Nano crystalline ZnO catalyzed one pot multicomponent reaction for an easy access of fully decorated 4H-pyran scaffolds and its rearrangement to 2-pyridone nucleus in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2012.06.086

A green and highly efficient protocol has been developed for the synthesis of 4H-pyran scaffolds installing a one-pot three-component coupling reaction of an aldehyde, malononitrile, and a 1,3-diketo compound using nano structured ZnO as the catalyst in a

Full text of DOI:10.1016/j.tetlet.2012.06.086

Tetrahedron Letters 53 (2012) 4687–4691
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Tetrahedron Letters
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Nano crystalline ZnO catalyzed one pot multicomponent reaction for an
easy access of fully decorated 4H-pyran scaffolds and its rearrangement to
2-pyridone nucleus in aqueous media
⇑
Pranabes Bhattacharyya, Koyel Pradhan, 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:
A green and highly efficient protocol has been developed for the synthesis of 4H-pyran scaffolds installing
a one-pot three-component coupling reaction of an aldehyde, malononitrile, and a 1,3-diketo compound
using nano structured ZnO as the catalyst in aqueous alcoholic medium. A greener method to synthesize
3,4-dihydropyridin-2-one has also been developed by rearranging 4H-pyran derivatives in aqueous med-
ium applying p-TSOH as the right catalyst source. A wide spectrum of functional groups was tolerated in
both the developed synthetic protocols with good to excellent yield of the targeted molecules.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 29 May 2012
Revised 14 June 2012
Accepted 16 June 2012
Available online 29 June 2012
Keywords:
Nano structured ZnO
4H-Pyrans
3,4-Dihydropyridin-2-one
Organic acid catalyzed rearrangement
Polyfunctionalized 4H-pyran derivatives are important to the
synthetic chemists due to their pronounced biological and pharma-
cological activities.1 These compounds are used as anti-coagulants,
anticancer agents, spasmolytics, anti-anaphylactics, etc.2,3 In addi-
tion,4H-pyrans containing heterocyclic rings (compound I, Fig. 1)
are increasingly used for their pharmacological activities.4 Further-
more, a number of 2-amino-4H-pyran derivatives are useful as
photoactive materials.5 Generally, 3-substituted-6-amino-4-aryl-
5-cyano-2-methyl-4H-pyrans are prepared from arylidenemalono-
nitriles and activated methylene compounds in the presence of or-
ganic bases.6 It is also necessary to mention that the synthesis of 2-
pyridone nucleus is a challenge to the synthetic and medicinal
chemists as its derivatives have important biological and pharma-
cological activities.7–9 It has been shown that 3,4-dihydropyridin-
2-one derivative possesses HIV-1 specific reverse transcriptase
inhibition capability.10 Compounds II and III (Fig. 1) have been
found to show hypolipidemic and 5a-reductase inhibitory activi-
ties, respectively. In view of the immense importance of 4H-pyran
and 2-pyridone derivatives there is renewed interest in developing
new methodologies for the synthesis of these compounds.
lammonium bromide,14 silica nanoparticles,15 and nano metal
oxide/ionic liquid combocatalyst16 have been already employed
to achieve the synthesis of 6-amino pyran derivatives. But, so far
only a few methods are available for the synthesis of 2-pyridone
derivatives.17 Although these methods have their own merits, still
these classical reactions have significant limitations like harsh
reaction conditions, use of mineral acids,17 low yields, tedious
work-up procedure. Thus, it is desirable to design an efficient
and convenient method to construct such heterocyclic molecules.
In continuation of our interest in developing methodologies for
carbon–carbon bond formation using nano metal oxide as cata-
lyst18,19 herein we disclose an efficient and high yielding protocol
for the synthesis of 4H-pyran derivatives starting from aldehyde,
X
R
H
CN
N
O
N
O
HO
O
NH2
X= Me, Br
Quite a good number of methods have been already reported in
the literature for the synthesis of 6-amino pyran derivatives.
Reagents, such as TMG-[bmim][X],11 tetrabutylammonium
bromide,12 rare earth perfluorooctanoates,13 hexadecyltrimethy-
I
II
R= Phenyl,
III
Piperonyl,
Indolyl,
2-chloro-3-qinolyl
⇑
Corresponding author. Tel.: +91 33 23501014/9433120265; fax: +91
3323519754.
Figure 1. Biologically active 2-amino pyran and 3,4-dihydropyridin-2-one
E-mail addresses: ardas66@rediffmail.com, ardchem@caluniv.ac.in (A.R. Das).
derivatives.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.086

4688
P. Bhattacharyya et al. / Tetrahedron Letters 53 (2012) 4687–4691
Table 2
Solvent screening for the model reactiona
O
Entry
Solvent
Yieldb (%)
O
Catalyst
H2O, RT
CHO
CN
CN
CN
O
+
1
2
3
4
5
6
7
8
9
Et2O
CHCl3
CH2Cl2
Toluene
Acetone
DMSO
DMF
H2O
38
47
43
56
64
68
72
84
96
92
H C
2
+
O
O
O
NH2
4a
3a
1a
2
Scheme 1. Synthesis of 6-amino pyran derivative via a three component coupling
of benzaldehyde (1a), malononitrile (2), and ethylacetoacetate (3a).
H2O + ethanol (1:1)
Ethanol
10
a
Benzaldehyde (1a) (1 mmol), malononitrile (2) (1 mmol), and ethylacetoacetate
(3a) (1 mmol) were stirred in 5 mL solvent in the presence of 10 mol % nano ZnO at
Table 1
room temperature for 3 h.
Optimization of reaction condition using different catalystsa
b
Isolated yield of the pure product.
Entry
Catalyst
Time (h)
Yieldb (%)
1
2
3
4
5
6
—
24
6
6
6
6
Trace
32
36
42
46
MgO (10 mol %)
CaO (10 mol %)
Nano Al2O3 (10 mol %)
Nano SiO2 (10 mol %)
to check the viability of this protocol in obtaining a library of
substituted 4H-pyrans (Table 3).
The optimized methodology21 tolerated a wide spectrum of
aldehydes and dicarbonyl compounds with good to excellent yield
of the targeted molecules. The aromatic aldehydes with electron
withdrawing groups reacted faster with slightly improved yields
than their electron donating counter parts. The method is also
applicable to aliphatic aldehydes (Table 3, entry 9) and heterocy-
clic aldehydes (Table 3, entries 8, 18, 26, and 27). The catalyst
can be recycled five times without significant loss of the activity.
The reusability of the catalyst was checked for the synthesis of
6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylic acid
ethyl ester (Table 3, entry 1). The study revealed that even after
five cycles, the catalyst was able to carry out the reaction offering
almost same catalytic activity.
6
58
L-Proline (10 mol %)
7
8
9
Bu4NBr (10 mol %)
Bulk ZnO (10 mol %)
Nano ZnO (10 mol %)
6
3
3
52
68
84
a
Benzaldehyde (1a) (1 mmol), malononitrile (2) (1 mmol), and ethylacetoacetate
(3a) (1 mmol) were stirred in 5 mL water at room temperature in the presence of
10 mol % of the catalyst.
b
Isolated yield of the pure product.
‘
malononitrile, and 1,3-diketone in aqueous alcoholic medium
using nano crystalline ZnO as the catalyst. As 4H-pyran nucleus
is very much sensitive to aqueous acid due to its cyclic enol-ether
ligation, we also demonstrate here the acid-catalyzed rearrange-
ment of 4H-pyran leading to the very easy access of 2-pyridone
derivative.
Initially, we focused on systematic evaluation of different cata-
lysts for the model reaction of benzaldehyde (1a), malononitrile
(2), and ethylacetoacetate (3a) in water at room temperature
(Scheme 1). We have applied a wide range of catalysts including
As we observed the excellent catalytic activity of nano ZnO (rod
like morphology)(characterized by SEM, X-ray diffraction study)
(particle sizes are found to lie between 10 and 11 nm, Supplemen-
tary data) in this synthesis, we could propose a plausible mecha-
nistic insight of the reaction which involves, consequent
Knoevenagel condensation, Michael addition and finally intra
molecular ring closure leading to the formation of 4H-pyran deriv-
ative catalyzed by nano ZnO as presented in Scheme 3. In the first
step, the Knoevenagel condensation between aldehyde and malon-
onitrile was catalyzed by amphoteric nano ZnO which during the
removal of acidic proton from active methylene group of malono-
nitrile unit acted like a base and during dehydration, it showed its
acidic behavior. During ring closure, the catalyst played the key
role where ZnO acted as a mild acid and not only minimized the
1,2 dipolar repulsion between the geminal nitrile groups but also
activated one of the nitrile groups by polarization (through coordi-
MgO, CaO, Nano Al2O3, Nano SiO2, L-proline, Bu4NBr, Bulk ZnO,
and Nano ZnO to improve the yield for the specific synthesis of
2-amino pyran derivatives. As shown in Table 1, the reaction did
not take place without any catalyst (Table 1, entry 1). As men-
tioned in Table 1, most interesting result was obtained with ZnO
as the catalyst and the yield of the desired product was maximized
when nano crystalline ZnO was used replacing bulk ZnO (Table 1,
entries 8 and 9).
We then tried to screen the reaction in various organic solvents
in order to optimize the reaction conditions using nano ZnO as cat-
alyst (Table 2). The results revealed that solvents show great effect
on the catalytic activity of ZnO. The highest yield was obtained
with solvent system water/ethanol (1:1) (Table 2, entry 9).
As nano ZnO had emerged as the most suitable catalyst for the
reaction in 1:1 ethanol/water media, we then tried to optimize the
catalyst load for the cyclocondensation reaction leading to the
rapid formation of 4H-pyran nucleus. Our optimization studies
revealed that the yield increased smoothly with catalyst load up
to 10 mol % and then remained unaltered up to 25 mol % after that
there was a sharp drop in the yield (Fig 2). This drop may be attrib-
uted to the coagulation of ZnO nano particles which decreased the
effective surface area of the catalyst.
98
96
94
92
90
88
86
84
82
80
0
20
40
60
80
100
Catalyst Load (mol %)
We next concentrated on the scope of this reaction with a vari-
ety of aldehydes and a series of 1,3-diketo compounds (Scheme 2)
Figure 2. Catalyst load optimization study.

P. Bhattacharyya et al. / Tetrahedron Letters 53 (2012) 4687–4691
4689
O
R
O
O
O
CN
CN
CN
nano ZnO 10 mol %
CHO
+
+
R
H2C
Ethanol+H2O(1:1)/ r.t.
3 hr
NH2
1
2
3
4
Scheme 2. Synthesis of 4H-pyran.
Table 3
Substrate scopea
Entry
Product No.
R
1,3-Diketone
Time (h)
Yieldb,c (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
Ph
Ethylacetoacetate
Ethylacetoacetate
Ethylacetoacetate
Ethylacetoacetate
Ethylacetoacetate
Ethylacetoacetate
Ethylacetoacetate
Ethylacetoacetate
Ethylacetoacetate
Ethylacetoacetate
Acetylacetone
Acetylacetone
Acetylacetone
Acetylacetone
Acetylacetone
Acetylacetone
Acetylacetone
Acetylacetone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
3.0
2.5
3.0
2.5
2.5
3.5
4.0
2.0
3.5
4.0
3.5
2.5
3
96,93d
98
97
97
96
92
88
93
83
86
92
95
94
94
93
88
90
89
86
91
88
90
81
83
79
84
81
4-NO2–C6H4–
3-NO2–C6H4–
4-F–C6H4–
4-Cl–C6H4–
4-CH3–C6H4–
4-OCH3–C6H4–
2-Fur
n-Propyl
4-OH–C6H4–
Ph-
4-NO2–C6H4–
3-NO2–C6H4–
4-F–C6H4–
4-Cl–C6H4–
4-OCH3–C6H4–
4-CH3–C6H4–
2-Fur
2.5
3
4.0
3.5
3.5
3.5
3.0
3.5
3.0
4.0
3.5
4.0
3.0
4.0
4s
4t
Ph–
4-NO2–C6H4–
3-NO2–C6H4–
4-F–C6H4–
4-OCH3–C6H4–
4-CH3–C6H4–
4-N(CH3)2–C6H4
2-Fur
4u
4v
4w
4x
4y
4z
4
ae
4-Pyr
a
Aldehyde (1 mmol), malononitrile (1 mmol), and 1,3-diketone (1 mmol) were stirred in 5 ml 1:1 mixture of ethanol and H2O in the presence of 10 mol % nano ZnO at
room temperature.
b
Isolated yield of the pure product.
c
The products were characterized by 1H NMR, 13C NMR, IR, HRMS, and elemental analysis.
d
Yield obtained after five catalytic cycles.
e
The structure of the compound (4
a
) was confirmed by X-ray analysis of single crystal (Supplementary data).
O
CN
Ar
+
NC
Ar
H
H
CN
CN
nano
ZnO
H
O
EtOH-H2O
nano
ZnO
O
Ar
O
O
Ar
O
CN
NH
CN
NH2
nano
ZnO
O
H
Ar
Ar
CN
CN
CN
C
O
H
N
nano
ZnO
O
O
nano
ZnO
Scheme 3. Proposed mechanism of formation of 4H-pyrans catalyzed by nano crystalline ZnO.

4690
P. Bhattacharyya et al. / Tetrahedron Letters 53 (2012) 4687–4691
nation) and hence facilitated the intramolecular nucleophilic
attack by the enolic OH group leading to the easy formation of
the final product (4H-pyran) and the catalyst entered into the
catalytic cycle.
To take an advantage of the elaborated green protocol a little
amount of ethanol was added to the reaction mixture and the
filtrate on concentrating gave the pure product. This procedure ex-
cluded the use of expensive silica gel chromatography, and appli-
cation of small amount of ethanol instead of chromatographic
eluent seemed to be advantageous from the green chemistry
perception.
O
O
CN
O
CN
Catalyst
O
O
H2O/ 70 °C
N
H
5a
O
NH2
4a
Scheme 4. Optimization of reaction condition for rearrangement of 4H-pyran into
3,4-dihydropyridin-2-one.
After the successful synthesis of 4H-pyran, we then focused on
the rearrangement of 4H-pyran nucleus. We envisaged sequential
ring opening followed by ring closure(Scheme 5) involving hydra-
tion and dehydration of the 4H-pyran nucleus leading to 3,4-dihy-
dropyridone derivatives in aqueous medium. To find a suitable
catalyst for this rearrangement, we initially screened the water sol-
uble organic acids as well as Lewis acid catalysts. When the rear-
rangement was carried out with different organic acids and Lewis
acids it did not give the expected rearranged product. However,
treatment with p-TsOH transformed the 4H-pyran nucleus into 2-
pyridone scaffold (with 10% loading) (Table 4, entry 11, bold). Sub-
sequent increase in the catalyst load did not improve the product
yield of the rearrangement reaction to any extent Table 5.
As shown in Table 5, the reaction was performed in CHCl3, CCl4,
THF, CH3CN, methanol, DMF, toluene, dioxane, and water (entries
1–9) to judge the right catalytic activity of p-TSOH and the best
suited medium of transformation. Interestingly, we found that
the reaction using water as the solvent (Table 5, entry 9, bold) re-
sulted in higher yields than any other solvents.
Table 4
Catalyst screening and catalyst load optimizationa
Entry
Catalyst
Catalyst load (mol %)
Yieldb (%)
1
2
3
4
5
6
7
8
9
CH3COOH
(COOH)2
10
10
10
10
10
10
10
10
10
10
10
15
—
28
21
24
11
17
—
—
—
—
87
87
Citric acid
Tartaric acid
Benzoic acid
Lactic acid
Al2O3
ZnCl2
SiO2
Alum
p-CH3–C6H4–SO3H
p-CH3–C6H4–SO3H
10
11
12
a
6-Amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylic acid ethyl ester
(4a) (1 mmol), was heated at 70 °C in 5 ml water for 3 h in the presence of specific
amount of catalyst.
b
Isolated yield of 5a.
Table 5
We then investigated the scope of this synthetic methodology22
(Table 6) toward the exploration of a new series of 3,4-dihydro-
pyridin-2-one libraries by the rearrangement (Scheme 4) of substi-
tuted 4H-pyrans.
Solvent screening for the synthesis of 3,4-dihydropyridin-2-onea
Entry
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
CHCl3
CCl4
THF
CH3CN
Ethanol
DMF
12
12
12
12
6
—
—
—
From Table 6, it is evident that the reaction proceeded smoothly
for both electron rich and electron deficient aryl aldehydes with
varied 1,3-diketone moieties. The methodology is so mild that it
was also conveniently applied for the synthesis of 4-heteroaryl
pyridin-2-one derivatives (Table 6, entries 8 and 22) with reason-
ably good yield.
We have demonstrated the use of nano structured-ZnO as a
catalyst for the synthesis of substituted 4H-pyrans. We are also suc-
cessful in developing a method to obtain the 3,4-dihydropyridin-2-
—
48
52
58
54
87
6
Toluene
Dioxane
H2O
6
6
3
a
6-Amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylic acid ethyl ester
(4a) (1 mmol), was heated at 70 °C in 5 mL solvent for stipulated time in the
presence of 10 mol % TsOH.
b
Isolated yield of the pure product.
O
O
O
CN
H+
CN
O
O
CN
O
H2O
O
NH2
O
H
NH2
OH NH2
OH
O
O
CN
-H2O
O
CN
O
N
H
O
O
O
H2N
Scheme 5. Proposed mechanism of rearrangement of 4H-pyrans to 3,4-dihydropyridin-2-one.

P. Bhattacharyya et al. / Tetrahedron Letters 53 (2012) 4687–4691
4691
Table 6
Substrate scope for synthesis of 3,4-dihydro pyridin-2-one
Entry
Product
Ar
1,3-Diketo compound
Time (h)c
Yielda,b (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
5a
5b
5c
5d
5e
5f
5g
5h
5k
5l
5m
5n
5o
5q
5s
Ph
Ethylacetoacetate
Ethylacetoacetate
Ethylacetoacetate
Ethylacetoacetate
Ethylacetoacetate
Ethylacetoacetate
Ethylacetoacetate
Ethylacetoacetate
Acetylacetone
Acetylacetone
Acetylacetone
Acetylacetone
Acetylacetone
Acetylacetone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
3
2
87
91
90
88
87
84
82
85
84
87
88
86
85
82
82
86
85
85
78
80
76
79
4-NO2–C6H4–
3-NO2–C6H4–
4-F–C6H4–
4-Cl–C6H4–
4-CH3–C6H4–
4-OCH3–C6H4–
2-Fur
2.5
2.5
3
3.5
4
3
3
Ph–
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
2.5
2.5
2.5
3
3.5
6
5
5.5
5
7
7
7.5
7
5t
5ud
5v
5w
5x
5y
5z
a
b
c
Isolated yield of the pure product.
The products were characterized by 1H NMR, 13C NMR, IR, HRMS, and elemental analysis.
1 mmol of 4H-pyran was heated at 70 °C in 5 ml water for stipulated time in the presence of 10 mol % TsOH.
The structure of the compound (5u)was confirmed by X-ray analysis of single crystal (Supplementary data).
d
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one derivatives applying the hydrolytic rearrangement reaction on
4H-pyran derivatives.
Acknowledgements
We acknowledge the financial support from the University of
Calcutta. P.B. thanks CSIR, New Delhi, India for his fellowship
(Grant No. 09/028(0768)/2010). K.P. and S.P. thank UGC for their
respective fellowships. Crystallography was performed at the
DST-FIST, India-funded Single Crystal Diffractometer Facility at
the Department of Chemistry, University of Calcutta.
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Supplementary data
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19. Ghosh, P. P.; Das, A. R. Tetrahedron Lett. 2012, 53, 3140.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.06.
086.
21. General procedure of preparation of 4H-pyran:
A mixture of an aldehyde
References and notes
(1 mmol), malononitrile (1 mmol), 1,3-diketo compound (1 mmol) and nano
ZnO (10 mol %) was stirred at room temperature in 5 ml ethanol–water
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hexane = 3:7). After completion of the reaction 10 ml ethanol was added to the
reaction mixture and filtered to remove ZnO. Upon concentrating the reaction
mixture the desired product crystallized out. As the purity of the product was
high no further recrystallization was required.
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22. General procedure of preparation of 3, 4-dihydropyridin-2-one via rearrangement:
A mixture of 4H-pyran (1 mmol) and p-toluelesulphonic acid (10 mol %) was
heated at 70 °C in 5 ml H2O. The progress of the reaction was monitored by TLC
(EtOAc/hexane = 3:7). After completion of the reaction the reaction mixture
was cooled to room temperature and the precipitated crude product was
filtered. On recrystalizing from ethanol pure product (2-pyridone) was
obtained.