Eco-friendly synthesis of diverse and valuable 2-pyridones by catalyst- and solvent-free thermal multicomponent domino reaction

Article abstract of DOI:10.1039/c5gc01526j

An efficient and highly eco-friendly synthesis of diverse and functionalized 2-pyridone derivatives in good yield via the thermal multicomponent reaction of 4-oxo-4H-chromene-3-carbaldehydes with 1,3-diketoesters and anilines or primary aliphatic amines under catalyst- and solvent-free conditions is described. This reaction proceeds via domino Knoevenagel condensation/Michael addition/ring opening/ring closure reactions.

Full text of DOI:10.1039/c5gc01526j

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Eco-friendly synthesis of diverse and valuable
2-pyridones by catalyst- and solvent-free thermal
Cite this: DOI: 10.1039/c5gc01526j
multicomponent domino reaction†
Tej Narayan Poudel,a Yong Rok Lee*a and Sung Hong Kimb
An efficient and highly eco-friendly synthesis of diverse and functionalized 2-pyridone derivatives in good
yield via the thermal multicomponent reaction of 4-oxo-4H-chromene-3-carbaldehydes with 1,3-diketo-
esters and anilines or primary aliphatic amines under catalyst- and solvent-free conditions is described.
This reaction proceeds via domino Knoevenagel condensation/Michael addition/ring opening/ring
closure reactions.
Received 7th July 2015,
Accepted 15th July 2015
DOI: 10.1039/c5gc01526j
www.rsc.org/greenchem
In addition, 2-pyridone derivatives are widely used as valu-
able building blocks for the synthesis of bioactive natural pro-
Introduction
2-Pyridones are important compounds that are found in many ducts12 and functional materials.13 They are also used as a
active natural products and pharmaceuticals (Fig. 1).1 These versatile synthon for the synthesis of a variety of other nitro-
pyridone-based molecules have shown a broad range of bio- gen-containing heterocyclic compounds like β-lactams, quino-
logical properties such as antifungal,2 anti-HIV,3 antitumoral,4 lizidines, pyridines, piperidines, and indolizidine alkaloids.14
anti-hepatitis B,5 MEK-1 inhibitors,6 receptor tyrosine kinase
Several synthetic methods have been developed for the syn-
c-Kit inhibitors,7 anaplastic lymphoma kinase inhibitors,8 thesis of 2-pyridones and their derivatives because of their
antimycobacterium tuberculosis agents,9 human rhinovirus importance and utility.15–25 The typical strategies involve Ni(0),
3C proteases10 and anti Pim-1 kinase activities.11
Rh(I), or Ru(II)-catalyzed cycloaddition of 1,6-diynes with iso-
cyanates,15 ring-closing metathesis of α-amino acrylamides,16
t-BuOK-mediated condensation of enones with cyanoacet-
amides,17 tandem Blaise reaction of nitriles with propiolates,18
FeCl3·6H2O-catalyzed intramolecular cascade reaction of acet-
oacetanilide with 3-formyl chromone,19 CsF-catalyzed reaction
of α,β-unsaturated diester chromones with aromatic amines,20
Ni-catalyzed reaction of alkynes via azazirconacycles,21 1,4-
addition reaction of 2-(phenylsulfinyl)acetamide to α,β-unsatu-
rated ketones followed by cyclization and elimination of sulfox-
ide,22 nucleophilic addition of malonic esters to alkynyl
imines,23 intramolecular ketene trapping of functionalized
enamine-dioxinones,24 and gold-catalyzed cycloisomerization
of N-alkenyl alkynylamides.25 Related to this work, the other
synthesis of 2-pyridones using 3-formyl chromones has been
reported.26 Recently, various 2-pyridone-3-carboxylic acid
derivatives have also been synthesized by the three-component
reaction of 3-formyl chromone with Meldrum’s acid and
primary amines.27
Fig. 1 Selected natural products bearing a 2-pyridone moiety.
aSchool of Chemical Engineering, Yeungnam University, Gyeongsan 712-749,
Republic of Korea. E-mail: yrlee@yu.ac.kr; Fax: +82-53-810-4631;
Tel: +82-53-810-2529
Although a number of methods for the synthesis of 2-pyri-
dones have been developed, more environmentally benign and
efficient approaches are still needed to reduce the use of
expensive metal catalysts, solvents, and toxic reagents. Among
these, catalyst- and solvent-free multicomponent reactions are
preferred over these conventional synthetic methods for the
bAnalysis Research Division, Daegu Center, Korea Basic Science Institute,
Daegu 702-701, Republic of Korea
†Electronic supplementary information (ESI) available: Characterization and
synthesis of new compounds, general procedures, proton and carbon NMR
spectra. See DOI: 10.1039/c5gc01526j
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reduce the reaction time and increase the yield. As expected,
the desired product was obtained in increased yield with
reduced reaction time (entries 3–5). The optimal yield (78%)
was obtained at 100 °C for 8 h. However, increasing the reac-
tion temperature to 120 °C for 8 h failed to improve the yield.
Moreover, when the reaction was performed under microwave
irradiation at 100 °C for 1 h using 300 W, product 4a was
obtained in only 15% yield. The structure of 4a was assigned
by its spectroscopic data and a comparison with structurally
related compounds.19 The 1H NMR spectrum of 4a revealed
two vinylic protons of a 2-pyridone ring at δ = 8.58 (d, J = 2.1
Hz) and 8.18 (d, J = 2.1 Hz) ppm as the two doublets due to
long range coupling and a methoxy peak at 3.88 ppm as a
singlet.
Scheme 1 Novel and green approach for the synthesis of various and
diverse 2-pyridone derivatives.
following advantages: reduced pollutant production, reduced
use or elimination of toxic and hazardous chemicals, oper-
ational simplicity, reduced reaction time, easy isolation of pure
products that avoids tedious purification, high yields, and
reduced costs.28
Under the optimized reaction conditions, the generality of
this thermal multicomponent reaction was further explored by
employing different 4-oxo-4H-chromene-3-carbaldehydes, 1,3-
diketoesters, and aniline (Table 2). The reaction of 1a with
diethyl malonate (2b) and aniline (3a) at 100 °C for 8 h pro-
vided 4b in 73% yield. The reactions were also successful
using the other 4-oxo-4H-chromene-3-carbaldehydes 1b–1g
bearing electron-donating or electron-withdrawing groups on
the aromatic ring. For example, the treatment of 1b–1e bearing
electron-donating groups with 2a or 2b and 3a provided the
desired products 4c–4f in 77, 75, 73 and 74% yield, respecti-
vely. The reactions of 4-oxo-4H-chromene-3-carbaldehydes 1f
and 1g with electron-withdrawing groups with 2b and 3a
afforded products 4g and 4h in 73 and 75% yield, respectively.
Furthermore, 4-oxo-4H-chromene-3-carbaldehyde 1h contain-
ing both electron-donating and -withdrawing groups on the
aromatic ring was also transformed to product 4i in 71% yield.
With other 1,3-diketoesters, such as dibenzyl malonate (2c)
and methyl acetoacetate (2d), the desired products 4j and 4k
were also produced in 76 and 78% yield, respectively. Interest-
ingly, reaction of 4-oxo-4H-benzo[h]chromene-3-carbaldehyde
(1i) with 2b and 3a provided product 4l bearing a 2-hydroxy-
naphthoyl moiety at the 5-position of the pyridone skeleton in
74% yield. Additional reactions of 1,3-diketoesters such as
ethyl 3-oxo-3-phenylpropanoate (2e), ethyl 3-(4-methoxy-
phenyl)-3-oxopropanoate (2f) and ethyl 3-(4-nitrophenyl)-3-oxo-
propanoate (2g) also afforded the desired products 4m–4o in 68,
65 and 64% yield, respectively. These reactions provide a rapid
route for the synthesis of various 2-pyridone derivatives as a
one-pot procedure.
As part of an ongoing study of catalyst- and solvent-free
multicomponent reactions as a powerful means of synthesiz-
ing heterocycles and novel compounds, we describe the cata-
lyst- and solvent-free thermal multicomponent reactions of
commercially available 4-oxo-4H-chromene-3-carbaldehydes
with 1,3-diketoesters and anilines (or amines) for the synthesis
of structurally diverse 2-pyridone derivatives (Scheme 1).
This is the first example of the one-pot synthesis of a variety
of 2-pyridone derivatives under catalyst- and solvent-free
conditions.
Results and discussion
To optimize the reaction conditions, the reaction of 4-oxo-4H-
chromene-3-carbaldehyde (1a) with dimethyl malonate (2a)
and aniline (3a), under catalyst- and solvent-free conditions
at various temperatures was first investigated (Table 1). When
the reaction was performed at room temperature for 24 h,
products were not formed (entry 1). On the other hand,
at 40 °C for 24 h, product 4a was obtained in 15% yield
(entry 2). The reaction temperature was increased gradually to
Table 1 Optimization of reaction conditions for the synthesis of 4aa
The multicomponent reaction with various substituted ani-
lines bearing electron-donating and -withdrawing groups was
next explored. The results are listed in Table 3. The reaction of
1a with 2b and 3b or 3c bearing electron donating-groups pro-
vided the desired products 5a (72%) and 5b (76%). Reactions
of 1a with 2b and diamine 3d or amino benzyl alcohol 3e pro-
vided the desired products 5c and 5d in 72 and 68% yield,
respectively. However, reactions of 4-aminobenzenethiol or
3-amino phenol under both air and inert conditions were not
successful, instead, inseparable mixtures were obtained.
Further reactions of anilines 3f–3k bearing electron-withdraw-
ing groups such as halo, nitro, cyano, or carbonyl substituents
Temperature
(°C)
Time
(h)
Yieldb
(%)
Entry
1
2
3
4
5
6
7
25
40
60
80
100
120
100, MW
24
24
24
18
8
8
1
0
15
42
61
78
70
15c
a Reaction conditions: 1a (1 mmol), 2a (1 mmol), 3a (1 mmol).
b Isolated yield. c Microwave heating at 100 °C for 1 h using 300 W
power.
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Table 2 Formation of 2-pyridone derivatives 4b–4o from chromene-3-carbaldehydes 1a–1i, 1,3-dicarbonyls 2a–2g and aniline (3a)
Entry
1
Chromene-3-carbaldehyde
1,3-Dicarbonyl
Aniline
Time
8 h
Product
Yield
73%
2
3
3a
3a
8 h
8 h
77%
75%
2b
2b
4
5
3a
3a
8 h
8 h
73%
74%
2b
6
7
8
9
2b
2b
2b
3a
3a
3a
3a
8 h
9 h
9 h
8 h
73%
75%
71%
76%
1b
1b
10
11
3a
3a
8 h
8 h
78%
74%
2b
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Table 2 (Contd.)
Entry
12
Chromene-3-carbaldehyde
1,3-Dicarbonyl
Aniline
Time
9 h
Product
Yield
68%
1a
1a
1a
3a
13
14
3a
3a
8 h
8 h
65%
64%
Table 3 Formation of 2-pyridone derivatives 5a–5n from 1a, 1b, 1g and 2b, 2c and anilines 3b–3k bearing substituents
Entry
1
Chromene-3-carbaldehyde
1,3-Dicarbonyl
Aniline
Time
9 h
Product
Yield
72%
2
3
1a
1a
2b
2b
8 h
9 h
76%
72%
4
5
1a
1a
2b
2b
8 h
9 h
68%
74%
6
1a
2b
8 h
75%
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Table 3 (Contd.)
Entry
7
Chromene-3-carbaldehyde
1,3-Dicarbonyl
Aniline
Time
8 h
Product
Yield
52%
1a
2b
8
9
1a
1a
2b
9 h
9 h
77%
73%
3i
10
11
1a
1a
2b
2b
9 h
9 h
41%
53%
12
13
2b
2b
3i
9 h
9 h
78%
69%
3c
14
1g
2b
3i
8 h
75%
on the benzene ring afforded 5e–5k in the range of 41–77% ponent, this study tested the possibility of using primary
yield. However, reactions of 1a and 2b with 4-nitroaniline or aliphatic amines, which will lead to the formation of other
4-amino acetophenone were unsuccessful. The use of combi- types of 2-pyridone derivatives (Table 4). Reactions of 1a, 1b or
nations of 1b or 1g, and 2b with 4-isopropylaniline (3c) or 1g with 2a–2c in combination with 2-phenylethylamine (3l)
4-fluoroaniline (3i) provided products 5l–5n in the range of provided products 6a–6e in the range of 72–78% yield. With
69–78% yield.
tryptamine (3m), the desired product 6f was obtained in 65%
Considering the general applicability of the multicompo- yield. Moreover, reaction of 1a with 2b and chiral amine
nent reaction by employing different anilines as the com- L-(−)-α-methyl benzylamine (3n) provided the desired chiral
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Table 4 Formation of 2-pyridone derivatives 6a–6h from 1a, 1b, 1g or 1j with 2a or 2b or 2c and primary amines 3l, 3m and 3n
Entry
1
Chromene-3-carbaldehyde
1,3-Dicarbonyls
Aniline
Time
8 h
Product
Yield
78%
2
3
4
5
1a
1a
3l
3l
3l
3l
7 h
8 h
8 h
8 h
76%
75%
77%
72%
2b
2b
6
1a
1a
2b
12 h
65%
7
8
2b
2b
10 h
10 h
67%
58%
3l
compound 6g in 67% yield. Interestingly, reaction of 6-nitro-4-
oxo-4H-chromene-3-carbaldehyde (1j) with 2b and 2-phenyl-
ethylamine (3l) provided an unexpected product 6h in 58%
yield.
Scheme 2 presents the proposed mechanism for the for-
mation of 4a via a domino reaction. Knoevenagel condensation
between 1a and 2a first takes place to form intermediate 7,
which then undergoes Michael addition through nucleophilic
attack of aniline (3a) to provide another intermediate 8.
Ring opening of 8 followed by ring closure affords the final
product 4a.
Scheme 2 Proposed mechanism for the formation of 4a via a domino
reaction.
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P. Lee, J. Winkler and K. Koch, J. Med. Chem., 2006, 49,
441.
Conclusions
A highly sustainable and efficient multicomponent domino
reaction of readily available 4-oxo-4H-chromene-3-carbalde-
hydes with 1,3-ketoesters and anilines or primary aliphatic
amines was developed for the synthesis of substituted 2-pyri-
done derivatives in good yield. This catalyst- and solvent-free
multicomponent reaction readily allows the synthesis of novel
and diverse functionalized 2-pyridone derivatives, which could
be used widely for the synthesis of bioactive natural products
and pharmaceuticals.
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This research was supported by the Nano Material Technology
Development Program of the Korean National Research Foun-
dation (NRF) funded by the Korean Ministry of Education,
Science, and Technology (Grant no. 2012-049675). This work
was also supported by the National Research Foundation of
Korea (NRF) grant funded by the Korean government (MSIP)
(NRF-2014R1A2A1A11052391).
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