Baker's yeast catalyzed one-pot three-component synthesis of polyfunctionalized 4H-pyrans

Article abstract of DOI:10.1016/j.tetlet.2011.08.135

Baker's yeast catalyzed one-pot three-component cyclocondensation of aryl aldehydes, malononitrile, and b-dicarbonyls in organic medium has been carried out to obtain polyfunctionalized 4H-pyrans. The reaction has been carried out at room temperature in o

Full text of DOI:10.1016/j.tetlet.2011.08.135

Tetrahedron Letters 52 (2011) 5817–5819
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Tetrahedron Letters
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Baker’s yeast catalyzed one-pot three-component synthesis of
polyfunctionalized 4H-pyrans
⇑
Umesh R. Pratap, Dhanaji V. Jawale, Prashant D. Netankar, Ramrao A. Mane
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Baker’s yeast catalyzed one-pot three-component cyclocondensation of aryl aldehydes, malononitrile,
and b-dicarbonyls in organic medium has been carried out to obtain polyfunctionalized 4H-pyrans.
The reaction has been carried out at room temperature in organic solvent, dimethylacetamide and the
products obtained in good to moderate yields with simple work up procedure.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 28 July 2011
Revised 21 August 2011
Accepted 23 August 2011
Available online 31 August 2011
Keywords:
Baker’s yeast
4H-Pyran
Cyclocondensation
Biocatalysis
One-pot
Polyfunctionalised 4H-pyrans are the important heterocyclic
availability, ease of handling, and versatile nature to catalyze a
wide range of organic transformations viz reduction of variety of
carbonyl compounds, oxidation of thioethers to sulfoxides, reduc-
tion of C@C bond and some of the cyclocondensation reactions.20
Biocatalyzed reactions in nonaqueous media become a popular
approach and several reviews appeared in the literature.21 Most of
the organic transformations are condensations and cyclocondensa-
tions where the removal of water molecule is crucial and also most
of the organic substrates are insoluble in water. Hence, the use of
aqueous media for these transformations is not advisable. The
use of organic solvents overcomes these drawbacks.
compounds because of their wide biological and pharmaceutical
1
2
properties. 4H-Pyran is a constituent of some natural products.
4
H-Pyrans possess potent biological activities like antitumor, anti-
3–9
bacterial, antiviral, spasmolytic, and antianaphylactic.
In addi-
tion to this, these compounds are used in the treatment of
Alzheimer, Schizophrenia, and Mycolonous diseases.10 The deriva-
1
1
tives of 2-amino 4H-pyran are the useful photoactive materials.
Considering the broad spectrum of biological activities of 4H-
pyrans synthetic chemists have developed numerous protocols
for their syntheses including two-step as well as one-pot three-
12
component synthesis, catalyzed by ionic liquids, hexadecyltrim-
Considering the diverse applications of 4H-pyrans, limitation
with the reported synthetic routes and our earlier interest in bioca-
1
3
14
ethyl ammonium bromide, Mg/La mixed metal oxides, Cu(II)
oxymetasilicate, organic bases, MgO,4 and rubidinium fluo-
1
5
16
talysis, herein we report one-pot three-component synthesis of
22
1
7
ride. However, these methods often suffer from one or the other
kind of drawbacks and most of them give moderate yields even
after prolonged reaction time. This has clearly indicated that there
is still scope to develop an efficient and ecosustainable method for
the synthesis of 4H-pyrans.
polyfunctionalised 4H-pyrans by cyclocondensing aryl aldehydes,
malononitrile, and ethyl acetoacetate or acetyl acetone using active
baker’s yeast as a whole cell biocatalyst in nonaqueous media.
To find the best experimental conditions we started the investi-
gations by performing one-pot three-component synthesis of 4H-
pyran by allowing the cyclocondensation of anisaldehyde, (1a)
malononitrile (2), and ethyl acetoacetate (3a) using baker’s yeast
as biocatalyst and this reaction was considered as a model
reaction.
The use of biocatalysis in organic synthesis has been increasing
day by day because of its various advantages. It catalyzes the trans-
formations under mild conditions, with specificities and without
1
8
side reactions.
Among the biocatalysts used in organic synthesis baker’s yeast
To check the effect of solvents the model reaction was sepa-
rately carried out in various solvents viz. water, ethanol, methanol,
dimethylformamide (DMF), and dimethylacetamide (DMAc) under
stirring at room temperature. The use of water did not give the
desired product, 4H-pyran but found to yield an intermediate, 2-
(4-methoxybenzylidene) malononitrile (Table 1, entry 1). When
(
Saccharomyces cerevisiae)19 is the most popular due to its easy
⇑
Corresponding author. Tel.: +91 0240 02403311; fax: +91 0240 02403113.
E-mail addresses: manera@indiatimes.com, manera2011@gmail.com (R.A.
Mane).
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.135

5
818
U. R. Pratap et al. / Tetrahedron Letters 52 (2011) 5817–5819
Table 1
Table 2
Effect of solvent on the cyclocondensation of anisaldehyde, malononitrile, and ethyl
acetoacetatea
Synthesis of polyfunctionalized 4H-pyrans catalyzed by baker’s yeast in DMAca
Entry
R
R1
Productsb
Yields (%)c
Entry
Solvents
Yield (%)b
1
2
3
4
5
6
7
8
9
4-OCH
C H
6 5
3-ClC H
6 4
3
C
6
H
4
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
4a
4b
4c
4d
4e
4f
4g
4h
4i
62
65
67
78
79
83
78
62
48
57
55
67
76
1
2
3
4
5
6
Water
Ethanol
Methanol
DMF
DMAc
DMAc
n.d.
37
42
3
4-CH C
6
H
4
51
4-ClC H
6 4
62
4-NO
3-NO
2
C
C
6
H
H
4
4
n.d.b
2
6
6 4
4-OHC H
a
Reaction conditions: Anisaldehyde (8 mmol), malononitrile (8 mmol), ethyl
3-pyridyl
acetoacetate (8 mmol) in solvent (30 mL), stir, rt 30 h.
10
11
12
13
C
6
H
5
CH
CH
CH
CH
3
4j
4k
4l
b
Isolated yields, n.d., not detected: Model reaction without baker’s yeast.
4-OCH
4-CH
4-FC
3
C
6
H
4
3
3
3
3
C
H
6
H
4
6
4
4m
solvents like ethanol, methanol, and DMF were used the condensa-
tion was found to occur successfully yielding 4H-pyran with mod-
erate yield (Table 1, entry 2–4).
a
Reaction conditions: Aryl aldehyde (8 mmol), malononitrile (8 mmol), ethyl
acetoacetate (8 mmol) in DMAc (30 mL), stir, rt 30 h.
b
1
Products are well characterized by the comparison of their spectral ( H NMR,
14,4,24
Mass) and physical data with those reported in literature.
When the model reaction was run in dimethylacetamide the
yield of the product was relatively superior (Table 1, entry 5).
Therefore, the dimethylacetamide was selected as a medium for
this transformation. We carried the control experiment to examine
the catalytical efficiency of active baker’s yeast. The model reaction
was performed in the absence of baker’s yeast in dimethylacet-
amide and we noticed that the condensation did not undergo
completion and partial conversion of the reactants to intermediate,
c
Isolated yields.
Baker’s yeast is a known source of oxidoreductases and li-
2
3
pases. Among these enzymes oxidoreductases have been found
to be utilized in organic syntheses. However, the use of lipases pro-
duced by baker’s yeast has not been explored to undergo Knoeve-
nagel condensation or similar type of condensations. In this route
the lipases, produced by baker’s yeast might be catalyzing the
Knoevenagel condensation of aldehydes and malononitrile to gen-
erate intermediates, arylidenyl malononitriles.
expedites the Michael addition of 1,3-dicarbonyls on the arylidenyl
malononitriles leading to the desired 4H-pyrans.
2
-(4-methoxybenzylidene) malononitrile was recorded (Table 1,
entry 6). This reaction was also run by employing inactivated ba-
ker’s yeast (inactivation was carried out by boiling yeast in water)
as a catalyst but we did not find the formation of the desired prod-
uct. These results indicate that baker’s yeast is necessary to cata-
lyze the reaction.
2
6
This probably
To generalize this methodology a variety of substituted aryl
aldehydes with electron withdrawing and donating functionalities
were successfully cyclocondensed with malononitrile and ethyl
acetoacetate to yield respective polyfunctionalised 4H-pyrans
We have developed a novel baker’s yeast catalyzed methodol-
ogy for the cyclocondensation of aryl/heteryl aldehydes, malono-
nitrile, and ethyl acetoacetate/acetyl acetone in an organic
solvent, dimethylacetamide. This is one of the extended applica-
tions of baker’s yeast in organic synthesis. The developed protocol
might be useful for the synthesis of new pyran derivatives.
(Scheme 1, Table 2). Heteryl aldehyde, pyridine-3-cabaxaldehyde
has also been successfully condensed with malononitrile and ethyl
acetoacetate in the presence of baker’s yeast to respective pyran
with 48% yield (Table 2, entry 9).
Acknowledgments
We have also performed the cyclocondensation by subjecting
aldehydes, malononitrile, and acetyl acetone in the presence of ba-
ker’s yeast under the above optimized conditions and obtained the
The authors are thankful to Head, Department of Chemistry, Dr.
Babasaheb Ambedkar Marathwada University, Aurangabad (India)
for providing necessary laboratory facilities. Authors are grateful to
the Professor D. B. Ingle for his valuable discussions and sugges-
tions. One of the authors U.R.P. is thankful to the University Grants
Commission, New Delhi, India for the award of senior research
fellowship.
2
5
respective 4H-pyrans (Table 2, entry 10–13) with good yields.
To know the reaction sequence the model reaction was carried
out in two steps under the optimized reaction conditions. In first
step p-anisaldehyde was condensed with malononitrile and the
intermediate, 2-(4-methoxybenzylidene) malononitrile obtained
was subsequently cyclized with ethyl acetoacetate in the second
step. The cyclized product was found to be the desired 4H-pyran.
An attempt was also made to first condense the ethyl acetoacetate
with anisaldehyde under the optimized reaction conditions. It was
noticed that the condensation did not yield the intermediate, ary-
lidene. Thus it was concluded that the path would have two steps,
wherein the aldehyde of the first step undergoes Knoevenagel con-
densation with malononitrile and the resulting intermediate in situ
reacts with ethyl acetoacetate to yield the 4H-pyran.
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Scheme 1. Baker’s yeast catalyzed one-pot three-component synthesis of poly-
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3
3 3
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