A one-pot two-step microwave-assisted synthesis of N1-substituted 5,6-ring-fused 2-pyridones

Article abstract of DOI:10.1016/j.tetlet.2013.10.054

A fast, versatile and practical one-pot, two-step microwave-assisted protocol for the direct synthesis of N1-substituted 5,6-ring-fused 2-pyridones has been developed. The present method proved to be effective on a series of commercially available aldehydes, ketones and amines and could be profitably exploited in drug-discovery settings for the rapid identification of biologically relevant hit compounds.

Full text of DOI:10.1016/j.tetlet.2013.10.054

Accepted Manuscript
A one-pot two-step microwave-assisted synthesis of N1-substituted 5,6-ring-
fused 2-pyridones
Marco Radi, Gian Paolo Vallerini, Alessia Petrelli, Paolo Vincetti, Gabriele
Costantino
PII:
S0040-4039(13)01789-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.10.054
TETL 43692
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
4 September 2013
4 October 2013
8 October 2013
Please cite this article as: Radi, M., Vallerini, G.P., Petrelli, A., Vincetti, P., Costantino, G., A one-pot two-step
microwave-assisted synthesis of N1-substituted 5,6-ring-fused 2-pyridones, Tetrahedron Letters (2013), doi: http://
dx.doi.org/10.1016/j.tetlet.2013.10.054
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A one-pot two-step microwave-assisted synthesis of
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Marco Radi,* Gian Paolo Vallerini, Alessia Petrelli, Paolo Vincetti and Gabriele Costantino

1
Tetrahedron Letters
journal hom epage: www.elsevier.com
A one-pot two-step microwave-assisted synthesis of N1-substituted 5,6-ring-fused 2-
pyridones
Marco Radi,* Gian Paolo Vallerini, Alessia Petrelli, Paolo Vincetti and Gabriele Costantino
Dipartimento di Farmacia, Università degli Studi di Parma, Viale delle Scienze, 27/A, 43124 Parma, Italy
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A fast, versatile and practical one-pot, two-step microwave-assisted protocol for the direct
synthesis of N1-substituted 5,6-ring-fused 2-pyridones has been developed. The present method
proved to be effective on a series of commercially available aldehydes, ketones and amines and
could be profitably exploited in drug-discovery settings for the rapid identification of
biologically relevant hit compounds.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reaction, 2-Pyridones, Microwave,
N1-substituted, One-pot two step, Ring-fused
Nitrogen-containing heterocycles represent a wide class of
organic molecules broadly distributed in nature and often
endowed with attracting biological properties. Within this class,
wide range of alkylating agents could be employed, further
functionalization at positions C3 and C5 requires additional
synthetic steps, and often the use of hazardous reagents. Among
1
0
2
-pyridones represent ubiquitous scaffolds frequently found in
the available multistep strategies, Kibou et al. recently reported
a solvent-free protocol comprising a Knoevenagel condensation
of ethyl cyanoacetate with acetophenones, followed by formation
of an enaminonitrile intermediate which was finally cyclized in
presence of a primary amine to give 1,3,4-substituted 2-
natural products and pharmaceutical compounds (Figure 1). 2-
Pyridone analogues are currently used in the treatment of
1
congestive heart failure (Amrinone and Milrinone), idiopatic
2
pulmonary fibrosis (Pirfenidone) or as antitumor agents
3
11
(
Topotecan). Other representative ring-fused 2-pyridones are
pyridones. This approach worked well with a wide range of
4
reported as acetylcholinesterase inhibitors (Huperzine A),
PARP-1 inhibitors (PJ34) and anti-HIV agents (INDOPY-1)
reactants, but allowed access to 5,6-unsubstituted derivatives
5
6
only. In recent years,
a few interesting multicomponent
(
Figure 1). Due to their wide application in medicinal chemistry,
approaches for the synthesis of substituted 2-pyridones have also
1
2
it is not surprising that the synthesis of 2-pyridone derivatives has
attracted organic chemists for many years, and several effective
procedures for the synthesis of highly functionalized derivatives
been developed. Sun et al. reported a domino reaction of
arylamines, methyl propiolate, aromatic aldehydes and ethyl
cyanoacetate, in the presence of catalytic triethylamine, to give
1,3,4,5-substituted 2-pyridones in moderate yields after stirring
7
are continuously being developed. Depending on the required
molecular complexity, different approaches can be employed for
the synthesis of the 2-pyridones: while multistep protocols
usually allow one to obtain a higher degree of chemical diversity
around the heterocyclic core, multicomponent approaches present
the advantage of atom- and cost-efficiency that, coupled with
microwaves techniques, may allow one to quickly generate new
8
chemical entities for drug discovery purposes.
The classical multistep approach for the synthesis of
substituted 2-pyridones requires the conversion of 4-hydroxy-6-
methylpyran-2-one
followed by C4 O-alkylation and N1-alkylation. Although a
into
4-hydroxy-6-methylpyridin-2-one
9
———
*
Corresponding author. Tel.: +39-0521-906080; fax: +39-0521-905006; e-mail: marco.radi@unipr.it

2
Tetrahedron Letters
Scheme 1. Application of the standard multicomponent procedure.
Table 1. Multicomponent synthesis of 2-aminopyridines and 2-pyridones
a
Cpd.
R
2
R
3
R
4
Yield (%)
3
3
a
Ph
H
-
80
20
b
-
4
4
a
H
Trace
-
Figure 1. Representative 2-pyridone-based bioactive compounds
b
Bn
1
3
for 24 hours. Yermolayev et al. developed a one-pot three-
step microwave-assisted method for the synthesis of N1-
a
Isolated yield
substituted
2,5-dioxo-1,2,5,6,7,8-hexahydro-3-
reaction vessel to better control the outcome of the individual
1
4
quinolinecarbonitrile derivatives while several authors reported
the preparation of 3,4,6-substituted 2-pyridones via one-pot
reaction between ketones (generally acetophenones), aldehydes
reactions: in the first step, the aldehyde and the ethyl
cyanoacetate were reacted to afford the Knoevenagel adduct; in
the second step, the in-situ generated imine (from the added
ketones and amines) cyclized with the alkylidene produced in the
first step to give the final 2-pyridone. The reaction conditions
were initially optimized for the synthesis of compounds 4a and
4b, used as model reactions to prepare N1-unsubstituted and N1-
substituted derivatives, respectively. Different solvents (DME,
(
generally aromatic), ammonium acetate and ethyl
15
cyanoacetate. Although the latter approach is the most utilized
for the synthesis of biologically relevant compounds, its
application to the development of ring-fused 2-pyridones is
poorly investigated and limited to N1-unsubstituted derivatives.
With the aim to develop a versatile synthetic protocol for the
direct synthesis of N1-functionalized ring-fused 2-pyridones and
as a continuation of our interest in microwave methodologies for
the synthesis of new heterocycles, herein we describe the
development of a microwave-assisted one-pot, two-step protocol
for the synthesis of 1,3,4-substituted 5,6-ring-fused 2-pyridones.
3 3
EtOH, t-BuOH, DMF), catalysts (Et N, piperidine, AlCl , L-
proline) temperatures and reaction times were used in both steps.
After several attempts, the best reaction conditions for the first
step were found to be those employing L-proline as a catalyst in
solvent-free, microwave-assisted conditions. The optimal
reaction conditions for the second step varied depending on the
nature of the amines used: ammonium acetate (Method A) or
primary amines (Method B). In the optimized model reaction
16
Our preliminary experiments were inspired by the work
published in 2005 by Shi, et al., which reported the
multicomponent synthesis of 2-amino-3-cyanopyridine
derivatives without solvent in a domestic microwave oven. The
results obtained by Shi and colleagues were initially reproduced
1
7
(
Table 2), benzaldehyde 1a and ethyl cyanoacetate were
irradiated, in the presence of catalytic L-proline, for 5 minutes at
o
8
0 C in a microwave sealed tube to quantitatively obtain the
arylidene 2.
in
a
microwave oven for organic synthesis, reacting
benzaldehyde 1 with malononitrile and acetophenone 2a in the
presence of ammonium acetate at 250 C in open vessel mode
Table 2. Optimized one-pot, two-step protocol
o
(
Scheme 1, Table 1). Compound 3a was thus obtained after 10
minutes in 80% yield. The same protocol was then applied to
cyclic ketones: substitution of acetophenone 2a with
cyclohexanone 2b led to the ring-fused derivative 3b, even if
with low yields. To obtain the corresponding ring-fused 2-
pyridones, benzaldehyde 1, ethylcyanoacetate, cyclohexanone 2b
and ammonium acetate were reacted under the above reported
conditions but only traces of compound 4a were identified. We
also tried to replace ammonium acetate with a primary amine to
obtain the desired 1,3,4-substituted 5,6-ring-fused 2-pyridones.
Unfortunately, when benzylamine was used in this
multicomponent protocol, a very complex mixture was obtained
and 4b was never isolated. A systematic study of this
multicomponent reaction with the aim of obtaining the desired
N1-substituted 5,6-ring-fused 2-pyridones was undertaken. Based
16
on the reaction mechanism proposed by Shi et al., we decided
to divide the reaction in two consecutive steps in the same

3
a
a
Entry
Cpd.
R
3
Method
Yield (%)
Entry
1
Cpd.
5a
R
4
R
3
Yield (%)
30
32
50
b
1
2
4a
4b
H
A
44
35
2
3
5b
5c
c
Bn
B
OH
3
4
4c
Bn
Bn
B
B
33
36
O
4d
4
5
5d
5e
35
30
5
4e
Bn
B
45
a
b
c
Isolated yield. Method A: neat, 200 W, 5 min; R
B: DME, 120 C, 15 min, AcOHcat; R
3
NH
2
= NH
4
OAc. Method
o
3
NH
2
= benzylamine.
O
Cyclohexanone 3a and ammonium acetate (Method A) were
then added and the resulting mixture was heated in the
microwave (200 W) for additional 5 minutes: the desired 5,6-
fused pyridone 4a was isolated as a pure product after a simple
precipitation by addition of diethyl ether (Table 2, entry 1).
Under optimized conditions for Method B, dimethoxyethane
DME), ketone (3a-d), catalytic acetic acid and benzylamine
were added to the ice-cooled arylidene 2 and the reaction mixture
was irradiated at 120 C for 15 minutes. The desired N1-
substituted 5,6-ring-fused 2-pyridones (4b-e) were obtained in
NH
N
6
7
8
5f
5g
5h
65
35
25
(
S
o
moderate to good yields after chromatographic purification
(
Table 2, entries 2-5). It should be noted that similar 1,3,4,5,6-
functionalized 2-pyridones are usually obtained with comparable
11,18
9
5i
34
overall yields after several synthetic steps,
while our approach
Table 3. N1-substituted 5,6-ring-fused 2-pyridone analogues
O
1
1
0
1
5j
nPr-
H
20
35
5k
a
Isolated yield.
provided the desired compounds after a 20 minutes reaction
followed by a chromatographic purification. Under classical
heating conditions, the optimized one-pot two-step protocol
allowed to obtain compound 4e in comparable yields (40%) but
after longer reaction times (1h for the first step and 12h for the
second step). To verify the versatility and efficiency of the
optimized microwave-assisted one-pot, two-step protocol, a
series of commercially available aldehydes (R
amines (R NH ) were used as building blocks in the reaction with
-indanone 3d to generate a collection of 1,4-substituted 2,9-
1
CHO) and primary
4
2
2
dihydro-2-oxo-1H, 2H, 9H-indeno[2,1-b]pyridine-3-carbonitrile
derivatives 5a-k (Table 3). In a first set of experiments,
benzaldehyde 1a was reacted, under the above reported
optimized conditions (Method B), with ethyl cyanoacetate, 2-
indanone 3d and a series of amines (instead of the previously
used benzylamine) that could also allow a subsequent elongation
of the N1-chain (Table 3): propargylamine (Entry 1) gave
product 5a, that could be further elaborated via click-chemistry
reaction; 2-aminoethanol (Entry 2) gave product 5b, that could be
further elongated via O-alkylation; phenoxyethylamine (Entry 3)
gave product 5c in good yields. Anilines did not react under the
optimized reaction conditions. In a second set of experiments,
different aldehydes 1a-i were reacted in the one-pot, two-step
protocol with ethyl cyanoacetate, 2-indanone 3d and
benzylamine to give a series of 4-substituted 1-benzyl-2-oxo-2,9-
dihydro-1H-indeno[2,1-b]pyridine-3-carbonitriles 5d-j (Table 3,
Entries 4-10). The synthetic protocol proved to be effective with

4
Tetrahedron Letters
aromatic aldehydes (Entries 4-5), heteroaromatic aldehydes
Entries 6-7) and different aliphatic aldehydes (Entries 8-10).
Stanculeanu, D.; Timcheva, C.; Tzekova, V.; Zakotnik, B.;
Zielinski, C. C.; Zwitter, M. Lung Cancer. 2010, 70, 7-13.
Kozikowski, A. P.; Tückmantel, W. Acc. Chem. Res. 1999, 32,
(
4
5
.
.
Details on the synthetic procedures and compounds’
characterization are reported in the Supplementary Material.
Finally, it is interesting to note that para-formaldehyde (Entry 11)
can be used in place of aromatic/aliphatic aldehydes to access
C4-unsubstituted derivatives (e.g. 5k) that, to the best of our
knowledge, have never been obtained with a multicomponent
procedure, but only after several synthetic steps. Additional
experiments are ongoing in our laboratory to evaluate the
versatility of this para-formaldehyde-based procedure and will be
reported in due course.
6
41–650.
Jagtap, P.; Soriano, F. G.; Virag, L.; Liaudet, L.; Mabley, J.;
Szabo, E.; Hasko, G.; Marton, A.; Lorigados, C. B.; Gallyas, F.,
Jr.; Sumegi, B.; Hoyt, D. G.; Baloglu, E.; VanDuzer, J.; Salzman,
A. L.; Southan, G. J.; Szabo, C. Crit. Care Med. 2002, 30, 1071–
1
082.
6
.
Jochmans, D.; Deval, J.; Kesteleyn, B.; Van Marck, H.; Bettens,
E.; De Baere, I.; Dehertogh, P.; Ivens, T.; Van Ginderen, M.; Van
Schoubroeck, B.; Ehteshami, M.; Wigerinck, P.; Gotte, M.;
Hertogs, K. J. Virol. 2006, 80, 12283-12292. b) Zhang, Z.;
Walker, M.; Xu, W.; Shim, J. H.; Girardet, J. L.; Hamatake, R. K.;
Hong, Z. Antimicrob. Agents Chemother. 2006, 50, 2772-2781.
In summary, a fast and versatile microwave-assisted one-pot
two-steps protocol for the synthesis of N1-substituted 5,6-ring-
fused 2-pyridones has been developed. Different reaction
conditions were optimized depending on the nature of the reacted
amines: using ammonium acetate (Method A), N1-unsubstituted
7. Torres, M.; Gil, S.; Parra, M. Curr. Org. Chem. 2005, 9, 1757-
779.
Dömling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112,
083−3135.
1
8
9
.
.
3
Selness, S. R.; Boehm, T. L.; Walker, J. K.; Devadas, B.; Durley,
R. C.; Kurumbail, R.; Shieh, H.; Xing, L.; Hepperle, M.; Rucker,
P. V.; Jerome, K. D.; Benson, A. G.; Marrufo, L. D.; Madsen, H.
M.; Hitchcock, J.; Owen, T. J.; Christie, L.; Promo, M. A.;
Hickory, B. S.; Alvira, E.; Naing, W.; Blevis-Bal, R.; Devraj, R.
V.; Messing, D.; Schindler, J. F.; Hirsch, J.; Saabye, M.; Bonar,
S.; Webb, E.; Anderson, G.; Monahan, J. B. Bioorg. Med. Chem.
Lett. 2011, 21, 4059–4065.
5
,6-ring-fused 2-pyridones were obtained while using primary
amines (Method B), N1-substituted 5,6-ring-fused 2-pyridones
were generated. The present method can be used for the
generation of N1-substituted 2-pyridones starting from
commercially available aldehydes, ketones and amines in only 10
to 20 minutes and could be profitably exploited in drug-discovery
settings for the rapid identification of biologically relevant hit
compounds.
10. Baškovč, J.; Dahmann, G.; Golobič, A.; Grošelj, U.; Kočar, D.;
Stanovnik, B.; Svete, J. ACS Comb. Sci. 2012, 14, 513−519.
1
1. Kibou, Z.; Cheikh, N.; Villemin, D.; Choukchou-Braham, N.;
Mostefa-Kara, B; Benabdallah1, M. Int. J. Org. Chem. 2011, 1,
2
42-249.
12. a) Pathak, S.; Kundu, A.; Pramanik , A. Tetrahedron Lett. 2012,
3, 3030–3034. b) Gorobets, N. Y.; Yousefi, B. H.; Belaj, F.;
Acknowledgments
5
Kappe, C. O. Tetrahedron, 2004, 60, 8633–8644. c) Serry, A. M.;
Luik, S.; Laufer, S.; Abadi, A. H. J. Comb. Chem. 2010, 12, 559–
This work was supported by the Italian Ministry for Research
National Interest Research Project PRIN 20103W4779_005) and
by the University of Parma.
(
5
65.
3. Sun, J.; Sun, Y.; Xia, E. Y.; Yan, C. G. ACS Comb. Sci. 2011, 13,
36–441.
1
4
Supplementary Material
14. Yermolayev, S. A.; Gorobets, N. Y.; Desenko, S. M. J. Comb.
Chem. 2009, 11, 44–46.
1
1
5. Abadi, A. H.; Ibrahim, T. M.; Abouzid, K. M.; Lehmann, J.;
Tinsley, H. N.; Gary, B. D.; Piazza, G. A. Bioorg. Med. Chem.
2009, 17, 5974–5982. b) Bayoumi, W. A.; Elsayed, M. A.;
Baraka, H. N.; Laila Abou-zeid, L. Arch. Pharm. Chem. Life Sci.
Supplementary data associated with this article can be found,
in the online version, at
2
012, 345, 902–910.
References and notes
6. a) Radi, M.; Bernardo, V.; Bechi, B.; Castagnolo, D.; Pagano, M.;
Botta, M. Tetrahedron Lett. 2009, 50, 6572–6575. b) Radi, M.;
Casaluce, G.; Botta, M. Synlett 2011, 14, 1997–2000. c) Radi, M.;
Botta, L.; Casaluce, G.; Bernardini, M.; Botta, M. J. Comb. Chem.
1
2
3
.
.
.
Hamada, Y.; Kawachi, K.; Yamamoto, T.; Nakata, T.; Kashu, Y.;
Sato, M.; Watanabe, Y. Jpn. Circ. J. 1999, 63, 605-609.
Adamali, H. I.; Maher, T. M. Drug Des. Devel. Ther. 2012, 6,
2
010, 12, 200–205.
2
61-272.
1
1
7. Shi, F.; Tu, S.; Fang, F.; Li, T. Arkivoc 2005 (i) 137-142.
8. a) Imase, H.; Noguchi, K.; Hirano, M.; Tanaka, K. Org. Lett.
Pirker, R.; Berzinec, P.; Brincat, S.; Kasan, P.; Ostoros, G.; Pesek,
M.; Plāte, S.; Purkalne, G.; Rooneem, R.; Skricková, J.;
2
008, 10, 3563-3566. b) Bayne, C. D.; Johnson, A. T.; Lu, S. P.;
Mohan, R.; Griffith, R. C. WO 03/59884 A1.

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Graphical Abstract
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A one-pot two-step microwave-assisted synthesis of
N1-substituted 5,6-ring-fused 2-pyridones
Leave this area blank for abstract info.
Marco Radi,* Gian Paolo Vallerini, Alessia Petrelli, Paolo Vincetti and Gabriele Costantino