Facile synthesis of highly substituted 2-pyrone derivatives via a tandem Knoevenagel condensation/lactonization reaction of β-formyl-esters and 1,3-cyclohexadiones

Article abstract of DOI:10.1016/j.tetlet.2014.02.104

A mild and efficient tandem process for the synthesis of new highly substituted 2-pyrones starting from commercially available 2-arylacetic acids has been developed. The synthesis is based on the Knoevenagel condensation of 1,3-cyclohexadiones with various β-formyl-esters, followed by lactonization in the presence of nano ZnO (20 mol %). Moderate to high yields and readily available cheap starting materials are the key features of the present method.

Full text of DOI:10.1016/j.tetlet.2014.02.104

Tetrahedron Letters 55 (2014) 2908–2911
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile synthesis of highly substituted 2-pyrone derivatives via
a tandem Knoevenagel condensation/lactonization reaction
of b-formyl-esters and 1,3-cyclohexadiones
b
a
a
Firouz Matloubi Moghaddam a, , Zohreh Mirjafary , Marjan Jebeli Javan , Sara Motamen ,
⇑
Hamid Saeidian c
a Laboratory of Organic Synthesis and Natural Products, Department of Chemistry, Sharif University of Technology, PO Box 11155-9516, Tehran, Iran
b Department of Chemistry, Tehran Science and Research Branch, Islamic Azad University, Tehran, Iran
c Department of Science, Payame Noor University (PNU), PO Box 19395-4697, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and efficient tandem process for the synthesis of new highly substituted 2-pyrones starting from
commercially available 2-arylacetic acids has been developed. The synthesis is based on the Knoevenagel
condensation of 1,3-cyclohexadiones with various b-formyl-esters, followed by lactonization in the pres-
ence of nano ZnO (20 mol %). Moderate to high yields and readily available cheap starting materials are
the key features of the present method.
Received 2 November 2013
Revised 8 February 2014
Accepted 25 February 2014
Available online 4 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
2-Pyrone derivatives
b-Formyl-esters
Knoevenagel condensation
Lactonization
ZnO nanoparticles
2-Pyrone derivatives are versatile and valuable building blocks
for a number of biologically and pharmaceutically active com-
pounds.1 They serve as conjugated dienes for the synthesis of com-
plex compounds in Diels–Alder cycloaddition reactions and as
precursors to other heterocyclic systems.2 This moiety is found in
a large number of biologically active compounds, which exhibit a
wide range of activities such as pheromonal,3 antifungal,4 antitu-
mor,5 antileukemia,6 antimicrobial7 and neurotoxic effects.8
Figure 1 shows some important representatives of this heterocyclic
system.
The synthesis of such compounds has been the subject of sev-
eral reports which show the high importance of these pyrones.11
However, limited attention has been given to the synthesis of 3-
aryl-2-pyrone derivatives.12 Wolfbeis et al. reported a two-step
method for the synthesis of 3-aryl-substituted 2-pyrone deriva-
tives via condensation of cyclohexane-1,3-dione derivatives with
It is evident that the need for the development of new and flex-
ible protocols is required to access 3-aryl-substituted 2-pyrone
derivatives without using toxic reagents and avoiding harsh condi-
tions. Ethyl 2-formyl-2-aryl acetates have been found to be very
effective 1,3-dielectrophiles reacting with a variety of nucleo-
philes, and have been used mainly for the synthesis of five- and
six-membered heterocyclic compounds.13
The literature has highlighted the importance of nanosized
materials in several scientific and technological areas, and many
research councils have increased investments in nanotechnology.14
In any metal oxide, surface atoms make a distinct contribution to
catalytic activity. Nano zinc oxide is a very interesting metal oxide,
because it has special surface properties, which suggests that a
wide scope of organic chemistry may occur there. High yields,
selectivity and recyclability have been reported for a variety of
nanocatalyst-based organic reactions using ZnO.15 During our
studies on the preparation of ZnO nanoparticles by controlled
microwave heating and their promising applications in O-acylation
of alcohols16a and the synthesis of b-acetamido ketones/esters16b
via a multicomponent reaction, we became interested in the syn-
thesis of highly substituted 2-pyrones using nano ZnO as a nano-
catalyst. In the context of our general interest in the synthesis of
heterocyclic compounds,17 herein, we report an efficient tandem
reaction of commercially available 1,3-cyclohexadiones and
triethoxymethane and various ureas to afford compounds
I
(Scheme 1). The reaction of I with activated acetonitriles in the
presence of a strong base in DMF gave the title compounds in mod-
erate yields.12a
⇑
Corresponding author. Tel.: +98 2166165309.
E-mail address: Matloubi@sharif.edu (F.M. Moghaddam).
http://dx.doi.org/10.1016/j.tetlet.2014.02.104
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

F. M. Moghaddam et al. / Tetrahedron Letters 55 (2014) 2908–2911
2909
O
R
O
OH
O
OH
O
O
HO
O
O
N
H
HO
OH
O
R = alkyl and aryl
antimicrobial agent
O
anti-HIV agent
arzanol, anti-inflammatory agent
antitumor agent
Figure 1. Examples of 2-pyrone-containing bioactive compounds.9,10
Table 1
O
O
O
CN
Optimization of the model reaction conditionsa
HC(OEt)3
NH2CONH2
N
H
NH2
Entry
Base
Solvent
Temp (°C)
Yield (%)
+
1
2
3
4
5
6
7
8
K2CO3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
EtOH
CH3CN
Toluene
Acetone
Solvent-free
Toluene
Toluene
80
80
80
80
80
80
80
110
60
Trace
Trace
Trace
Trace
38
Trace
66
36
41
73
70
98
O
O
Piperidine
p-TsOH
I2
DABCO
Piperidine
Nano ZnO
Et3N
Nano ZnO
Nano ZnO
ZnO
I
O
O
DMF
base
H3O
CN
O
9
O
O
10
11
12
100
110
110
Scheme 1. Reported method for the synthesis of 2-pyrones.
Nano ZnO
a
Reaction conditions: solvent (5 mL), ethyl 2-formyl-2-(4-methoxyphenyl)ace-
O
H
O
tate (1b) (1.3 mmol), dimedone 2 (1.0 mmol), catalyst (20 mol %), 15 h.
OH
OEt
1. EtOH, H2SO4
2. NaH, HCO2Et
Table 2
O
Synthesis of highly substituted 2-pyrones
X
X
1
O
R
O
O
H
O
O
O
R
O
H
O
O
R
R
nano ZnO
OEt
+
OEt
Ar
O
nano ZnO
toluene
O
+
Ar
O
3
X
1
2
O
X
1
2
3
O
Entry
Ar
R
Product
Yielda (%)
Scheme 2. Efficient synthesis of highly substituted 2-pyrones.
1
2
3
4
5
6
7
8
C6H5
Me
Me
Me
Me
H
H
H
H
3a
3b
3c
3d
3e
3f
83
98
78
76
71
68
70
61
4-MeOC6H4
4-HOC6H4
2-Naphthyl
C6H5
4-MeOC6H4
4-HOC6H4
2-Naphthyl
b-formyl-esters in the presence of ZnO nanoparticles, which leads
to highly substituted 2-pyrones in moderate to high yields
(Scheme 2).
3g
3h
2-Formyl-2-aryl acetates 1 were synthesized in-house by an
existing method.18 The ZnO nanoparticles were prepared according
a
Isolated yields.
16a
to our previously reported procedure.
Initially we set out to
investigate the effect of solvents and bases on the reaction of ethyl
2-formyl-2-(4-methoxyphenyl)acetate (1b) and dimedone (2) as
simple model substrates (see Table 2, entry 2). At room tempera-
ture, only a trace amount of the desired 2-pyrone was observed.
However, the desired product was obtained in a good overall yield
when conducted at higher temperatures. The results showed that
the presence of a catalyst was required to achieve the synthesis
of the desired products. During optimization of the reaction condi-
tions, toluene and 20 mol % of ZnO nanoparticles were found to be
the best solvent and catalyst, respectively (Table 1, entry 12). Un-
der the optimized conditions, commercially available ZnO was also
evaluated for the synthesis of the title compounds. Using ZnO
nanoparticles as the catalyst, the reaction time was reduced, pro-
ducing the product in higher yields, than when bulk ZnO was em-
ployed (98% vs 70%).
110 °C in the presence of 20 mol % of ZnO to afford highly
substituted 2-pyrones. All the substrates consistently furnished
the desired 2-pyrones in moderate to high yields and were not lim-
ited to ethyl 2-formyl-2-phenylacetate; ethyl 2-formyl-2-(naph-
thalen-3-yl)acetate also afforded the desired products 3d and 3h
in good yields (Table 2, entries 4 and 8).19
The structures of the products were confirmed by EI-MS, 1H
NMR and 13C NMR spectroscopy, and CHN analysis. It should be
mentioned that the structure of 3a was confirmed by a comparison
with an authentic sample prepared by a reported method.12a
The characteristic signals for 3b in the 1H NMR spectrum were a
singlet for the protons of the methoxy group at 3.87 ppm, a singlet
for the methyl protons of the dimedone ring at 1.22 ppm, two sing-
lets for the methylene protons at 2.46 and 2.78 ppm, and another
singlet for the aromatic proton of the pyrone ring at 7.90 ppm.
Using the optimized procedure, the reactions of 1,3-cyclohex-
adiones with various b-formyl-esters proceeded smoothly at

2910
F. M. Moghaddam et al. / Tetrahedron Letters 55 (2014) 2908–2911
O
O
H
O
Acknowledgment
H
O
EtO2C
O
O
OEt
+
We gratefully acknowledge financial support from the Research
Council of Sharif University of Technology. Z. M. thanks the Na-
tional Elite Foundation for a scholarship.
ZnO
MeO
4
MeO
1b
MeO
O
Supplementary data
Supplementary data (copies of 1H NMR, 13C NMR and EI-MS
spectra) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2014.02.104.
O
O
5 (45%)
Scheme 3. Synthesis of 5-acetyl-3-(4-methoxyphenyl)-6-methyl-2H-pyran-2-one
(5).
References and notes
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Synthesis 1988, 383; (e) Ellis, G. P. In Comprehensive Heterocyclic Chemistry,
Katritzky, A. R.; Rees, C. W., Eds.; Pergamon: New York, 1984, Vol. 3, Part 2B,
Chapter 2.23, 647; (f) Afarinkia, K.; Vinader, V.; Nelson, T. D.; Posner, G. H.
Tetrahedron 1992, 48, 9111.
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71.
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7. Fairlamb, I. J. S.; Morrison, L. R.; Dickinson, J. M.; Lu, F. J.; Schmidt, J. P. Bioorg.
Med. Chem. 2004, 12, 4285.
O
O
O
2+Zn
H
O
Zn2+
O
OH
O
O
OEt
OEt
1
O
O
-H2O
8. Aytemir, M. D.; Calis, U. Arch. Pharm. 2010, 343, 173.
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Ruwart, M. J.; Wilkinson, K. F.; Rush, B. D.; Zipp, G. L.; Dalga, R. J.; Schwende, F.
J.; Howard, G. M.; Padbury, G. E.; Toth, L. N.; Zhao, Z.; Koeplinger, K. A.; Kakuk,
T. J.; Cole, S. L.; Zaya, R. M.; Piper, R. C.; Jeffrey, P. J. Med. Chem. 1994, 37, 3200.
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Zheng, S. L.; Schreiber, S. L. Org. Lett. 2011, 13, 2834; (c) Liang, Y.; Xie, Y. X.; Li, J.
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O
O
O
H
-EtOH
O
OEt
O
O
OEt
O
O
O
3a
6
Scheme 4. Suggested reaction mechanism for the formation of 3-aryl-2-pyrones
3a–h.
12. (a) Trummer, I.; Ziegler, E.; Wolfbeis, S. O. Synthesis 1981, 225; (b) Lyukmanov,
N. F.; Kovshev, E. I. Chem. Heterocycl. Compd. 1985, 21, 1215.
The 13C NMR spectrum of 3b showed 15 distinct resonances in
agreement with the proposed structure.
When we carried out the reaction between ethyl 2-formyl-2-
phenylacetate and pentane-2,4-dione, the expected 2-pyrone 5
was obtained in low yields (45%) after a long reaction time. It is
thought that the intramolecular hydrogen bonding in intermediate
4 was responsible for this result (Scheme 3).
A plausible mechanism for the present reaction is proposed in
Scheme 4. In the first step, ZnO nanoparticles are coordinated to
the oxygen of the aldehyde and the ester, which activates the alde-
hyde carbonyl group for nucleophilic attack. Also, ZnO nanoparti-
cles facilitate enolization of dimedone, such that it can undergo a
Knoevenagel condensation with ethyl 2-formyl-2-phenylacetate
in refluxing toluene to afford the intermediate 6 with the release
of H2O. Subsequently, the ring closure occurs through an intramo-
lecular lactonization with loss of EtOH to give the desired 2-pyr-
ones 3a–h.
In summary, we have described a simple and efficient protocol
for the synthesis of highly substituted 2-pyrones in moderate to
high yields via one-pot tandem reactions. The synthesis is based
on the Knoevenagel condensation of 1,3-cyclohexadiones with var-
ious b-formyl-esters, followed by lactonization using nano ZnO
(20 mol %) as the nanocatalyst. Further studies on the synthesis
of highly substituted 2-pyrone derivatives utilizing ZnO nanoparti-
cles is in progress.
13. (a) Isabelle, P.; Cedric, B.; Andre, T.; Arnaud, G.; Francisco, C.; Jean, B. A.; Solo, G.
Bioorg. Med. Chem. 2011, 19, 2517; (b) Bulut, M.; Erk, C. J. Heterocycl. Chem.
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Zakhar, S. O.; Alexander, A. S. J. Org. Chem. 2010, 75, 8487; (d) Jiau, H. L.; Chieh,
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Paul, S.; Gupta, R.; Loupy, A. Tetrahedron Lett. 2005, 46, 4957; (c) Sharghi, H.;
Hosseini-Sarvari, M. Synthesis 2002, 1057; (d) Tamaddon, F.; Amrollahi, A. M.;
Sharafat, L. Tetrahedron Lett. 2005, 46, 7841; (e) Hosseini-Sarvari, M.; Sharghi,
H. J. Org. Chem. 2006, 71, 6652.
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Z.; Saeidian, H.; Sadeghi, A.; Matloubi, F. M. Catal. Commun. 2008, 9, 299.
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Pure Appl. Chem. 2011, 83, 709. and references cited therein.
18. Aguilar, C. A.; Llado, J. B.; Garcia, P. C.; Onrubia Miguel, M. C.; Madrid, N. S. US
patent 6506941 B1, 2001; Chem. Abstr. 2001, 134, 147402.
19. General procedure for the synthesis of highly substituted 2-pyrones 3a–h: To a
stirred suspension of nano ZnO (18 mg) in toluene (5 mL) were added 1,3-
cyclohexadione (2) (1.0 mmol) and the b-formyl-ester (1.3 mmol). The mixture
was stirred at 110 °C for 15 h. The progress of the reaction was monitored by
TLC. After completion of the reaction, the catalyst was recovered by filtration.
The nano ZnO can be reused in subsequent reactions without losing any
significant activity. The solvent was removed under reduced pressure, and the
residue was separated by flash column chromatography on silica gel with
petroleum ether/EtOAc (5:1) as eluent to afford the desired pure compound
3a–h.
Representative spectroscopic data:
7,8-Dihydro-3-(4-methoxyphenyl)-7,7-dimethyl-6H-chromene-2,5-dione
(3b):
Mp: 142–144 °C. 1H NMR (500 MHz, CDC13): d = 7.90 (s, 1H), 7.66 (d,
J = 8.7 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 3.87 (s, 3H), 2.78 (s, 2H), 2.46 (s, 2H),

F. M. Moghaddam et al. / Tetrahedron Letters 55 (2014) 2908–2911
2911
1.22 (s, 6H) ppm. 13C NMR (125 MHz, CDCl3): d = 194.1, 171.2, 170.9, 170.8,
133.9, 129.1, 125.6, 125.1, 113.7, 113.0, 55.3, 50.7, 41.9, 32.9, 28.5 ppm. Anal.
Calcd for C18H18O4: C, 72.47; H, 6.08. Found: C, 72.28; H, 5.98.
(300 MHz, CDC13): d = 7.75 (s, 1H), 7.62 (d, J = 8.9 Hz, 2H), 6.95 (d, J = 8.9 Hz,
2H), 3.84 (s, 3H), 2.64 (s, 3H), 2.51 (s, 3H) ppm. Anal. Calcd for C15H14O4: C,
69.76; H, 5.46. Found: C, 69.89; H, 5.51.
5-Acetyl-3-(4-methoxyphenyl)-6-methyl-2H-pyran-2-one (5): 1H NMR