Preparation of catalyst (KF-Al2O3)
The catalyst, KF-Al2O3 was prepared according to the method reported in the literature,
with some modification.[39] A mixture of potassium fluoride (5.8 g, 10 mmol) and acti-
vated neutral alumina (10 g, 10 mmol) in water (10 mL) was stirred at room temperature
for 12 h. The resulting suspension was concentrated on rotary evaporator at 60 ꢁC, and
then dried in a desiccator under vacuum for 6–8 h. After activation in hot oven at
140 ꢁC for 4–6 h, KF-Al2O3 was used for catalysis.
General procedure
Synthesis of Cyanoacetic hydrazide (3)
Cyanoacetic acid hydrazide was obtained by careful addition of 22.62 g (0.20 mol) of
ethyl cyanoacetate to hydrazine hydrate (10.01 g, 0.20 mol) with stirring at 0 ꢁC.[40] The
solid cyanoacetic acid hydrazide so formed was filtered, washed with Et2O and dried, in
which a yield of 95% is obtained.
Synthesis of N-amino-2-pyridone derivatives 4 (a-p)
A mixture of aromatic aldehydes 1 (2 mmol), active methylene compound 2 (2.1 mmol)
and cyanoacetic hydrazide 3 (2.1 mmol), 15 mol% of KF-Al2O3 in EtOH-H2O (1:1) was

1824
B. KSHIAR ET AL.
stirred at room temperature and the progress of the reaction was monitored by TLC.
On completion, the reaction solution was filtered and washed with ethyl acetate and the
catalyst was recovered and recycled. The solvent was evaporated and the solid which
separated out was collected and recrystallized with ethanol to get the pure product. A
few members of the synthesised products were purified by column chromatography. The
1
synthesised products were characterised from their H NMR, 13C NMR, FT-IR and sin-
gle crystal XRD analyses.
1,6-Diamino-4-(4-methoxyphenyl)-3,5-dicyano-2-pyridone 4(b)
White crystals; yield: 96%, mp 221–224 ꢁC [Lit.[19], mp 225 ꢁC] IR (KBr): ꢀmax 3479,
1
3343, 3229, 2218, 1637, 1610, 1243 cmꢂ1; H NMR (400 MHz, DMSO-d6) d 8.42 (s, 2H,
NH2), 7.45 (d, J ¼ 8.4 Hz, 2H, CHAr), 7.09 (d, J ¼ 8.4 Hz, 2H, CHAr), 5.64 (s, 2H, NH2),
3.83 (s, 3H, OCH3) ppm; 13C NMR (101 MHz, DMSO-d6) d 160.64, 159.35, 159.19,
156.62, 130.65, 129.80, 126.42, 116.65, 115.76, 113.87, 113.24, 86.06, 74.24, 55.27 ppm;
MS (ESþ) calcd. for C14H11N5O2: 281.2, found m/z 282.1 [M þ H]þ. Anal. Calcd. for
C14H11N5O: C 59.78, H 3.94, N 24.90%, found C 59.66, H 3.99, N 24.77%.
Conclusions
In summary, we have established a simple and efficient method for the synthesis of N-
amino-2-pyridones following an environment friendly protocol using KF-Al2O3 as a
recyclable catalyst. The method offers several advantages involving short reaction time,
simple work-up procedure with little or no purification required affording good to
excellent yields of the desired products. Due to its operational simplicity, this
facile method is expected to have wider application for the preparation of N-amino-2-
pyridone derivatives.
Acknowledgments
The authors thank the UGC for financial support through research fellowship and DST-PURSE
for the XRD facility. The authors also acknowledge the support of SAIF-NEHU, Shillong, SAIF-
CDRI, Lucknow and the Department of Chemistry-NEHU for providing the analytical support.
ORCID
B. Kshiar
O. R. Shangpliang
B. Myrboh
http://orcid.org/0000-0002-4276-8427
http://orcid.org/0000-0001-5293-9851
http://orcid.org/0000-0001-9349-2216
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