Synthesis of 3,4-dihydropyridin-2-one derivatives in convergent mode applying bio catalyst vitamin B1 and polymer supported catalyst PEG-SO3H from two different sets of building blocks

Article abstract of DOI:10.1016/j.tetlet.2012.08.030

Two highly efficient, green protocols have been developed for the synthesis of 3,4-dihydropyridin-2-one derivatives from different starting materials exploring two reaction specific catalysts, vitamin B₁ (VB ₁), and PEG-SO₃

Full text of DOI:10.1016/j.tetlet.2012.08.030

Tetrahedron Letters 53 (2012) 5840–5844
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 3,4-dihydropyridin-2-one derivatives in convergent mode
applying bio catalyst vitamin B1 and polymer supported catalyst PEG–SO3H
from two different sets of building blocks
⇑
Koyel Pradhan, Pranabes Bhattacharyya, Sanjay Paul, Asish R. Das
Department of Chemistry, University of Calcutta, Kolkata 700009, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Two highly efficient, green protocols have been developed for the synthesis of 3,4-dihydropyridin-2-one
derivatives from different starting materials exploring two reaction specific catalysts, vitamin B1 (VB1),
and PEG–SO3H. VB1 catalyzed simple and convenient protocol has been developed for the synthesis of
3,4-dihydropyridin-2-one derivatives by the installation of aldehyde, cyanoacetamide, and 1,3-dicar-
bonyl compounds. In addition, 3,4-dihydropyridin-2-one derivatives have also been synthesized by sim-
ply combining aldehyde, malononitrile, and 1,3-dicarbonyl compounds via the formation of 4H-pyran
nucleus and PEG–SO3H catalyzed one-pot rearrangement.
Received 26 June 2012
Revised 6 August 2012
Accepted 8 August 2012
Available online 25 August 2012
Keywords:
3,4-Dihydropyridin-2-one
VB1
Ó 2012 Elsevier Ltd. All rights reserved.
PEG–SO3H
Rearrangement
In recent years, much attention has been devoted toward dihy-
dropyridone derivatives due to their significant therapeutic and
biological activities, such as antibacterial,1 antifungal,2 and
antitumor,3 also served as HIV-1 specific reverse transcriptase
inhibitors.4 Homoclausenamide5 and neoclausenamide6 are 3,4-
dihydropyridin- 2-one and pyrrolidin-2-one core containing
alkaloids, respectively, isolated from the leaf extract of Rutaceae
clausena lansium (Lour.) skeels, a fruit tree widely distributed in
the southern China. Pyridone I, (Fig. 1) has been found to be
specific non-nucleoside reverse transcriptase inhibitor of human
immunodeficiency virus-1 (HIV-1) and pyridone II (Fig. 1) shows
very strong antiprotozoal and antimicrobial activity.7,8 Milrinone
(III), (Fig. 1) Amrinone (IV),9 (Fig. 1) and their analogues10–12 are
potent cardiotonic agents for the treatment of heart failure.
2-Pyridones are also used as an important intermediate for the
synthesis of biologically and pharmacologically potent polycyclic
compounds as illustrated by the recent synthetic approaches
toward the camptothecin family of antitumor agents.13
core containing heterocyclic molecules, still these classical reac-
tions have significant drawbacks such as availability of precursors,
functional group compatibility, long reaction time, and harsh reac-
tion conditions, which limit their scope. Multicomponent coupling
reaction (MCR) is a powerful synthetic tool for the synthesis of bio-
logically active compounds.19 In recent years, with the increasing
environmental concerns, development of environmentally benevo-
lent organic reactions has become a crucial and challenging re-
search area in modern organic chemistry. Herein, we have
uncovered two highly efficient and environmentally benign multi-
component coupling reactions catalyzed by VB1 and PEG–SO3H for
the synthesis of 3,4-dihydropyridin-2-one derivatives. VB1 is a
nonflammable, inexpensive, and non-toxic reagent which has been
used as the catalyst for the synthesis of heterocyclic compounds,
such as pyrimidinones,20a dihydropyridines,20b and 1,2-dihydro-
naphth[1,2-e][1,3]oxazine-3-one.20c PEG–SO3H is a polymer sup-
ported catalyst that is functionalized by acidic groups and is a mild,
non-volatile, and non-corrosive organic acid which has been used
for the synthesis of several heterocyclic molecules.21 These reports
inspired us to explore the utility of these green catalysts in the syn-
thesis of an array of 3,4-dihydropyridin-2-one derivatives.
The astonishing drug activity of the 2-pyridone derivatives not
only attracted many synthetic and medicinal chemists to synthe-
size this heterocyclic nucleus but also became an active research
area of enduring interest. So far, only a few convenient methods
have been reported in the literature.14–18 Although these methods
are very helpful for the construction of 3,4-dihydropyridin-2-one
At the commencement of our work we focused on systematic
assessment of different catalysts for the two model reactions
(Schemes 1 and 2). A wide array of catalysts including ZnCl2,
MgCl2, SiO2, Al2O3, Alum, I2, p-toluene sulfonic acid, AcOH, and
VB1 were employed to improve the yield for the specific synthesis
of 3,4-dihydropyridin-2-one derivatives. The results are presented
in Table 1. In the preliminary experiment, the above mentioned
⇑
Corresponding author. Tel.: +91 3323501014, +91 9433120265; fax: +91
3323519754.
E-mail addresses: ardchem@caluniv.ac.in, ardas66@rediffmail.com (A.R. Das).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.030

K. Pradhan et al. / Tetrahedron Letters 53 (2012) 5840–5844
5841
Cl
O
CN
NH2
OH
N
H
N
O
N
O
N
O
Cl
NH
NH
Et
N
OMe
O
N
H
O
III
IV
II
I
Figure 1. Biologically active pyridin-2-one compounds.
Table 2
NO2
Influence of different solvents and catalyst concentration on the synthesis of 3,4-
dihydro pyridin-2-onea
CHO
NO2
Entry Scheme 1
Scheme 2
Solvent
Yieldb (%)
O
O
O
CN
VB1 (mol %) PEG–SO3H (mol %)
Scheme 1 Scheme 2
CN
O
Catalyst
H2O ,100 oC
O
O
CONH2
1
2
3
6
6
10
15
20
25
20
20
20
20
20
H2O
H2O
H2O
H2O
H2O
THF
59
68
73
80
80
30
39
47
68
81
81
—
61
—
18
25
N
H
3
4
5
6
7
8
9
10
10
15
20
15
15
15
15
15
Scheme 1. Synthesis of 3,4-dihydropyridin-2-one using three component coupling
reaction of 4-nitrobenzaldehyde, cyanoacetamide, and ethyl acetoacetate.
Toluene 48
MeCN
MeOH
EtOH
41
56
71
NO2
a
4-Nitrobenzaldehyde (1 mmol), malononitrile (1 mmol), and ethyl acetoacetate
CHO
O
(1 mmol) were stirred in 5 mL solvent in the presence of catalyst under refluxing
condition.
O
CN
CN
CN
O
Catalyst
H2O/ 100 oC
b
+
O
+
Isolated yield of the pure product.
O
O
N
H
NO2
first synthetic protocol. Interestingly, the installation of VB1 as
the catalyst for the first protocol (Scheme 1) not only increased
the product yield, but also decreased the reaction time from 8 h
to 4 h. In comparison with these Lewis acid catalysts, strong organ-
ic acids and VB1; PEG–SO3H have proved to be the most efficient
catalysts for the synthesis of 3,4-dihydropyridin-2-one derivatives
applying the second synthetic method (Scheme 2).
Various solvents were also screened to test the efficiency of
these catalysts in different reaction medium and the results are
summarized in Table 2. It was evident that the polar solvents affor-
ded better yield than the nonpolar ones and in case of both the
synthetic protocols water showed superiority over the other sol-
vents. It is noteworthy to mention that quantity of the catalyst
plays a vital role in the formation of the desired product. An
Scheme 2. Synthesis of 3,4-dihydropyridin-2-one via a three component coupling
reaction of 4-nitrobenzaldehyde, malononitrile and ethyl acetoacetate.
reactions were performed in the absence of any catalyst employing
water as the solvent. It was evident that the reaction proceeded
very slowly in the absence of catalyst and the expected product
was isolated in a very small quantity after heating the reaction
mixture for about 24 h at 100 °C (Table 1, entry 1). It was also evi-
dent that in case of both the synthetic protocols (Schemes 1 and 2),
with the use of ZnCl2, MgCl2, SiO2, Al2O3, alum, and I2 the product
was formed in poor yields (Table 1), whereas using strong organic
acids like p-toluene sulfonic acid and AcOH (Table 1, entries 8 and
9) the product was obtained in moderate yields by applying the
Table 1
Screening of different catalysts for the synthesis of 3,4-dihydro pyridin-2-one
Entry
Catalyst
Time (h)
Yieldc (%)
Scheme 1
Scheme 2
Scheme 1a
Scheme 2b
1
2
3
4
5
6
7
8
—
ZnCl2
MgCl2
SiO2
Al2O3
Alum
I2
p-Toluene sulfonic acid
AcOH
PEG–SO3H
VB1
24
8
8
8
8
8
8
8
8
8
4
48
9
9
9
9
9
9
7
7
Trace
—
—
—
—
—
—
10
10
5
—
—
—
—
—
—
—
64
38
81
—
9
10
11
5.5
9
80
a
4-Nitrobenzaldehyde (1 mmol), cyanoacetamide (1 mmol), and ethyl acetoacetate (1 mmol) were stirred in 5 mL H2O in the presence of catalyst (15 mol %) under
refluxing condition.
b
4-Nitrobenzaldehyde (1 mmol), malononitrile (1 mmol), and ethyl acetoacetate (1 mmol) were stirred in 5 mL H2O in the presence of catalyst (20 mol %) under refluxing
condition.
c
Isolated yield of the pure product.

5842
K. Pradhan et al. / Tetrahedron Letters 53 (2012) 5840–5844
Table 3
VB1 and PEG–SO3H catalyzed synthesis of 3,4-dihydropyridin-2-one derivatives in aqueous media
NO2
CHO
O
O
CHO
O
O
CN
CN
Method A:
VB1, H2O ,100oC
Method B:
CN
CN
O
PEG-SO3H,
CONH2
H2O ,100oC
N
H
O
NO2
NO2
Entry
Ar
Ph
1,3-Diketo compound
Product
Time (h)
Yieldc,d (%)
Method Aa
Method Bb
Method A
Method B
1
2
3
4
5
6
7
8
Ethylacetoacetate
Ethylacetoacetate
Ethylacetoacetate
Ethylacetoacetate
Ethylacetoacetate
Ethylacetoacetate
Ethylacetoacetate
Ethylacetoacetate
Acetylacetone
Acetylacetone
Acetylacetone
Acetylacetone
Acetylacetone
Acetylacetone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
1a
1b
1c
1d
1e
1f
4.5
4.0
4.5
4.0
4.5
4.5
5.0
4.5
4.5
4.0
4.5
4.0
4.5
4.5
4.5
4.0
4.5
4.0
5.0
4.5
5.0
4.5
6
5.5
6
6
6
6.5
7
6
78, 72e
80
84
81
82
78
76
79
78
81
82
85
83
76
79
81
83
83
72
74
71
76
78, 74e
81
80
79
76
72
70
76
72
77
78
77
76
73
74
79
77
76
69
72
67
71
4-NO2-C6H4-
3-NO2-C6H4-
4-F-C6H4-
4-Cl-C6H4-
4-CH3-C6H4-
4-OCH3-C6H4-
2-Fur
1gf
1h
1i
1j
1l
9
Ph-
6
10
11
12
13
14
15
16
17
18
19
20
21
22
4-NO2-C6H4-
3-NO2-C6H4-
4-F-C6H4-
4-Cl-C6H4-
4-CH3-C6H4-
Ph-
4-NO2-C6H4-
3-NO2-C6H4-
4-F-C6H4-
4-OCH3-C6H4-
4-CH3-C6H4-
4-N(CH3)2-C6H4
2-Fur
5.5
5.5
5
6
7
1l
1m
1n
1o
1p
1qf
1r
1s
1t
1u
1v
9
8.5
8.5
9
9.5
9
10
9.5
a
b
c
d
e
f
Aldehyde (1 mmol), cyanoacetamide (1 mmol), and 1,3-diketone (1 mmol) were heated in 5 mL H2O in the presence of 15 mol % VB1 at 100 °C
Aldehyde(1 mmol), malononitrile (1 mmol), and 1,3-diketone (1 mmol) were stirred in 5 mL H2O in the presence of PEG–SO3H (20 mol %) under refluxing condition.
Isolated yield of the pure product.
The products were characterized by 1H NMR, 13C NMR, IR, HRMS, and elemental analysis.
Yield obtained after five catalytic cycles.
The compounds 1g and 1q were crystallized from ethanol/water (7:3). Structure of the compounds were established by single crystal analysis (Supplementary data).23
increase in the amount of VB1 from 3 to 15 mol % increased the
yield of the desired product to a great extent (59–80%, Table 2).
For the second synthetic method, the best result was obtained by
using 20 mol % of PEG–SO3H as the catalyst at 100 °C temperature
in aqueous medium.
case of PEG–SO3H catalyzed three component coupling reaction it
involves mild polymer supported acid catalyzed Knoevenagel con-
densation, Michael addition, and then intra molecular cyclization
for the formation of 4H-pyran intermediate. Subsequently this
intermediate undergoes PEG–SO3H catalyzed sequential ring open-
ing and closing involving hydration and dehydration of the 4H-
pyran nucleus to form 3,4-dihydropyridin-2-one derivatives in
aqueous medium. The mild acid catalyzed Knoevenagel condensa-
tion, Michael reaction, ring annulation, and subsequent rearrange-
ment leading to the targeted 3,4-dihydropyridin-2-one derivatives
(VI) were confirmed by the isolation of the intermediate (V). The
formation of the 4H-pyran intermediate (V), was also established
by performing the PEG–SO3H catalyzed rearrangement of the iso-
lated intermediate.24 These experimental results clearly revealed
that in this multi component reaction initially 4H-pyran was gen-
erated which then undergoes PEG–SO3H catalyzed rearrangement
to 3,4-dihydropyridin-2-one derivative. VB1 was unable to catalyze
the second synthetic protocol. Although in the presence of VB1, 4H-
pyran intermediate (V) was isolated, the reaction did not proceed
further as VB1 could not catalyze the rearrangement step. More-
over the reaction can be scaled up to 10 mmol scale. In large scale
preparation, we have successfully recycled both the catalysts in
five new batches of reactions with almost same catalytic activity.22
In summary, we have successfully developed simple, conve-
nient, environmentally benign, mild, and safe synthetic methods
to afford highly substituted 3,4-dihydropyridin-2-one derivatives
Encouraged by the efficiency of the above reaction protocols, we
then devised two novel one pot three-component synthetic routes
for the synthesis of highly functionalized 3,4-dihydropyridin-2-one
derivatives under thermal conditions. To scrutinize the scope, lim-
itations, and generality of these protocols, we have advocated a
series of aldehydes and b-dicarbonyl compounds in the presence
of 15 mol % VB1 (Method A) or in the presence of 20 mol % of
PEG–SO3H (Method B) in H2O under refluxing condition. In case
of both the synthetic protocols22 the reactions occurred smoothly
with unsubstituted as well as substituted benzaldehydes. The re-
sults are summarized in Table 3. As mentioned in Table 3 hetero-
aromatic aldehydes also reacted efficiently to give the
corresponding 3,4-dihydropyridin-2-one derivatives in good yield.
The formation of 3,4-dihydropyridin-2-one derivatives through
VB1 catalyzed three component coupling reaction involves Knoeve-
nagel condensation, Michael addition, and then intra molecular
cyclization as presented in Scheme 3. Only the Knoevenagel con-
densation product was isolated when PEG–SO3H was administered
as the catalyst but the targeted molecule was formed in poor yield
(5%) after long reaction time. VB1 played a very crucial role in the
MCR but the exact role of the catalyst, is not very clear. Whereas in

K. Pradhan et al. / Tetrahedron Letters 53 (2012) 5840–5844
5843
O
Method B
CN
O
H
O
NC
O
H
O
CN
O
CN
HO
CN
NC
H
C
N
S
PEG
O
Step IIB
O
Step IIIB
O
NH2
..
Step IB
V
H
O
CONH2
O
S
H
PEG
Method A
Step IA
Step IVB
S
O
CN
VB1
CONH2
CN
O
CN
OH
O
O
H
NH2
Step IIA
H2O
Step VB
O
H
CN
O
Step IIIA
Step VIB
O
CN
CN
C
O
O
H2N
..
O
NH2
N
H
O
OH
VI
Scheme 3. Plausible mechanistic course of the two methodologies for the synthesis of 3,4-dihydropyridin-2-one.
4. (a) Dolle, V.; Fan, E.; Nguyen, C. H.; Aubertin, A. M.; Kirn, A.; Andreola, M. L.;
Jamieson, G.; Tarragolitvak, L.; Bisagni, E. J. Med. Chem. 1995, 38, 4679–4686;
(b) Wai, J. S.; Williams, T. M.; Bamberger, D. L.; Fisher, T. E.; Hoffman, J. M.;
Hudcosky, R. J.; Mactough, S. C.; Rooney, C. S.; Saari, W. S.; Thomas, C. M.;
Goldman, M. E.; Obrien, J. A.; Emini, E. A.; Nunberg, J. H.; Quintero, J. C.; Schleif,
W. A.; Anderson, P. S. J. Med. Chem. 1993, 36, 249–255.
5. Yang, M.-H.; Chen, Y.-Y.; Huang, L. Phytochemistry 1988, 27, 445.
6. Yang, M.-H.; Chen, Y.-Y.; Huang, L. Chin. Chem. Lett. 1991, 2, 291.
7. De Clercq, E. Farmaco 1999, 54, 26–45.
8. (a) Parreira, R. L. T.; Abrahao, O.; Galembeck, S. E. Tetrahedron 2001, 57, 3243–
3253; (b) Kumarihamy, M.; Khan, S. I.; Jacob, M.; Tekwani, B. L.; Duke, S. O.;
Ferreira, D.; Nanayakkara, P. D. J. Nat. Prod. 2012, 75, 883–889.
9. Pastelin, G.; Mendez, R.; Kabela, E.; Farah, A. Life Sci. 1983, 33, 1787–1796.
10. Presti, E. L.; Boggia, R.; Feltrin, A.; Menozzi, G.; Dorigo, P.; Mosti, L. Farmaco
1999, 54, 465–474.
using the organocatalyst VB1 and polymer supported acidic cata-
lyst PEG–SO3H in aqueous media from two different sets of precur-
sors. The significant advantages of these methodologies are high
yields, simple work-up procedures, easy preparation of PEG–
SO3H, and handling of both the catalysts. We believe that these
one-pot catalytic transformations would be a very attractive choice
for the synthesis of 3,4-dihydropyridin-2-one libraries in chemical
as well as pharmaceutical industries.
Acknowledgments
We gratefully acknowledge the financial support from the U.G.C
and the Calcutta University. K.P. and S.P thank U.G.C, New Delhi,
India for the grant of their Junior Research fellowships. P.B. thanks
CSIR for Senior Research Fellowship. (Grant No. 09/028(0768)/
2010). Crystallography was performed at the DST-FIST, India-
funded Single Crystal Diffractometer Facility at the Department
of Chemistry, University of Calcutta.
11. Dorigo, P.; Fraccarolo, D.; Gaion, R. M.; Santostasi, G.; Borea, P. A.; Floreani, M.;
Mosti, L.; Maragno, I. Gen. Pharmacol. 1997, 28, 781–788.
12. Altomare, C.; Cellamare, S.; Summo, L.; Fossa, P.; Mosti, L.; Carotti, A. Bioorg.
Med. Chem. 2000, 8, 909–916.
13. (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.
14. Pendleton, M. D.; Beddoes, R. L.; Andrew, N. J.; Butters, M.; Joule, J. A. J. Chem.
Res., Synop. 1997, 86–87.
15. Yang, L.; Zheng, Q. Y.; Wang, D. X.; Huang, Z. T.; Wang, M. X. Org. Lett. 2008, 10,
2461–2464.
16. Paravidino, M.; Scheffelaar, R.; Schmitz, R. F.; De Kanter, F. J. J.; Groen, M. B.;
Ruijter, E.; Orru, R. V. A. J. Org. Chem. 2007, 72, 10239–10242.
17. Noguez, M. O.; Marcelino, V.; Rodríguez, H.; Martí, O.; Martínez, J. O.; Perez, F.
J.; Suarez, M.; Miranda, R. Int. J. Mol. Sci. 2011, 12, 2641–2649.
18. Liu, Z. Q.; Liu, B. K.; Wu, Q.; Lin, X. F. Tetrahedron 2011, 67, 9736–9740.
19. (a) Srivastava, R. G.; Venkataramani, P. S. Synth. Commun. 1988, 18, 1537–1544;
(b) Shen, M.; Driver, T. G. Org. Lett. 2008, 10, 3367–3370; (c) Bahrami, K.;
Khodaci, M. M.; Naali, F. J. Org. Chem. 2008, 73, 6835–6837.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.08.
030.
20. (a) Lei, M.; Ma, L.; Hu, L. Monatsh. Chem. 2010, 141, 1005; (b) Lei, M.; Ma, L.; Hu,
L. Synth. Commun. 2011, 41, 1969; (c) Lei, M.; Ma, L.; Hu, L. Synth. Commun.
2011, 41, 3424.
References and notes
1. Li, Q.; Mitscher, L. A.; Shen, L. L. Med. Res. Rev. 2000, 20, 231–293.
2. Cox, R. J.; Ohagan, D. J. Chem. Soc., Perkin Trans. 1 1991, 2537–2540.
3. (a) Nagarajan, M.; Xiao, X. S.; Antony, S.; Kohlhagen, G.; Pommier, Y.; Cushman,
M. J. Med. Chem. 2003, 46, 5712–5724; (b) Hasvold, L. A.; Wang, W. B.;
Gwaltney, S. L.; Rockway, T. W.; Nelson, L. T. J.; Mantei, R. A.; Fakhoury, S. A.;
Sullivan, G. M.; Li, Q.; Lin, N. H.; Wang, L.; Zhang, H. Y.; Cohen, J.; Gu, W. Z.;
Marsh, K.; Bauch, J.; Rosenberg, S.; Sham, F. L. Bioorg. Med. Chem. Lett. 2003, 13,
4001–4005.
21. (a) Kiasat, A. R.; Mehrjardi, M. F. Catal. Commun. 2008, 9, 1497; (b) Reddy, C. B.;
Kumar, K. S.; Kumar, M. A.; Reddy, M. V. N.; Krishna, B. S.; Naveen, M.;
Arunasree, M. K.; Reddy, C. S.; Naga Raju, C.; Reddy, C. D. Eur. J. Med. Chem.
2012, 47, 553; (c) Kumar, R.; Nandi, G. C.; Verma, R. K.; Singh, M. S. Tetrahedron
Lett. 2010, 51, 442; (d) Gong, K.; Fong, D.; Wang, H. L.; Zhou, X. L.; Liu, Z. L. Dyes
Pigm. 2009, 80, 30; (e) Nazeruddin, G. M.; Pandharpatte, M. S.; Mulani, K. B. C.
R. Chimia 2012, 15, 91; (f) Paul, S.; Das, A. R. Catal. Sci. Technol. 2012, 2, 1130–
1135.

5844
K. Pradhan et al. / Tetrahedron Letters 53 (2012) 5840–5844
22. Method A: A mixture of aldehyde (1.0 mmol), cyanoacetamide (1.0 mmol), 1,3-
dicarbonyl compound (1.0 mmol), and VB1(15 mol %) was stirred in 5 ml of
water at 100 °C for the required period of time(TLC). After the completion of
the reaction, the mixture was extracted with ethyl acetate (3 Â 10 ml) and was
purified by column chromatography (silicagel, ethyl acetate, hexane 1:3) to
afford the desired product of 3,4-dihydropyridin-2-ones.
(75 MHz, CDCl3): d 19.7, 29.6, 41.5, 47.3, 113.8, 115.7, 116.4, 116.7, 129.8,
129.9, 130.6, 145.1, 161.9, 194.4; Anal. Calcd for C15H14N2O2: C, 70.85; H, 5.55;
N, 11.02. Found: C, 70.82; H, 5.53; N, 11.04; HRMS of [C15H14N2O2+H+]: calcd:
255.1134 found: 255.1132.
23. Crystallographic data for the structure 1g and 1q have been deposited with the
Cambridge Crystallographic Data Center as supplementary publication No.
CCDC 876417 and CCDC 876418 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).
The aqueous part was evaporated to dryness under reduced pressure and the
resulting solid was washed three times with 5 ml ethyl acetate and was dried
under reduced pressure to get back the catalyst which was used for the new set
of reaction.
24. The
intermediate
6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-
Method B: A mixture of aldehyde (1.0 mmol), malononitrile (1.0 mmol), 1,3-
dicarbonyl compound (1.0 mmol), and PEG–SO3H (20 mol %) was stirred in
5 ml of water at 100 °C for the required period of time(TLC). After the
completion of the reaction, the mixture was extracted with ethyl acetate
(3 Â 10 ml) and was purified by column chromatography (silicagel, ethyl
acetate, hexane 1:3) to afford the desired product of 3,4-dihydropyridin-2-
ones.
carboxylicacid ethyl ester was isolated by stirring a mixture of benzaldehyde
(1.0 mmol), malononitrile (1.0 mmol), ethyl acetoacetate (1.0 mmol), and PEG–
SO3H (20 mol %) in 5 ml of water at 100 °C for 30 min. After the completion of
the reaction, the mixture was filtered to obtain the 4H-pyran intermediate
(Characterization data presented in Supplementary data).
The catalyst was recovered by evaporating the aqueous part under reduced
pressure, and the resulting gummy solid was washed with diethyl ether, and
dried under reduced pressure.
5-Cyano-2-methyl-6-oxo-4-phenyl-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid
ethyl ester (1a)
O
O
CN
CN
NH2
O
PEG-SO3H
H2O, 100 oC
O
Characteristics: White crystalline solid; Mp: 104 °C; IR (KBr): 3322, 2192, 1676,
1652 cmÀ1
;
1H NMR (300 MHz, CDCl3): d 1.19(3H, t, J = 6.9 Hz), 2.42 (3H, s),
N
H
O
4.06–4.18 (3H,m), 4.49 (2H,d, J = 6.9 Hz), 7.24–7.35 (5H,m), 8.53(1H,s); 13C
NMR (75 MHz, CDCl3): d 13.9, 18.8, 41.2, 41.5, 60.7, 107.7, 114.1, 127.7, 128.4,
128.9, 136.0, 145.9, 163.1, 165.4; Anal. Calcd for C16H16N2O3: C, 67.59; H, 5.67;
N, 9.85. Found: C, 67.57; H, 5.68; N, 9.82. HRMS of [C16H16N2O3+H+]: calcd:
285.1240 found: 285.1236
O
A
mixture of the intermediate 6-amino-5-cyano-2-methyl-4-phenyl-4H-
pyran-3-carboxylic acid ethyl ester (1.0 mmol), and PEG–SO3H (20 mol %)
was stirred in 5 ml of water at 100 °C for 5 h. After completion of the reaction,
the mixture was extracted with ethyl acetate (3 Â 10 ml) and was purified by
column chromatography (silicagel, ethyl acetate, hexane 1:3) to afford the
desired product 3,4-dihydropyridin-2-ones.
5-Acetyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydro-pyridine-3-carbonitrile
(1i):
Characteristics: white crystalline solid; Mp: 156 °C; IR (KBr): 3352, 2188, 1694,
1662 cmÀ1 1H NMR (300 MHz, CDCl3): d 1.94 (3H, s), 2.16 (3H, s), 3.80 (2H, d,
;
J = 3.6 Hz), 4.15 (2H, d, J = 3.6 Hz), 6.94–7.18 (5H, m), 8.09 (1H,s); 13C NMR