Conjugate addition of malononitrile on chalcone: Biocatalytic [Formula presented] bond formation

Article abstract of DOI:10.1016/j.molcatb.2016.08.004

An efficient, cost effective and environmentally friendly protocol has been developed for the Michael addition of malononitrile on 1,3-diaryl-2-propen-1-ones (Chalcones) using very cheaper, easily available natural catalyst, baker's yeast. The whole cells of yeast excellently worked in nonaqueous medium, ethanol without decrease in catalytic activity.

Full text of DOI:10.1016/j.molcatb.2016.08.004

Journal of Molecular Catalysis B: Enzymatic 133 (2016) 124–126
Contents lists available at ScienceDirect
Journal of Molecular Catalysis B: Enzymatic
journal homepage: www.elsevier.com/locate/molcatb
Conjugate addition of malononitrile on chalcone: Biocatalytic C C
bond formation
Nitesh D. Punyapreddiwar, Sangesh P. Zodape, Atul V. Wankhade, Umesh R. Pratap∗
Departmenent of Chemistry, Visvesvaraya National Institute of Technology, Nagpur, 440 010 Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, cost effective and environmentally friendly protocol has been developed for the Michael
addition of malononitrile on 1,3-diaryl-2-propen-1-ones (Chalcones) using very cheaper, easily avail-
able natural catalyst, baker’s yeast. The whole cells of yeast excellently worked in nonaqueous medium,
ethanol without decrease in catalytic activity.
Received 6 January 2016
Received in revised form 14 July 2016
Accepted 10 August 2016
Available online 10 August 2016
© 2016 Elsevier B.V. All rights reserved.
Keywords:
C
C bond formation
Baker’s yeast
Malononitrile
Michael addition
1,3-diaryl-2-propen-1-one
1. Introduction
further transformations [6]. Therefore, the development of efficient
Michael addition involved malononitrile is still highly desirable.
The Michael addition of nucleophile to ␣, ␤-unsaturated
carbonyl compounds represents one of the most important
carbon–carbon forming reactions in organic synthesis.This reac-
tion is an excellent way to make variety of synthetic and natural
bioactive molecules [1].
The Michael addition on chalcones i.e. 1,3-diaryl-2-propen-
1-ones is largely studied becuase of their utility in making of
polysubstituted benzenes and some other heterocyclic molecules
[2]. The chalcones are the natural compounds belong to flavoid
family, they are having diverse biological activities,such as anti-
malarial, anticancer, antiprotozoal, antiulcer, antiinflamatory etc
[3]. The Michael addition on chalcone with malononitrile produces
highly useful intermediate for the synthesis of biological active
heterocyclic ring due to presence of nitrile group [4].
The Michael additions are generaly conducted using strong base
at elevated temperature. Due to the presence of strong base, with
side reactions occur such as multiple condensations, polymeri-
ations and rearrangements [5].
The conjugate addition of malononitrile on chalcone is relatively
less explored. The malononitrile is an equivalent of 1,3-dicarbonyl
compound and it has strong electron withdrawing property due to
the presence of nitrile group. It is a versatile functional group for
A few methods were reported for the Michael addition of
malononitrile on chalcones using different catalysts, which are suf-
fering with one or otherkinds of disadvantages. Wang et al., have
used squaramide as organocatalyst in which catalyst preparations
is necessary that reqiures more time [7]. Guandium lactate ionic
liquiud catalysed protocol is also reported which involve the mak-
ing of catalyst and reaction need lowering of tempreture i.e 0 ◦C
[8]. Russo et al., reported cinchona alkoloids catalyst which is much
more costlier [9]. The readily available TBAB as a catalyst has also
been utilized but reaction require elevated tempreture i.e reflux for
the completion of reaction [10]. Li et al., have developed a method
using ruthenium complex i.e. RuCl2[(R, R)-DPEN](PPh3)2 [11]. The
use of ruthenium copmplexes is a costly affair due to the high price
of ruthenium salts. Shi et al., reported quinine catalysed reaction
but required more time (80 h) [12]. When chemical catalysts are
used for this reaction, the process always suffer with lower yields
of the products, tedious work-up procedures, possibility of side
reactions etc. [13–16] Therefore there is need to over come these
drawbaks for Michael addition of malononitrile on chalcone.
Biocatalysts are the key elements in the toolbox of organic
chemist becuase of their pathbreaking applications in non natural
reactions like aldol reaction [17], Henry reaction [18], Knovenagel
condensation, [19] Michael addition [20,22] etc. Among the known
biocatalysts to date baker’s yeast is a versatile, cheaper whole cell
biocatalyst having applications in oxidations, reductions, cyclocon-
densations and Michael addition reactions [23]. It was found that
∗
Corresponding author.
E-mail address: umeshpratap2014@gmail.com (U.R. Pratap).
http://dx.doi.org/10.1016/j.molcatb.2016.08.004
1381-1177/© 2016 Elsevier B.V. All rights reserved.

N.D. Punyapreddiwar et al. / Journal of Molecular Catalysis B: Enzymatic 133 (2016) 124–126
125
Table 1
Effect of solvent on Michael addition on chalcone catalysed by baker’s yeast.a
Table 2
Michael addition on chalcone with malononitrile catalysed by baker’s yeast.a
Entry
Solvent
Time (h)
Yieldb (%)
Entry
R1
R2
Productc
Yieldb(%)
1
2
3
4
5
6
7
8
9
H2O
25
18
18
25
25
25
25
25
25
–
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
H
H
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
83
76
85
74
67
78
65
70
65
52
66
60
68
66
72
MeOH
EtOH
DCM
DMF
ACN
DMSO
THF
EtOH
71
83
30
45
51
61
50
–
4-NO2
4-Cl
2-Cl
4-N(CH3)2
4-OCH3
2-Furyl
4-F
4-CH3
H
H
H
4-OH
4- OCH3
4 −OCH3
4-OH
2-OH
2-OH
a
Reaction condition: Chalcone (5 mmol), malononitrile (5 mmol), 2 g baker’s
yeast and 20 mL solvent at room temp.
4-Cl
4-Cl
H
b
Isolated yield.
4-Cl
the baker’s yeast is not much explored as a catalyst for Michael
addition for C C bond formation.
a
Reaction condition: Chalcone (5 mmol), malononitrile (5 mmol), 2 g baker’s
yeast and 20 mL ethanol at room temp).
b
Naturaly biocatalysts work efficiently in aqueous environment
but it is not much useful for most of the organic reactions because
substrates are not soluble in aqueous medium and also there is pos-
sibility of side reactions, therefore the use of biocatalyst in organic
solvent is gaining much importance.The advantages of biocatalyst
in organic solvent such as (1) high solubility of organic substrates
(2) easy recovery of the product (3) insolubility of biocatalysts in
organic solvents permit their easy recovery and reuse [21–24].
Considering the above facts, we have developed an efficient
methodology for the Michael addition of malononitrile on chalcone
in organic solvent under relatively mild reaction conditions using
baker’s yeast as catalyst, which is easily available and cheaper than
other chemical catalyst used for catalysing this reaction.
Isolated yield.
c
Product were confirmed by physical constant, 1H NMR and 13C NMR analysis
[8,9,11,12].
3a. Then we again increased amount of yeast to 2, 3 and 4 g to
run model reaction. When 3 and 4 g of catalyst were used, there
was no proper stirring to reaction mixture takes place beacuse of
increase in mass, hence the reactants not mixed properly, results
in a unreacted chalcone isolation. Based on above result we have
concluded that the 2 g of yeast for model reaction is optimum.
To generalise this methodology the variety of chalcones were
reacted with malononitrile (Scheme 1) using baker’s yeast in
ethanol to obtain desired products in good to moderate yields
(Table 2, entry 1–15). The required chalcones were prepared by
using substituted acetophenones and benzaldehydes in presence
of sodium hydroxide in aqueous ethanol.
2. Results and discussion
When the malononitrile was added on chalcone of unsub-
stituted acetophenone and aldehyde with electron withdrawing
substituent resulted in higher yields of the products (Table 2, entry
2–9) and when it is added on chalcone where both the aryl ring are
substituted then the yields of the products are decreased (Table 2,
entry 10–15).
To examine the need of baker’s yeast to catalyse C C bond for-
mation, the model reaction was run in absence of baker’s yeast in
ethanol. It was found that there was no conversion even after 25 h
(Table 1 entry 9). From this result it is cleared that baker’s yeast is
essential to carry out the C C bond formation between chalcone
and malononitrile.
In order to obtain best experimental conditions, we have con-
sidered reaction of chalcone (1a) with malononitrile in presence of
baker’s yeast as standard model reaction to get product 3a.
The optimization study was started by screening of various sol-
vents for model reaction.The screening of the solvent was initiated
from natural solvent i.e water (H2O), the malononitrile (5 mmol)
and chalcone (5 mmol) in water (20 mL) was stirred for 25 h but
there was no formtion of desired product observed (Table 1, entry
1). It may be due to the in solubility of chalcone in water.
To overcome this problem we turned our attention towards the
use of various organic solvents e.g. protic, aprotic, polarand nonpo-
lar solvents.
Then the model reaction was run in methanol (MeOH). Interest-
ingly within 18 h of the reaction 71% yield of desired product was
isolated (Table 1, entry 2). Inspired by this result model recation
was carried out in ethanol (EtOH), surprisingly 83% yield of desired
product was obtained in 18 h of reaction time (Table 1, entry 3).
Then other solvents like dichloromethane (DCM), dimethylfor-
mamide (DMF), acetonitrile (ACN), dimethylsulphoxide (DMSO),
tetrahydrofuran (THF) were screened for model reaction, even after
25 h less yield of product 3a was obtained as compared to yield
obtained in ethanol (Table 1, Entry 4–8).
The model reaction proceeds in all organic solvents but it was
interesting to observe that the yield of product 3a obatined was
highest in ethanol within 18 h of stirring (Table 1, entry 2). There-
fore ethanol was selected as a solvent for the Michael addition of
malononitrile on different chalcones.
3. Experimental Section
3.1. General
The active dry baker’s yeast is procured from AB Mauri India
Pvt. Ltd. All chemicals were purchased from commercial suppliers
and used without further purifications. 1H NMR and 13C NMR spec-
tra were recorded on Bruker Avance II 400 MHz spectrometer at
ambient temperatures in CDCl3 as solvent, Thin Layer chromatog-
raphy was carried out using aluminium backed plates precoated
with silica gel 60 were visualized by quenching of UV fluorescence.
3.2. Typical procedure for the synthesis of 3a
To find out optimum amount of baker’s yeast needed for the
reaction, various amounts of yeast were studied. Initailly reaction
was done using 0.5 g of yeast which doesn’t gave desired product
even after 25 h of stirring. Therefore amount was increased to 1 g,
then the reaction was incomplete in 25 h giving 35% yield of the
A mixture of 1,3-phenyl-2-propen-1-one, 1a (5 mmol), and mal-
ononitrile, 2 (5 mmol) was stirred at room temperature in ethanol
(20 mL), after homogeneous solution is formed, baker’s yeast (2
gm) was added to reaction mixture.Then the reaction was con-
tinuously stirred at room temperature at 500 rpm on magnetc

126
N.D. Punyapreddiwar et al. / Journal of Molecular Catalysis B: Enzymatic 133 (2016) 124–126
Scheme 1. Baker’s yeast catalysed Michael addition of malononitrile on chalcones.
stirrer.The progress of the reaction mixture was monitored by thin
layer chromatography, after 18 h reaction mixture was filtered to
remove the catalyst and washed with excess of ethanol.There action
mixture was concentrated under vacuum followed by addition
of ethylacetate.Thus obtained organic layer was separated, dried
over anhydrous Na2SO4. The organic layer was evaporated under
vacum to obtain crude product, 3a. The crude product obtained was
purified by column chromatography using silica as adsorbent and
mixture of ethyl acetate and n-haxane (1:3) as a mobile pahse.
All other products (3b-o) are synthesized following above pro-
cedure. The structures of the products are confirmed by NMR
spectroscopy.
valuable discussions. Authors are also thankful to SAIF, Chandigarh
for providing analytical services.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.molcatb.2016.08.
004.
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