Regioselective synthesis of two types of highly substituted 2-pyridones through similar multicomponent reactions

Article abstract of DOI:10.1016/j.tetlet.2012.04.010

The refluxing of a mixture of ethylcyanoacetate, aromatic aldehydes, and primary monoamines in ethanol produces highly substituted 2-amino-6-pyridones such as 2-amino-1-(alkyl)-5-cyano-6-oxo-4-(aryl)-1,6-dihydropyridine-3- ethylcarboxylates in one-pot. On the other hand the refluxing of a mixture of ethylcyanoacetate, aromatic aldehydes, and primary diamines (1,2- ethylenediamine/1,3-propylenediamine) in ethanol furnishes symmetrical zwitterionic 2-pyridones such as 1-(2-amino-ethyl/3-amino-propyl)-6-hydroxy-2- oxo-4-(aryl)-1,2-dihydropyridine-3,5-dicarbonitriles. The result shows that primary diamines and monoamines react differently in the reactions, which provides new mechanistic insight into the regioselective synthesis of these biologically important compounds.

Full text of DOI:10.1016/j.tetlet.2012.04.010

Tetrahedron Letters 53 (2012) 3030–3034
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective synthesis of two types of highly substituted 2-pyridones through
similar multicomponent reactions
⇑
Sudipta Pathak, Ashis Kundu, Animesh Pramanik
Department of Chemistry, University of Calcutta, 92, A.P.C. Road, Kolkata 700 009, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The refluxing of a mixture of ethylcyanoacetate, aromatic aldehydes, and primary monoamines in ethanol
produces highly substituted 2-amino-6-pyridones such as 2-amino-1-(alkyl)-5-cyano-6-oxo-4-(aryl)-
1,6-dihydropyridine-3-ethylcarboxylates in one-pot. On the other hand the refluxing of a mixture of eth-
ylcyanoacetate, aromatic aldehydes, and primary diamines (1,2-ethylenediamine/1,3-propylenediamine)
in ethanol furnishes symmetrical zwitterionic 2-pyridones such as 1-(2-amino-ethyl/3-amino-propyl)-6-
hydroxy-2-oxo-4-(aryl)-1,2-dihydropyridine-3,5-dicarbonitriles. The result shows that primary diamines
and monoamines react differently in the reactions, which provides new mechanistic insight into the reg-
ioselective synthesis of these biologically important compounds.
Received 16 January 2012
Revised 2 April 2012
Accepted 3 April 2012
Available online 10 April 2012
Keywords:
2-Pyridones
Zwitterion
Aromatic aldehyde
Ethylcyanoacetate
Primary diamines
Primary monoamines
Three component reaction
Aerial oxidation
Ó 2012 Elsevier Ltd. All rights reserved.
Apart from having environmental and economically positive
implications, one-pot multicomponent coupling reactions (MCRs)
have been proven to be a very elegant and rapid way to access
complex structures in a single synthetic operation from simple
building blocks. They also address fundamental principles of syn-
thetic efficiency and reaction design, and show atom-economy
and selectivity.1 In this context, Hantzsch reaction for the synthesis
of dihydropyridines (DHPs) shows interesting features of MCR.
More than a century ago the first 1,4-DHPs were obtained by
Hantzsch.2 After that a number of modified methods under
improved conditions have been reported.3 Hantzsch 1,4-dihydro-
pyridine derivatives are often regarded as the models of the natural
reduced nicotinamide-adenine dinucleotide (NADH) coenzyme
which functions as redox reagent in biological reactions.4 In our
strategy, DHP which is formed as an intermediate, subsequently
undergoes spontaneous oxidation to form 2-pyridones. 2-Pyridones
have been used as lead compounds for the preparation of several
drugs such as selective anticancer agents,5 antiviral agents,6 or
inhibitors of Ab-peptide aggregation, which play an important role
in amyloid formation in Alzheimer’s disease.7 2-Pyridones are
important intermediates for the synthesis of polycyclic compounds
having biological significance as illustrated by the recent synthetic
approaches toward the camptothecin family of antitumor agents.8
2-Pyridones have been prepared by numerous methods,9 for
Ar
Ar
Ar
ArCHO
+
NC
O
CO2Et
NH2
(CH2)n
NC
O
CN
O
NC
O
CN
O
R-NH2
NH2
H2N
-
N
)
Ethanol
Reflux
Ethanol
Reflux
EtO2C
CN
N
R
N
)
(
(
n
n
NH
+
NH
+
3
3
1a-f
2a-i when n=2
3a-c when n=3
Scheme 1. Synthesis of hexasubstituted 2-pyridones 1–3.
⇑
Corresponding author. Tel.: +91 33 2484 1647; fax: +91 33 2351 9755.
E-mail address: animesh_in2001@yahoo.co.in (A. Pramanik).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.010

S. Pathak et al. / Tetrahedron Letters 53 (2012) 3030–3034
3031
Table 1
Formation of 2-pyridones 1a–f using primary monoamines
Entry
1
Ar of ArCHO
Amines (R-NH2)
Benzylamine
Products
Yield (%)
71
Melting point (°C)
1a
202
158
NO2
2
Benzylamine
1b
69
3
4
5
6
Benzylamine
n-Propylamine
n-Propylamine
n-Butylamine
1c
1d
1e
1f
67
61
63
68
184
192
234
204
Cl
Cl
Table 2
Formation of products 2 and 3 using primary diamines
Entry
Ar of ArCHO
Diamines
Products
Time (min)
90
Yield (%)
Melting point (°C)
NH2
NH2
H2N
1
2a
52
54
>320
NO2
H2N
H2N
2
3
2b
2c
60
90
315
320
MeO
NH2
49
NH2
NH2
NH2
H2N
H2N
H2N
4
5
Cl
F
2d
2e
90
45
50
53
314
N
>320
6
2f
45
51
319
NH2
NH2
NH2
H2N
H2N
H2N
H2N
H2N
7
8
OMe
2g
2h
90
60
47
49
288
N
>320
9
2i
60
90
48
50
>320
>320
O
NH2
NH2
10
3a
NO2
N
11
12
3b
3c
75
60
51
52
318
H2N
NH2
>320
example, oxidation of an N-substituted pyridinium salt,10 by
Knoevenagel-type reactions,11 such as cross-condensation of
cyanoacetoamide and b-dicarbonyl compounds with basic catalysts
or by the reaction of 2-pyrones with amides. Despite this large
number of existing methods for their synthesis, new procedures
are continuously being developed.12
5-cyano-6-oxo-4-(aryl)-1,6-dihydropyridine-3-ethylcarboxylates
(1a–f) and 1-(2-amino-ethyl/3-amino-propyl)-6-hydroxy-2-oxo-4-
(aryl)-1,2-dihydropyridine-3,5-dicarbonitriles (2 or 3) using pri-
mary monoamines and primary diamines as product determining
factor (Scheme 1). The significance of the protocol relies on the con-
struction of the pyridin-2(1H)-one skeleton with dense substitution
patterns in one-pot. When an ethanolic solution of primary mono-
amines, aromatic aldehydes, and ethylcyanoacetate in 1:1:2 molar
Herein we like to introduce an approach for the synthesis of two
types of highly substituted 2-pyridones, such as 2-amino-1-(alkyl)-

3032
S. Pathak et al. / Tetrahedron Letters 53 (2012) 3030–3034
proportion is refluxed for 16 h, 2-pyridones 1 are formed (Scheme 1
and Table 1).13 But interestingly when primary diamines (1,2-ethy-
lenediamine/1,3-propylenediamine) are used instead of primary
monoamines, the symmetrical zwitterionic 2-pyridones (2 or 3)
are precipitated out from the reaction mixture within 45 min–2 h
under similar reaction condition (Scheme 1 and Table 2).13 Some
pirfenidone analogs which are antifibrotic agents and structurally
close to compounds 1 such as 2-amino-1-(aryl)-5-cyano-6-oxo-4-
(aryl)-1,6-dihydropyridine-3-ethylcarboxylates have been synthe-
sized previously through stepwise procedure.14
The Knoevenagel condensation of aromatic aldehydes and eth-
ylcyanoacetate, followed by Michael addition in the basic medium
leads to adduct 4 (Scheme 2). Subsequently the primary amine
attacks the ester carbonyl of adduct 4 to produce amide intermedi-
ates 5. Then the intramolecular nucleophilic attack of amide nitro-
gen to the cyano group generates six-membered nitrogenous
heterocycles 6 in a regioselective way. Probably, the sterically
hindered secondary amide nitrogen prefers to attack the less
hindered linear cyano group compared to ester carbonyl, although
ester carbonyl is more reactive than cyano group. Subsequently the
spontaneously oxidizes to 2-pyridones 1 under the reaction condi-
tions, confirmed by X-ray crystallography (Fig. 1).15 All the com-
pounds are also characterized by 1H and 13C NMR spectroscopy.16
It has been observed that this multicomponent reaction does not
take place with aromatic primary amines due to their low
nucleophilicity.
The synthesis of symmetrical 2-pyridones 2 or 3 comprises of
an interesting mechanistic path way (Scheme 3). The intermediate
4 so formed (Scheme 2) undergoes a nucleophilic attack by dia-
mine (1,2-ethylenediamine/1,3-propylenediamine) to the ester
carbonyl to produce acyclic intermediate 8. Then most likely the
reaction involves an intramolecular nucleophilic attack on the
remaining ester carbonyl to generate nine/ten-membered lactam
intermediate 9. Subsequently intramolecular nucleophilic attack
of the amide nitrogen on the other amide carbonyl generates bicy-
clic intermediate 10 which produces monocyclic compound 11
through ring opening. After that the intermediate 11 follows the
same reaction pathway as discussed earlier (Scheme 2) to produce
intermediate 12 which furnishes zwitterionic 2-pyridones 13
through proton exchange. It was not possible to isolate any of
the intermediates 4–12 under the reaction conditions. This is the
tautomerization of compound
6
leads to 1,4-DHP
7
which
Ar
Ar
CO2Et
ArCHO
NC
CN
NC
Base
+
R-NH2
O
EtO
OEt
EtO2C
CN
N
R
H
O
O
N
5
4
Ar
Ar
N
Ar
NC
HO
CO2Et
NC
O
CO2Et
NH2
NC
O
CO2Et
NH
Tautomerisation
Aerial Oxidation
N
R
7
NH2
N
R
6
R
1
Scheme 2. Reaction mechanism of three-component one-pot cyclization in the formation of 1 with primary monoamines.
Figure 1. ORTEP diagram of compound 1c with atom numbering scheme. Thermal ellipsoids are shown at the 50% probability. Color code: red, oxygen; blue, nitrogen; green,
chlorine; large white, carbon; small white, hydrogen.

S. Pathak et al. / Tetrahedron Letters 53 (2012) 3030–3034
3033
Ar
Ar
NC
O
CN
OEt
NH2
NC
O
CN
O
(CH2)n
NH2
H2N
O
4
HN
N
H
n =1 or 2
NH
9
(CH2)n
(CH2)n
8
Ar
Ar
Ar
N
CN
NC
CN
O
NC
O
NC
O
CN
OH
i) Tautomerisation
ii) Aerial oxidation
-
O
N
O
N
NH
(CH2)n
NH2
NH2
(CH2)n
11
(CH2)n
12
10
Proton Exchange
Ar
Ar
N
CN
O
NC
CN
NC
O
-
-
N
O
O
(CH2)n
(CH2)n
H3N
+
H N
+
3
13
2 or 3
Scheme 3. Reaction mechanism of three-component one-pot cyclization for the formation of zwitterionic 2 and 3 with primary diamines.
first example of formation of zwitterions where highly acidic phe-
nolic hydroxyl group participates in generating zwitterion with
primary amine. The zwitterion 13 mainly exists as delocalized
compounds 2 or 3 confirmed by NMR16 and X-ray crystallogra-
phy15 (Fig. 2). It is obvious from the NMR spectra that only one
amino group of ethylenediamine/propylenediamine is involved in
the reaction. The second amino group becomes nonreactive for fur-
ther reaction since it loses its nucleophilicity through protonation
in products 2 or 3. The zwitterionic compounds 2 or 3 are precip-
itated out from the reaction mixture due to its high polarity. Gen-
erally in 1H NMR spectra the protons of the aliphatic amino groups
come at d ꢀ0.5–3 ppm. In the products 2 or 3 due to strong
electron-withdrawing effect of positively charged nitrogen atom,
the attached three protons become deshielded (d 6.0–8.0 ppm).
Figure 2 shows the crystal structure of 2a where nitrogen atom
N1 is quaternary and positively charged. The 2-pyridone ring is
found planar indicating all the atoms in the ring are sp2 hybridized.
In the crystal structure the C9–O2 and C10–O1 bond distances are
almost same, 1.23 and 1.24 Å, respectively. This indicates that the
2-pyridone ring in product 2a is symmetrical which is further con-
firmed by 13C NMR spectroscopy where the carbon atoms of two
cyano groups (C12 and C13), the two ring carbon atoms attached
to cyano groups (C8 and C11), and the two amide carbons (C9
and C10) are found pair wise equivalent.
The formation of zwitterionic compound 2a and its charge
distribution is evident from the solvent mediated crystal
packing. The packing diagram in Figure 2 shows that each 2a mol-
ecule forms hydrogen bonds with three water molecules such
C3
C2
C4
N4
C12
C1
C6
C13
C11
C9
C7
C8
C5
C10
O1
N2
C14
N3
O2
C15
N1
O3
Figure 2. Crystal structure and packing diagram of compound 2a (hydrogen bondings are shown in dotted line).

3034
S. Pathak et al. / Tetrahedron Letters 53 (2012) 3030–3034
as –CNÁ Á ÁH–OH, –COÁ Á ÁH–OH, and –N+–HÁ Á ÁOH2. Remaining one –
CN and one –CO of 2a form hydrogen bonds with –N+–H groups
of neighboring molecules as a result the compounds 2a are aligned
in an antiparallel fashion. This arrangement allows further electro-
static interactions between the oppositely charged groups of two
closely packed 2a molecules. It is interesting to note that a small
molecule like 2a is capable of forming seven intermolecular hydro-
gen bonds.
8. (a) Josein, H.; Ko, S.-B.; Bom, D.; Curran, D. P. Chem. Eur. J. 1998, 4, 67; (b)
Comins, D. L.; Saha, J. K. J. Org. Chem. 1996, 61, 9623.
9. (a) Chikhalikar, S.; Bhawe, V.; Ghotekar, B.; Jachak, M.; Ghagare, M. J. Org. Chem.
2011, 76, 3829; (b) Jones, G. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A., Rees, C. W., Scriven, E. F., Eds.; Pergamon Press: Oxford, 1996; pp
395–510.
10. (a) Decker, H. Chem. Ber. 1892, 25, 443; (b) Mohrle, H.; Weber, H. Tetrahedron
1970, 26, 2953; (c) McKillop, A.; Boulton, A. In Comprehensive Heterocyclic
Chemistry; McKillop, A., Boulton, A., Eds.; Pergamon: Oxford, 1984; Vol. 2, p 67.
11. Jones, G. Org. React. 1967, 15, 204.
12. (a) Deodhar, K.; Kekare, M.; Pednekar, S. Synthesis 1985, 328; (b) Barluenga, J.;
Tomás, M.; Suárez-Sobrino, A.; Gotor, V. Tetrahedron Lett. 1988, 29, 4855; (c)
Katritzky, A.; Belyakov, S.; Sorochinsky, A.; Henderson, S.; Chen, J. J. Org. Chem.
1997, 62, 6210; (d) Ghosez, L.; Jnoff, E.; Bayard, P.; Sainte, F.; Beaudegnies, R.
Tetrahedron 1999, 55, 3387; (e) Grosche, P.; Höltzel, A.; Walk, T.; Trautwein, A.;
Jung, G. Synthesis 1999, 1961; (f) Zhang, S.; Liebeskind, L. J. Org. Chem. 1999, 64,
4042; (g) Alberola, A.; Calvo, L.; Ortega, A.; Carmen Sanudo Ruiz, M.; Yustos, P.
J. Org. Chem. 1999, 64, 9493; (h) Paulvannan, K.; Chen, T. J. Org. Chem. 2000, 65,
6160; (i) Chandra Sheker Reddy, A.; Narsaiah, B.; Venkataratnam, R.
Tetrahedron Lett. 1996, 37, 2829; (j) Takaoka, K.; Aoyama, T.; Shioiri, T.
Tetrahedron Lett. 1996, 37, 4973; (k) Shimizu, M.; Hachiya, I.; Mizota, I. Chem.
Commun. 2009, 874; (l) Yi, H.; Song, L.; Wang, W.; Liu, J.; Zhu, S.; Deng, H.;
Shao, M. Chem. Commun. 2010, 46, 6941; (m) Torres, M.; Gil, S.; Parra, M. Curr.
Org. Chem. 2005, 9, 1757; (n) Kibou, Z.; Cheikh, N.; Choukchou-Braham, N.;
Mostefa-kara, B.; Benabdellah, M.; Villemin, D. J. Mater Environ. Sci. 2011, 2,
293.
In summary,
a multicomponent reaction involving ethyl-
cyanoacetate, amines, and aromatic or heteroaromatic aldehydes
to form hexasubstituted 2-pyridones has been developed. The pro-
cess, which can include an additional component in a multicompo-
nent protocol, allows the incorporation of two series of potentially
bio-active 2-pyridones. The result shows that primary diamines
and monoamines react differently in the reactions, which provides
new mechanistic insight into the regioselective synthesis of these
biologically important compounds. Further studies for the synthe-
sis of similar compounds from other amines and active methylene
compounds are currently underway to explore their biological
activities and various aspects of molecular aggregation. The highly
efficient binding motifs as observed in crystal structure of 2a might
be useful for the realization of water-stable supramolecular mate-
rials in future.
13. Typical procedure for preparation of 2-amino-1-benzyl-5-cyano-6-oxo-4-phenyl-
1,6-dihydro-pyridine-3-ethylcarboxylate (1a):
A mixture of benzaldehyde
(1 mL, 9.8 mmol), ethylcyanoacetate (2.1 mL, 19.6 mmol) and benzylamine
(1.1 mL, 9.8 mmol) is refluxed in ethanol (6.0 mL) for 16 h. The cold
reaction mixture is poured into ice-cold water and extracted with
ethylacetate. Then it is purified by column chromatography over silica gel
(71% yield). Typical procedure for the preparation of 1-(2-amino-ethyl)-6-
hydroxy-2-oxo-4-phenyl-1,2-dihydropyridine-3,5-dicarbonitrile (2a): A mixture
of benzaldehyde (2.3 mL, 22.5 mmol), ethylcyanoacetate (3.2 mL, 30 mmol)
and 1,2-ethylenediamine (1 mL, 15 mmol) was refluxed in ethanol (6.0 mL)
until a white solid product was precipitated out from the reaction mixture
(time is mentioned in Table 2). The white solid product 2a was isolated
through filtration and thorough washing with methanol (52% yield). Then
the compound 2a was crystallized from a mixture of dimethylsulphoxide
and water. Typical procedure for the preparation of 1-(3-amino-propyl)-6-
hydroxy-2-oxo-4-phenyl-1,2-dihydropyridine-3,5-dicarbonitrile (3a): A mixture
of benzaldehyde (1.9 mL, 18 mmol), ethylcyanoacetate (2.6 mL, 24 mmol)
and 1,3-propylenediamine (1 mL, 12 mmol) was refluxed in ethanol (6.0 mL)
Acknowledgements
S.P. and A.K. thank CSIR and UGC, New Delhi, India, respectively,
for Junior Research Fellowship (JRF). The financial assistance of
CSIR, New Delhi is acknowledged [Major Research Project, No.
02(0007)/11/EMR-II].
Supplementary data
Supplementary data (IR, 1H, 13C data of compounds 1, 2 and 3
and crystallographic data for 2b) associated with this article can
be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2012.04.010.
until
a white solid product was precipitated out from the reaction
mixture (time is mentioned in Table 2). Then the white solid product 3a
was isolated through filtration and thorough washing with methanol (50%
yield).
14. Ismail, M. M. F.; Noaman, E. Med. Chem. Res. 2006, 14, 382.
15. Crystallographic data for the structure 1c and 2a in this Letter have been
deposited with Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC 869051, 861220 respectively. Copies of the data can be
obtained, free of charge on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK, (fax: +44 01223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
16. 2-Amino-1-benzyl-5-cyano-6-oxo-4-phenyl-1,6-dihydro-pyridine-3-ethylcarb-
oxylate (1a): 1H NMR (300 MHz, CDCl3): d 7.41–7.24 (m, 10H), 5.35 (s, 2H), 3.74
(qt, J = 7.2 Hz, 2H), 0.57 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 167.1,
161.7, 159.6, 156.3, 143.1, 138.5, 133.1, 129.5, 128.6, 128.0, 126.7, 126.6, 116.0,
92.2, 92.0, 60.6, 45.7, 12.7. IR (in KBr): 3371(b), 2216, 1672 cmÀ1; Anal. Calcd
for C22H19N3O3: C, 70.76; H, 5.13; N, 11.25. Found C, 70.71; H, 5.11; N, 11.22. 1-
(2-Amino-ethyl)-6-hydroxy-2-oxo-4-phenyl-1,2-dihydropyridine-3,5-dicarboni-
trile (2a): 1H NMR (300 MHz, DMSO-d6): d 7.64–7.29 (m, 5H), 6.60 (br s, –NH3),
4.06 (t, J = 5.1 Hz, 2H), 2.96 (t, J = 5.1 Hz, 2H); 13C NMR (75 MHz, DMSO-d6): d
163.4, 160.5, 136.1, 129.6, 128.0, 127.5, 118.9, 82.0, 38.6, 37.7; IR (in KBr):
3052(b), 2205, 1633 cmÀ1; Anal. Calcd for C15H12N4O2: C, 64.28; H, 4.32; N, 19.
Found C, 64.23; H, 4.27; N, 19.92. 1-(3-Amino-propyl)-6-hydroxy-2-oxo-4-
phenyl-1,2-dihydropyridine-3,5-dicarbonitrile (3a): 1H NMR (300 MHz, DMSO-
d6): d 7.44–7.35 (m, 8H), 3.87 (t, J = 6.3 Hz, 2H), 2.72 (t, J = 7.2, 2H), 1.82–1.77
(m, 2H); 13C NMR (75 MHz, DMSO-d6): d 163.0, 160.1, 136.1, 129.4, 128.3,
127.9, 118.6, 81.7, 37.0, 36.1, 25.9; IR (in KBr): 3057(b), 2207, 1635 cmÀ1; Anal.
Calcd for C16H14N4O2: C, 65.30; H, 4.79; N, 19.04. Found C, 65.24; H, 4.73; N,
18.98.
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