CHAPTER 3 I: Synthesis of 2-Arylideneindane
Synthesis of 2-Arylideneindane
3.I.1 Introduction
Knoevenagel condensation is one of the most versatile carbon
forming reactions in the organic synthesis [1] named after scientist Emil Knoevenagel
(Fig. 3.I.1). Knoevenagel reaction has variety of applications in elegant synthesis of
fine chemicals [2], synthesis of carbocyclic and heterocyclic compounds and in
Diels-Alder reaction [3]. The Knoevenagel condensation products are not only the key
intermediate for the synthesis of natural and therapeutic drugs, polymer, cosmetics
and perfumes [4] but also have widespread applications including inhibition of
antiphosphorylation of EGF-receptor and antiproliferative activity [5].
Fig
Generally, Knoevenagel rea
active methylene compounds like malononitrile, barbituric acid, Meldrum’s acid
indoles and 1, 3-indanediones (Fig. 3.I.2
give alpha, beta conjugated enones and thus it is the best method for the formation of
substituted alkenes [6].
Fig. 3.I.2
Arylideneindane-1,3-diones by Knoevenagel Condensation
86
CHAPTER 3
Section-I
Arylideneindane-1,3-diones by Knoevenagel Condensation
Knoevenagel condensation is one of the most versatile carbon-carbon bond
in the organic synthesis [1] named after scientist Emil Knoevenagel
Knoevenagel reaction has variety of applications in elegant synthesis of
fine chemicals [2], synthesis of carbocyclic and heterocyclic compounds and in hetero
Alder reaction [3]. The Knoevenagel condensation products are not only the key
intermediate for the synthesis of natural and therapeutic drugs, polymer, cosmetics
and perfumes [4] but also have widespread applications including inhibition of
receptor and antiproliferative activity [5].
Fig. 3.I.1 Emil Knoevenagel
Generally, Knoevenagel reaction is carried out by a nucleophilic addition of
active methylene compounds like malononitrile, barbituric acid, Meldrum’s acid
(Fig. 3.I.2) to carbonyls followed by dehydration to
give alpha, beta conjugated enones and thus it is the best method for the formation of
Fig. 3.I.2 Active methylene molecules
diones by Knoevenagel Condensation
Knoevenagel
carbon bond
in the organic synthesis [1] named after scientist Emil Knoevenagel
Knoevenagel reaction has variety of applications in elegant synthesis of
hetero
Alder reaction [3]. The Knoevenagel condensation products are not only the key
intermediate for the synthesis of natural and therapeutic drugs, polymer, cosmetics
and perfumes [4] but also have widespread applications including inhibition of
philic addition of
active methylene compounds like malononitrile, barbituric acid, Meldrum’s acid,
to carbonyls followed by dehydration to
give alpha, beta conjugated enones and thus it is the best method for the formation of
CHAPTER 3 I: Synthesis of 2
Because of the chemistry and highly pronounced pharmacological properties
displayed by Knoevenagel products, have made them attractive synthetic targets
which can be readily realized from the appearance of vast number of articles dealing
with synthesis and biological act
Chen and group [
methylene compounds like malononitri
using triethylbenzylammonium chloride as catalyst
In 2005, Deb and co
Knoevenagel condensation of aromatic aldehydes with active methylenes in water at
room temeperature (Scheme
During last decade ionic liquids have emerged as gr
organic solvents and are used as recyclable cata
specific ionic liquid [bmIm]OH for Knoevenagel condensation of aromatic as we
aliphatic aldehydes with
protocol (Scheme 3.I.1).
Ware et al. [10] efficiently carried out Knoevenagel con
employing 1,8-diazabycyclo[5.4.0]undec
free conditions at ambient temperature
Synthesis of 2-Arylideneindane-1,3-diones by Knoevenagel Condensation
87
chemistry and highly pronounced pharmacological properties
displayed by Knoevenagel products, have made them attractive synthetic targets
which can be readily realized from the appearance of vast number of articles dealing
with synthesis and biological activities of these derivatives.
Chen and group [7] reported condensation of aromatic aldehydes with active
methylene compounds like malononitrile, barbituric acid, Meldrum’s acid in water
using triethylbenzylammonium chloride as catalyst (Scheme 3.I.1).
Scheme 3.I.1
In 2005, Deb and co-workers [8] were successful in carrying out uncatalysed
Knoevenagel condensation of aromatic aldehydes with active methylenes in water at
(Scheme 3.I.1).
During last decade ionic liquids have emerged as green alternatives to volatile
organic solvents and are used as recyclable catalysts. Jana et al. [9] envisioned task
specific ionic liquid [bmIm]OH for Knoevenagel condensation of aromatic as we
aliphatic aldehydes with active methylenes which proved general applicability of
.
] efficiently carried out Knoevenagel condensation reaction
diazabycyclo[5.4.0]undec-7-ene (DBU) as basic catalyst under solvent
free conditions at ambient temperature (Scheme 3.I.2).
diones by Knoevenagel Condensation
chemistry and highly pronounced pharmacological properties
displayed by Knoevenagel products, have made them attractive synthetic targets
which can be readily realized from the appearance of vast number of articles dealing
] reported condensation of aromatic aldehydes with active
acid in water
] were successful in carrying out uncatalysed
Knoevenagel condensation of aromatic aldehydes with active methylenes in water at
een alternatives to volatile
] envisioned task
specific ionic liquid [bmIm]OH for Knoevenagel condensation of aromatic as well as
eneral applicability of
densation reaction
ene (DBU) as basic catalyst under solvent
CHAPTER 3 I: Synthesis of 2-Arylideneindane-1,3-diones by Knoevenagel Condensation
88
Scheme 3.I.2
Solvent free Knoevenagel condensation reaction has been also reported by
Suresh and colleagues [11] in presence of alum as inexpensive and easily available
catalyst (Scheme 3.I.2).
Wang and co-workers [12] developed an efficient protocol for condensation
reaction of aryl aldehydes with malononitrile using inexpensive and easily available
inorganic zinc salts such as Zn(OAc)2.2H2O, ZnCl2 and ZnBr2 under solvent free
conditions (Scheme 3.I.2).
Benhida [13] reported microwave assisted Knoevenagel condensation under
solvent free condition using natural basic heterogenous catalyst hydroxyapatite
[Ca10(PO4)6(OH)2] (p-HAP) and described its mechanism as shown in (Scheme 3.I.3).
Scheme 3.I.3
α-Amino acids are organic molecules so far been used as chiral auxiliaries,
chiral ligands and chiral synthons for natural products and drugs. Organocatalysts like
proline have been widely reported as catalysts in organic synthesis. Rahmati et al.
[14] investigated role of organocatalysts such as L-Histidine and L-Arginine in
Knoevenagel condensation.
Deshmukh and associates [15] reported highly efficient and green reaction of
aryl aldehydes with malononitrile in presence of lemon juice as biocatalyst. Lemon
R-CHO +
CN
X
solvent- freeCN
XH
R
X=CN/ COOEt/ CONH2
CHAPTER 3 I: Synthesis of 2-Arylideneindane-1,3-diones by Knoevenagel Condensation
89
belongs to the citrus family and contains citric acid in 5-7 %. Due to the acidic nature
(pH 2-3) of juice, reaction proceeded efficiently.
Polyacrylonitrile fibre has been used in clothing industry as a fabric material
since it is corrosion and mildew resistant and has excellent mechanical strength. It has
also lots of cyano groups which can be transformed into carboxyl, amide or
amodoximes groups and it is suitable for preparing fiber catalyst.
Triethelynetetramine aminated fiber catalyst (Fig. 3.I.3) has been proposed to
catalyze condensation of aryl aldehydes with active methylenes by Li and group [16].
Fig. 3.I.3 Preparation of amine functionalised fiber catalyst
The potential use of ionic liquid [17] 1-methylimidazolium trifluoroactate
[Hmim]Tfa has been exploited in synthesis of alkenes from aryl aldehydes and
Meldrum’s acid by Darvatkar and colleagues (Scheme 3.I.4).
Scheme 3.I.4
Wilson et al. [18] reported Knoevenagel reaction of Meldrum’s acid and
aromatic aldehydes using catalytic amount of piperidine and [bmim]PF4 as recyclable
reaction medium (Scheme 3.I.4).
The mild, green and efficient synthesis of 2,2-dimethyl-5-[(4-oxo-4H-
chromen-3-yl)methylene]-1,3-dioxane-4, 6-diones has been achieved by Shelke et al.
CHAPTER 3 I: Synthesis of 2-Arylideneindane-1,3-diones by Knoevenagel Condensation
90
from 4-oxo-4H-benzopyran-3-carbaldehydes and Meldrum’s acid [19]. 1-Benzyl-3-
methylimidazolium chloride [bnmim](Cl) employed as recyclable ionic liquid
(Scheme 3.I.5).
Scheme 3.I.5
Cellulose is a biopolymer and is used as support material for various catalysts.
They possess attracting features over the organic and inorganic supports such as they
are extremely inert, inexpensive, biodegradable and environmentally benign and the
most abundant renewable material. Shelke and group [20] explored condensation of 3-
formylchromone/2-chloroquinoline-3-carbaldehyde with Meldrum’s acid/ethyl
cyanoacetate using recyclable bio-supported cellulose sulphuric acid by grinding
under solvent free conditions.
Thirupathi and group [21] exploited L-Tyrosine catalysed Knoevenagel
reaction of aryl aldehydes and Meldrum’s acid by grinding under solvent free
condition. This bifunctional, zwitterionic catalyst used is efficient and
environmentally benign.
Microwave-assisted organic synthesis has attracted considerable attention
because it leads to decreased reaction time, increased yield and easier work-up. In
2001, Ali and associates [22] demonstrated microwave assisted Knoevenagel
condensation of barbituric acid and aromatic aldehydes over basic alumina (Scheme
3.I.6).
Scheme 3.I.6
In our laboratory, Salunkhe et al. [23] successfully applied the novel concept
of Gel Entrapped Base Catalyst for Knoevenagel condensation of active methylenes
like barbituric acid and Meldrum’s acid with aryl aldehydes. These catalysts are
prepared by entrapping bases in aqueous gel matrix of agar-agar which is a polymer
CHAPTER 3 I: Synthesis of 2
composed of repeating agarobiose units alternating between 3
galactopyranosyl (G) and 4
(Scheme 3.I.7). The use of GEBC reduces the amount of bases and also prov
recyclability for the process.
Nagaraj et al. [24]
aldehydes with barbituric acid which afforded
reaction was carried out under non
(Scheme 3.I.8).
Jain and co-workers [
substituted alkenes from indole aldehyde and various active methylene compounds
using microwave irradiation and L
screened for antibacterial activity
Dubey et al. [26] also prepared novel indole alkenes with 3
(2) as active methylene compound employing triphenylphosphine catalyst a
temperature and synthesi
in PEG-600 to afford N,N
Synthesis of 2-Arylideneindane-1,3-diones by Knoevenagel Condensation
91
composed of repeating agarobiose units alternating between 3
ctopyranosyl (G) and 4-linked-3 6-anhydro-α-L-galactopyranosyl (LA) units
. The use of GEBC reduces the amount of bases and also prov
recyclability for the process.
Scheme 3.I.7
[24] successfully carried out the reaction of unsaturated
with barbituric acid which afforded biologically important products. The
reaction was carried out under non-catalytic and solvent free microwave irradiation
Scheme 3.I.8
workers [25] carried out pioneering work to synthesize
substituted alkenes from indole aldehyde and various active methylene compounds
ng microwave irradiation and L-proline as catalyst. Synthesized compounds
screened for antibacterial activity (Scheme 3.I.9).
Scheme 3.I.9
] also prepared novel indole alkenes with 3-cyanoacetylindole
as active methylene compound employing triphenylphosphine catalyst a
temperature and synthesized novel alkenes (3 and 5) used further to react with DMS
N1dimethyl (6) derivatives (Scheme 3.I.10).
diones by Knoevenagel Condensation
composed of repeating agarobiose units alternating between 3-linked-β-D-
galactopyranosyl (LA) units
. The use of GEBC reduces the amount of bases and also provides
out the reaction of unsaturated
biologically important products. The
catalytic and solvent free microwave irradiation
] carried out pioneering work to synthesize indole
substituted alkenes from indole aldehyde and various active methylene compounds
nthesized compounds
cyanoacetylindole
as active methylene compound employing triphenylphosphine catalyst at room
used further to react with DMS
CHAPTER 3 I: Synthesis of 2-Arylideneindane-1,3-diones by Knoevenagel Condensation
92
Scheme 3.I.10
Although Knoevenagel condensation reaction enjoys a rich array of reports
regarding the diverse active methylene compounds, very few articles are reported
regarding indanedione derivatives in literature. 1,3-indanedione is an aromatic trans-
fixed β-diketone, a yellow solid. It can be prepared by decarboxylation of the sodium
salt of 2-etoxycarbonyl-1,3-indandione, which itself is obtained by Claisen
condensation of ethyl acetate and dimethyl phthalate (Scheme 3.I.11).
Scheme 3.I.11
Certain derivatives of 1,3-indanedione are used in human medicine [27] which
acts as Vitamin K antagonist (Fig. 3.I.4), anticancer, analgesic, anti-inflammatory,
fungicidal and bactericidal agents. Phenindione (a) is an anticoagulant which
functions as Vitamin K antagonist. Clorindione (b) is derivative of Phenindione.
Diphenandione (c) also has anticoagulant effects and is used as rodenticide against
rats, mice, voles, ground squirrels and other rodents. It has longer activity than
warfarin and other synthetic indanedione anticoagulants.
O
O
O
O
O
O
Na+ +C2H5OH
O
O
O
O
2 CH3OH+-
Na+
O
O
O
O
+-
Na+
H2O + HCl
O
O
+ NaCl + CO2+2C2H5OH
CHAPTER 3 I: Synthesis of 2
Fig. 3.I.
2-Arylideneindane
because they are used as intermediates for
molecules [28]. As well as they possess important pharmacological activities such as
anticoagulants [29] and cytotoxics [30
synthesis of these derivatives. A classic route for
Knoevenagel condensation of 1,
reported methods operate under reflux conditions using various catalysts including
acids or bases.
In 1998, Bullington and co
arylideneindane-1,3-diones under the catalytic action of gaseous HCl and
under reflux condition
efficient method for the synthesis of
reaction of 1,3-indanedione and aromatic aldehydes using grinding method at room
temperature. Silica gel and MgO were employed as basic catalysts for this synthesis
(Scheme 3.I.12).
Synthesis of 2-Arylideneindane-1,3-diones by Knoevenagel Condensation
93
Fig. 3.I.4 Derivatives of 1,3-indanedione
Arylideneindane-1,3-dione scaffolds are industrially important precursors
because they are used as intermediates for the synthesis of different bio
]. As well as they possess important pharmacological activities such as
ants [29] and cytotoxics [30]. Very few reports are available for the
synthesis of these derivatives. A classic route for the synthesis of these derivatives is
Knoevenagel condensation of 1,3-indanedione with aryl aldehydes. Most of the
reported methods operate under reflux conditions using various catalysts including
In 1998, Bullington and co-workers [31] reported the synthesis of 2
diones under the catalytic action of gaseous HCl and
(Scheme 3.I.12). Wu and associates [32] developed an
efficient method for the synthesis of 2-arylideneindane-1,3-diones by condensation
indanedione and aromatic aldehydes using grinding method at room
temperature. Silica gel and MgO were employed as basic catalysts for this synthesis
Scheme 3.I.12
diones by Knoevenagel Condensation
dione scaffolds are industrially important precursors
the synthesis of different bio-active
]. As well as they possess important pharmacological activities such as
]. Very few reports are available for the
the synthesis of these derivatives is
indanedione with aryl aldehydes. Most of the
reported methods operate under reflux conditions using various catalysts including
the synthesis of 2-
diones under the catalytic action of gaseous HCl and p-TSA
] developed an
by condensation
indanedione and aromatic aldehydes using grinding method at room
temperature. Silica gel and MgO were employed as basic catalysts for this synthesis
CHAPTER 3 I: Synthesis of 2-Arylideneindane-1,3-diones by Knoevenagel Condensation
94
Karthik et al. [33] reported 2-arylideneindane-1,3-diones synthesis under
reflux condition in ethanol using piperidine. This protocol further extended to
synthesize spiro oxiranes and evaluated their anti-tubercular activity (Scheme 3.I.12).
Synthetic route to prepare arylideneindane-1,3-diones was given by Katarzyna
and co-workers [29] employing acetic acid and concentrated H2SO4. Synthesized
derivatives further screened for anticoagulant activity (Scheme 3.I.12).
Recently, Yang et al. [34] disclosed catalyst free route for synthesis of 2-
arylideneindane-1,3-dione derivatives in refluxing water (Scheme 3.I.12). The
presented method is very tedious and involves long reaction times.
3.I.2 Present Work
Avoiding the use of harmful organic solvents is a fundamental strategy to achieve
the environmentally benign and economic syntheses in the area of research that is
being vigorously pursued. One of the most attractive alternatives to organic solvents
is water, which has witnessed increasing popularity due to being inexpensive, readily
available, non-inflammable, non-toxic and environmentally benign [35]. However
organic reactions in water are often limited in scope due to the poor solubility of the
many organic compounds. To develop a novel catalytic system which enables to use
water as reaction medium, we selected natural surfactant as amphiphile for the present
transformation.
Green chemistry approaches not only offer significant potential to reduce by-
products, waste produced, and energy costs but also in the development of new
methodologies for previously unobtainable materials [36]. “The Perfectly Green”
reaction might be described as one which proceeds at room temperature, requires no
organic solvent, is highly selective, exhibit high atom efficiency, and yet produces no
waste products [37]. All these principles can be addressed using biosurfactants as part
of the chemical process, as an excellent alternative to volatile organic solvents in
more environmental friendly technologies due to their low toxicity, easy
biodegradability, ability to act as catalyst, non-inflammable and non-corrosive
properties as compared to chemical surfactants [38]. Also due to the high natural
abundance their production is potentially less expensive.
Biosurfactants (Surface Active Agents) are microbial amphiphilic polymers and
polyphilic polymers that tend to interact with the phase boundary between two phases
in heterogeneous system, known as interface. Biosurfactant is an emergent technology
CHAPTER 3 I: Synthesis of 2
with a great potential for industrial applications includin
recovery, crude oil drilling, lubricants, health care a
43]. Also full evaluations of the potential of these bio
formulations, foods and dermal or transdermal drug d
at an incredible rate [44-
and environmental biotechnology, much less efforts have been devoted for
accelerating the organic transformations using bio
medium.
The use of plant material in organic synthesis is quite novel and in true sense
worth in green chemistry which is superior to chemical methods as it is cost effective
and environmentally friendly.
chosen the fruit of Balanites roxburghii
abundance and also is inexpensive. As compared to chemical surfactants, it is having
very low cost i.e. Rs. 50/
tremendous medicinal applications and it was
anthelmintic, anti-fungal, and purgative, in whooping cough, skin diseases and snake
bite. Phytochemical study of this plant showed the presence of alkaloids, flavonoids
tannins, phenolic compounds and saponins [
Balanites roxburghii [48
surface activity due to the presence of various saponins
investigate catalytic activity of aqueous extract in acid mediated reactions. Adopting
the similar strategy, we recently reported aldimine synthesis using aqueous extract of
the pericarp of Sapindus trifoliatus
Synthesis of 2-Arylideneindane-1,3-diones by Knoevenagel Condensation
95
with a great potential for industrial applications including their use in enhanced oil
recovery, crude oil drilling, lubricants, health care and food processing industry [39
s of the potential of these biosurfactants in cosmetic and soap
formulations, foods and dermal or transdermal drug delivery systems are developing
-46]. Notably, despite their diverse applications in industry
and environmental biotechnology, much less efforts have been devoted for
ganic transformations using biosurfactant as catalyst and reaction
The use of plant material in organic synthesis is quite novel and in true sense
worth in green chemistry which is superior to chemical methods as it is cost effective
mentally friendly. In present work, as the source of biosurfactant, we
Balanites roxburghii i.e. Hingota because of its high natural
abundance and also is inexpensive. As compared to chemical surfactants, it is having
very low cost i.e. Rs. 50/- per Kg. Moreover, whole plant along wit
tremendous medicinal applications and it was traditionally used as emetic,
fungal, and purgative, in whooping cough, skin diseases and snake
bite. Phytochemical study of this plant showed the presence of alkaloids, flavonoids
tannins, phenolic compounds and saponins [47]. The aqueous fruit extract of
[48] exhibits acidic pH (ca 4.86) and displays remarkable
surface activity due to the presence of various saponins (Fig. 3.I.5). This spurred us to
investigate catalytic activity of aqueous extract in acid mediated reactions. Adopting
the similar strategy, we recently reported aldimine synthesis using aqueous extract of
Sapindus trifoliatus fruits [49].
Fig. 3.I.5 Structure of saponin
diones by Knoevenagel Condensation
g their use in enhanced oil
nd food processing industry [39-
surfactants in cosmetic and soap
elivery systems are developing
]. Notably, despite their diverse applications in industry
and environmental biotechnology, much less efforts have been devoted for
atalyst and reaction
The use of plant material in organic synthesis is quite novel and in true sense
worth in green chemistry which is superior to chemical methods as it is cost effective
of biosurfactant, we
because of its high natural
abundance and also is inexpensive. As compared to chemical surfactants, it is having
per Kg. Moreover, whole plant along with fruit has
traditionally used as emetic,
fungal, and purgative, in whooping cough, skin diseases and snake
bite. Phytochemical study of this plant showed the presence of alkaloids, flavonoids,
]. The aqueous fruit extract of
4.86) and displays remarkable
. This spurred us to
investigate catalytic activity of aqueous extract in acid mediated reactions. Adopting
the similar strategy, we recently reported aldimine synthesis using aqueous extract of
CHAPTER 3 I: Synthesis of 2-Arylideneindane-1,3-diones by Knoevenagel Condensation
96
3.I.3 Results and Discussion
Initially, efforts were made to prepare biosurfactant solution from Balanites
roxburghii fruit. For this purpose, dried single fruit (20 g) was soaked in distilled
water (100 mL) for 12 hours. The material was then macerated with the water in
which it was soaked and filtered. The filtrate was kept below 5 oC and is stable at least
for 30 days. This solution is wine red coloured and it was considered as 100 % and
various concentrations (% v/v) of solutions were prepared by dilution with distilled
water (Fig. 3.I.6).
Fig. 3.I.6 Preparation of Biosurfactant solution from Balanites roxburghii fruit
At the outset, 1,3-indanedione 1 (1 mmol) and 2-nitrobenzaldehyde 2h (1
mmol) were taken as precursors for optimizing reaction conditions in aqueous extract
of Balanites roxburghii fruit (5 mL) at room temperature (Scheme 3.I.13). By
observing visually (Fig. 3.I.7) completion of reaction was indicated by formation of
coloured precipitates which was also confirmed by TLC. On the completion of
reaction as monitored by TLC, the reaction mixture was diluted with cold water and
product separated out. The filtration of reaction mixture and washing with water and
ethanol afforded the corresponding product of high purity which displayed correct 1H
NMR and 13C NMR spectra.
Scheme 3.I.13
O
O
+
CHO
R
O
O
H
RAq. fruit extract
RT
1 2 (a-r) 3 (a-r)
CHAPTER 3 I: Synthesis of 2
With these results in hand, we
maximum conversion of the reactants in water to give maximum yield of the product.
Thus the model reaction was carried out with various concentrations (%
aqueous extract of Balanites
solution was considered as 100 % and various concentrations (%
were prepared by dilution with water
conversion rate of 2-arylideneindane
was diluted to 1 %. To understand this effect, pH of each solution was measured and
surprisingly it was observed that pH remained
indicated that the aqueous extract of fruit worked like buffer. Buffering action of the
catalytic solution is accounted on the basis of structure of saponins which are
generally amphiphilic molecules in which sugars
either a sterol or a triterpene non
as buffer and thus change in concentration by dilution with water doesn’t affect
catalytic properties of bio
concentration of catalyst up to 1 % without changing the yield of the product. To
compare the catalytic activity of natural surfactant with chemical surfactant, we also
carried out the model reaction using sodium dodecyl sul
proceeded same with respect to time and y
buffer system, chemical surfactant can’t be recycled. Furthermore, decrease in
concentration of SDS by dilution, greatly
A controlled reaction conducted in water under identical conditions and
devoid of biocatalyst gave no corresponding product, despite the prolonged react
times indicates role of bio
After the optimization of concentration, a s
aldehydes were treated with
Synthesis of 2-Arylideneindane-1,3-diones by Knoevenagel Condensation
97
Fig. 3.I.7 Coloured products
h these results in hand, we determined the optimum concentration for
maximum conversion of the reactants in water to give maximum yield of the product.
Thus the model reaction was carried out with various concentrations (%
Balanites roxburghii fruit at ambient temperature.
solution was considered as 100 % and various concentrations (% v/v) of
prepared by dilution with water. By changing concentration, no effect on the
arylideneindane-1,3-diones was observed even when solution
%. To understand this effect, pH of each solution was measured and
it was observed that pH remained constant for each solution, this
indicated that the aqueous extract of fruit worked like buffer. Buffering action of the
catalytic solution is accounted on the basis of structure of saponins which are
generally amphiphilic molecules in which sugars (hydrophilic part)
either a sterol or a triterpene non-polar group (hydrophobic part). Here, sugar part acts
as buffer and thus change in concentration by dilution with water doesn’t affect
catalytic properties of biosurfactant solution and it is beneficial as it reduces the
concentration of catalyst up to 1 % without changing the yield of the product. To
compare the catalytic activity of natural surfactant with chemical surfactant, we also
carried out the model reaction using sodium dodecyl sulphate (SDS). Both reactions
proceeded same with respect to time and yield. As natural surfactant is
buffer system, chemical surfactant can’t be recycled. Furthermore, decrease in
concentration of SDS by dilution, greatly affected the yield of product.
A controlled reaction conducted in water under identical conditions and
catalyst gave no corresponding product, despite the prolonged react
times indicates role of biocatalyst is decisive.
After the optimization of concentration, a series of structurally diverse aryl
hydes were treated with 1,3-indanedione in 1 % aqueous extract at ambient
diones by Knoevenagel Condensation
determined the optimum concentration for
maximum conversion of the reactants in water to give maximum yield of the product.
Thus the model reaction was carried out with various concentrations (% v/v) of
The prepared
) of solutions
. By changing concentration, no effect on the
ven when solution
%. To understand this effect, pH of each solution was measured and
constant for each solution, this
indicated that the aqueous extract of fruit worked like buffer. Buffering action of the
catalytic solution is accounted on the basis of structure of saponins which are
philic part) are linked to
. Here, sugar part acts
as buffer and thus change in concentration by dilution with water doesn’t affect the
is beneficial as it reduces the
concentration of catalyst up to 1 % without changing the yield of the product. To
compare the catalytic activity of natural surfactant with chemical surfactant, we also
phate (SDS). Both reactions
ield. As natural surfactant is recyclable
buffer system, chemical surfactant can’t be recycled. Furthermore, decrease in
A controlled reaction conducted in water under identical conditions and
catalyst gave no corresponding product, despite the prolonged reaction
eries of structurally diverse aryl
indanedione in 1 % aqueous extract at ambient
CHAPTER 3 I: Synthesis of 2-Arylideneindane-1,3-diones by Knoevenagel Condensation
98
temperature (Table 3.I.1). The reactions proceeded at room temperature within 5 to
20 minutes affording the desired products in excellent yields. The aryl aldehydes
bearing electron-donating as well as electron-withdrawing groups underwent reactions
successfully. In addition, heteroaromatic aldehydes such as thiophene-2-aldehyde and
furfuraldehyde reacted efficiently furnishing anticipated products in good yields. The
method is also suitable for the sterically hindered 1-naphthaldehyde. In all the cases 2-
arylideneindane-1,3-diones were the sole products and no anomalies were noted. Pure
products were obtained after recrystallization in ethanol which were then
characterised by their physical constants and spectral techniques.
Table 3.I.1 2-Arylideneindane-1,3-dionesa synthesis catalysed by aqueous extract of
Balanites roxburghii fruit
Sr. No.
Aldehyde
(2a-2r)
Product (3a-3r)
Time (min)
Yieldb (%)
M. P. [Lit.]c
(oC) 1 Ph 3a 5 93 150 [152-153]35
2 4-Me-C6H4 3b 15 92 150 [150-151]33
3 4-OMe-C6H4 3c 20 89 155 [156-157]33
4 4-Cl-C6H4 3d 5 92 180 [180-182]36
5 4-F-C6H4 3e 5 90 170 [170]34
6 2-OH-C6H4 3f 12 88 194 [193-195]36
7 4-OH-C6H4 3g 10 90 241 [241-243]36
8 2-NO2-C6H4 3h 5 94 190 [192-194]36
9 4-NO2-C6H4 3i 17 94 232 [234-236]36
10 1-naphthyl 3J 10 83 172 [174-176]35
11 4-N(Me)2-C6H4 3k 20 88 178 [180]34
12 4-OH, 3-OMe-C6H3 3l 15 93 218-220
13 3, 4, 5-(OMe)3-C6H2 3m 18 92 185 [185]34
14 Furyl-2-yl 3n 5 90 210 [209-211]35
15 Thiophene-2-yl 3o 5 94 178-180
16 2-CHO-C6H4 3p 5 92 218-220
17 4-Br-C6H4 3q 5 90 173-175
18 4-CN-C6H4 3r 5 93 238-240 a All products were characterized by IR, 1H NMR, 13C NMR spectroscopy and elemental analysis technique. b Isolated yields. c Literature values in parenthesis.
CHAPTER 3 I: Synthesis of 2-Arylideneindane-1,3-diones by Knoevenagel Condensation
99
The exceptionally higher catalytic activity of biosurfactant (aqueous extract of
Balanites roxburghii fruit) can be related to its ability to form micelles in water. The
molecules of reactants aggregate and reaction is facilitated by the hydrophobic
environment. As a result effective concentration of organic substrates gets increase
and this is the driving force to increase the rate of reaction. As the impact of micellar
solution the effective and efficient collision takes place and the hydrophobic interior
of micelle removes water generated during the progress of reaction. This facilitates
the shifting of equilibrium towards product formation with excellent yield.
Another striking feature of biosurfactant was its easy recovery from the
reaction mixture. As biosurfactants are more soluble in water than in organic solvents,
almost 100 % of it was quite easily recovered from the aqueous solution after the
reaction was completed. The reaction mixture was quenched with water and the
precipitated product was simply separated by filtration. To assess the reusability of
biosurfactant, recycling experiments were carried out with 2-nitrobenzaldehyde and
1,3-indanedione as substrates over the four reaction cycles. After each experiment, the
aqueous solution of catalyst was recovered by filtration, washed thoroughly with
diethyl ether, concentrated and then subjected to a new run with fresh reactants under
identical reaction conditions. It was interesting to note that catalytic solution showed
remarkable reusability and recyclability without any change in yield of the product
indicating the ‘in-flask’ recyclability. This is because of the buffering action of the
catalytic solution.
Characterisation of products:
2-(4-hydroxy, 3-methoxybenzylidene)-2H-indene-1,3-dione (Table 3.I.1, Entry
12)
O
O
H
OH
OMe4.15
9.04
O
O
H
OH
OMe56.1189.6
190.3
1H NMR 13C NMR
In IR spectrum (Fig. 3.I.8) characteristic peak for hydroxy group exhibited
frequency at 3453 cm-1. Two carbonyls appeared at frequency 1715 and 1672 cm-1.
The 1H NMR spectrum (Fig. 3.I.9) exhibited sharp singlet at δ 4.15 ppm for three
CHAPTER 3 I: Synthesis of 2-Arylideneindane-1,3-diones by Knoevenagel Condensation
100
protons of methoxy group. Olefinic proton along with remaining aromatic protons
resonated from δ 6.27-8.01 ppm. Doublet at δ 9.04 ppm is of hydroxy proton. 13C
spectrum (Fig. 3.I.10) exhibited signal in aliphatic region due to methoxy carbon at
56.1 ppm. Remaining carbons appeared in aromatic region at δ 114.5, 115.1, 122.9,
123.1, 126.1, 126.6, 132.2, 134.6, 134.8, 140.0, 142.4, 146.3, 147.7, 151.2 ppm.
Signals at 189.6 and 190.3 ppm corresponds to two carbonyl carbons respectively.
2-((1,3-dioxo-1H-inden-2(3H)-ylidene)methyl)benzaldehyde (Table 3.I.1, Entry
16)
O
O
H
CHO
10.16
O
O
H
CHO190.8
188.4
189.1
1H NMR 13C NMR
In IR spectrum (Fig. 3.I.11) characteristic peaks for two carbonyls appeared at
frequency 1723 and 1691 cm-1. The peak at 1710 cm-1 is of carbonyl of aldehyde
group. The 1H NMR spectrum (Fig. 3.I.12) is in full agreement with proposed
structure. Olefinic proton along with all aromatic protons resonated from δ 7.69-9.03
ppm. The aldehydic proton appeared as sharp singlet 10.16 ppm. 13C spectrum (Fig.
3.I.13) exhibited signals for aromatic carbons at δ 123.5, 123.6, 129.4, 130.6, 132.2,
133.8, 135.3, 135.4, 135.8, 136.9, 139.0, 140.2, 142.6, 144.5 ppm. Signals at 188.4
and 189.1 ppm corresponds to two carbonyl carbons respectively. Carbon of aldehyde
group appeared at 190.8 ppm. Masss spectrum (Fig. 3.I.14) exhibited molecular ion
peak at m/z = 262 along with characteristic M-1 peak at 261 because of aldehydic
group.
2-(4-cyanobenzylidene)-2H-indene-1,3-dione (Table 3.I.1, Entry 18)
O
O
H
CN
O
O
H
CN
117.9
188.2
188.9
1H NMR 13C NMR
CHAPTER 3 I: Synthesis of 2-Arylideneindane-1,3-diones by Knoevenagel Condensation
101
The IR spectrum (Fig. 3.I.15) exhibited characteristic peak for two carbonyls
at 1727 and 1689 cm-1 and cyano group resonated at 2227 cm-1. In 1H NMR spectrum
(Fig. 3.I.16) olefinic proton along with all aromatic protons resonated from δ 7.80-
8.54 ppm. 13C spectrum (Fig. 3.I.17) exhibited signals for aromatic carbons at δ
115.5, 123.6, 123.7, 131.8, 132.2, 133.7, 135.6, 135.7, 136.6, 140.2, 142.6, 143.2
ppm. Peak at 117.9 is of cyanide carbon. Signals at 188.2 and 188.9 ppm corresponds
to two carbonyl carbons respectively.
3.I.4 Conclusion
In summary, developed protocol employs a novel and green catalyst which is
easily available, inexpensive and absolutely harmless to human and environment. It
allows fast and general synthesis of inaccessible 2-arylideneindane-1,3-diones
offering very attractive features such as reduced reaction time, no energy
consumption, good waste management with easily biodegradable catalyst, no organic
solvents, easy work-up procedure, reusable, non-toxic and safer reaction medium
along with high yields.
3.I.5 Experimental Section
Solvents and reagents were commercially sourced from Sigma Aldrich and
used without further purification. Melting points were determined in an open capillary
and are uncorrected. Infrared spectra were measured with Perkin Elmer FT-IR
spectrophotometer. The samples were examined as KBr discs ~ 5% w/w. 1H NMR
and 13C NMR spectra were recorded on Bruker AC (300 MHz for 1H NMR and 75
MHz for 13C NMR) spectrometer using CDCl3 as solvent and tetramethylsilane
(TMS) as an internal standard. Chemical shifts are expressed in δ parts per million
(ppm) values with tetramethylsilane (TMS) as the internal reference and coupling
constants are expressed in hertz (Hz). Mass spectra were recorded on Shimadzu
QP2010 GCMS. Elemental analyses were performed on EURO EA 3000 Vectro
elemental analyzer.
Preparation of aqueous extract from plant material
Dried fruits of Balanites roxburghii were purchased from local market and
authenticated by the Department of Botany, Shivaji University, Kolhapur, India. The
dried single fruit (20 g) was soaked in distilled water (100 mL) for 12 hours. The
material was then macerated with the water in which it was soaked and filtered. The
filtrate was kept below 5 oC and is stable at least for 30 days.
CHAPTER 3 I: Synthesis of 2-Arylideneindane-1,3-diones by Knoevenagel Condensation
102
General procedure for synthesis of 2-Arylideneindane-1,3-diones
A mixture of 1,3-indanedione (1 mmol) and aldehyde (1 mmol) in aqueous
fruit extract of Balanites Roxburghii was stirred till the completion of reaction as
indicated by TLC. The solid products were separated by adding 50 mL water followed
by simple filtration. The recrystallization using ethanol afforded desired products of
high purity. The identity of all the compounds was ascertained on the basis of IR, 1H
NMR, 13C NMR and mass spectroscopy as well as by elemental analysis. The
physical and spectroscopic data are in consistent with the proposed structures and are
in correlation with the literature values.
Spectral data of representative compounds:
2-(4-chlorobenzylidene)-2H-indene-1,3-dione (3d): White solid; mp 180 °C.
IR (KBr): υ = 1726 (C=O), 1690 (C=O), 1580, 831, 736 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.49-7.52 (d, 2H), 7.84-7.88 (m, 3H), 8.02-8.06
(m, 2H), 8.44-8.46 (d, 2H) ppm. 13C NMR (75 MHz, CDCl3): δ = 123.4, 129.1, 129.5, 131.7, 135.3, 135.5, 139.5,
140.5, 143.0, 145.1, 189.1 (C=O), 190.3 (C=O) ppm.
Elemental Analysis requires: C, 71.52; H, 3.38; O, 11.91 %
(C16H9O2Cl): found: C, 71.49; H, 3.40; O, 11.92 %.
2-(4-bromobenzylidene)-2H-indene-1,3-dione (3q): Yellow solid; mp 173-175 oC.
IR (KBr): υ = 1725 (C=O), 1689 (C=O), 1578, 991, 736 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.66-7.88 (d, 2H), 7.82-7.88 (m, 3H), 8.02-8.05
(m, 2H), 8.35-8.38 (d, 2H) ppm. 13C NMR (75 MHz, CDCl3): δ = 123.4, 123.5, 128.3, 129.6, 131.9, 132.1, 135.2,
135.3, 135.4, 140.1, 142.6, 145.1, 188.7 (C=O),
189.6 (C=O) ppm.
Elemental Analysis requires: C, 61.37; H, 2.90; O, 10.22 %
(C16H9O2Br): found: C, 61.41; H, 2.91; O, 10.19 %.
2-(thiophen-2-yl)methylene)-2H-indane-1,3-dione (3o): Yellow solid; mp 178 oC.
IR (KBr): υ = 1724 (C=O), 1684 (C=O), 1585, 811, 726 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.25-7.27 (m, 1H), 7.79-7.83 (m, 1H), 7.87-7.88
(d, 1H), 7.98-8.06 (m, 3H), 8.10-8.11 (d, 1H) ppm.
CHAPTER 3 I: Synthesis of 2-Arylideneindane-1,3-diones by Knoevenagel Condensation
103
13C NMR (75 MHz, CDCl3): δ = 123.0, 123.1, 124.9, 128.5, 134.7, 134.9, 136.0,
137.5, 137.9, 140.4, 141.3, 142.1, 188.9 (C=O),
189.7 (C=O) ppm.
Elemental Analysis: requires: C, 69.98; H, 3.36; O, 13.32 %
(C14H8O2S): found: C, 69.96; H, 3.40; O, 13.35 %.
104
Fig. 3.I.8 IR spectrum of 2-(4-hydroxy, 3-methoxybenzylidene)-2H-indene-1,3-dione
105
Fig. 3.I.9 1H NMR spectrum of 2-(4-hydroxy, 3-methoxybenzylidene)-2H-indene-1,3-dione
106
Fig. 3.I.10 13C NMR spectrum of 2-(4-hydroxy, 3-methoxybenzylidene)-2H-indene-1,3-dione
107
Fig. 3.I.11 IR spectrum of 2-((1,3-dioxo-1H-inden-2(3H)-ylidene)methyl)benzaldehyde
108
Fig. 3.I.12 1H NMR spectrum of 2-((1,3-dioxo-1H-inden-2(3H)-ylidene)methyl)benzaldehyde
109
Fig. 3.I.12 13C NMR spectrum of 2-((1,3-dioxo-1H-inden-2(3H)-ylidene)methyl)benzaldehyde
110
Fig. 3.I.14 Mass spectrum of 2-((1,3-dioxo-1H-inden-2(3H)-ylidene)methyl)benzaldehyde
111
Fig. 3.I.15 IR spectrum of 2-(4-cyanobenzylidene)-2H-indene-1,3-dione
112
Fig. 3.I.16 1H NMR spectrum of 2-(4-cyanobenzylidene)-2H-indene-1,3-dione
113
Fig. 3.I.17 13C NMR spectrum of 2-(4-cyanobenzylidene)-2H-indene-1,3-dione
CHAPTER 3 I: Synthesis of 2-Arylideneindane-1,3-diones by Knoevenagel Condensation
114
3.I.7 References
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CHAPTER 3
Synthesis of Pyrazolones 3.II.1 Introduction
Heterocyclic compounds occur widely in nature and are essential to life.
Nitrogen containing heterocycles constitute the largest portion of chemical entities,
which are part of many natural products, fine chemicals and biologically active
pharmaceuticals essential for enhancing the quality of life [1]. High
screening and elimination of
i.e. pyrazoles. Pyrazole
heterocyclic compounds, occupy an important position in medicinal and p
chemistry with wide range of bioactivities [2].
Pyrazolone, derivative of pyrazole
containing two nitrogens and ketone in the same molecule with molecular formula of
C3H4N2O. There are two possible isomers: 3
3.II.1).
Pyrazolone is an active moiety as
nonsteroidal anti-inflammatory drugs (NSAID) used in the treatment of arthritis and
other musculoskeletal and joint disorders.
phenylbutazone (I), oxyphenbutazone
Phenazone or antipyrine
as lactam structure related compounds, are also widely used in preparing dyes a
pigments. For example, 1
intermediate to prepare dyes and pigments. 4
possibly can be used as an intermediate for the synthesis of pharmaceuticals
especially antipyretic and analgesic drugs. It i
determination of phenols.
CHAPTER 3 II: Synthesis of Pyrazolones by Tandem Knoevenagel
117
Section-II
Synthesis of Pyrazolones by Tandem Knoevenagel-Michael Reaction
Heterocyclic compounds occur widely in nature and are essential to life.
heterocycles constitute the largest portion of chemical entities,
which are part of many natural products, fine chemicals and biologically active
pharmaceuticals essential for enhancing the quality of life [1]. High
screening and elimination of promiscuous hits led to the elucidation of one hit class
razoles. Pyrazole and its derivatives, a class of well known nitrogen containing
heterocyclic compounds, occupy an important position in medicinal and p
wide range of bioactivities [2].
derivative of pyrazole is five-membered lacta
containing two nitrogens and ketone in the same molecule with molecular formula of
O. There are two possible isomers: 3-pyrazolone and 5
Fig. 3.II.1 Structure of pyrazolone
ne is an active moiety as pharmaceutical ingredient and refers to
inflammatory drugs (NSAID) used in the treatment of arthritis and
other musculoskeletal and joint disorders. Pyrazolone class (Fig. 3.II.2)
, oxyphenbutazone (II), dipyrone (III) as bio
antipyrine is an analgesic and antipyretic (IV). Pyrazolone derivatives,
as lactam structure related compounds, are also widely used in preparing dyes a
pigments. For example, 1-(2-chlorophenyl)-3-methyl-5-pyrazolone
intermediate to prepare dyes and pigments. 4-Aminoantipyrine or ampyrone
possibly can be used as an intermediate for the synthesis of pharmaceuticals
especially antipyretic and analgesic drugs. It is also used in the colorimetric
determination of phenols.
Knoevenagel-Michael Reaction
Michael Reaction
Heterocyclic compounds occur widely in nature and are essential to life.
heterocycles constitute the largest portion of chemical entities,
which are part of many natural products, fine chemicals and biologically active
pharmaceuticals essential for enhancing the quality of life [1]. High-throughput
promiscuous hits led to the elucidation of one hit class
and its derivatives, a class of well known nitrogen containing
heterocyclic compounds, occupy an important position in medicinal and pesticide
membered lactam ring compound
containing two nitrogens and ketone in the same molecule with molecular formula of
pyrazolone and 5-pyrazolone (Fig.
pharmaceutical ingredient and refers to
inflammatory drugs (NSAID) used in the treatment of arthritis and
(Fig. 3.II.2) includes
as bio-active molecules.
Pyrazolone derivatives,
as lactam structure related compounds, are also widely used in preparing dyes and
pyrazolone (V) is used as an
Aminoantipyrine or ampyrone (VI)
possibly can be used as an intermediate for the synthesis of pharmaceuticals
s also used in the colorimetric
CHAPTER 3 II: Synthesis of Pyrazolones by Tandem
Fig. 3.II.2 Bio-
Now days, the pyrazolone derivatives have been paid much attention because
of their propitious biological activities such as antitum
cytokine inhibitors [3-6]. Moreover, they are capable of prototropic tautomerism and
can be used as chelating agents for some metal ions and ligands [
3H-pyrazol-3-one derivatives including 4,4
1Hpyrazol-5-ols) being used as gastric secretion stimulatory, antidepressant,
antibacterial and antifilarial agents [
fungicides, pesticides, insecticides and dyestuffs [
Diverse approaches have been reported for the synthesis of
derivatives i.e. 4,4′-(arylmethylene)bis(3
conventional chemical approach to these bispyrazolones
Knoevenagel reaction of 1-phenyl
dihydro-3Hpyrazol-3-one) and aryl aldehydes to afford the corresponding
arylidenepyrazolones followed by base promoted Michael reaction [
hand, they have been also reported to be
Michael reaction of arylaldehydes with two equivalents of 1
5-one under variety of reaction conditions
Microwave-assisted organic synthesis has attracted considerable attention
because it leads to decreased reaction time, increased yield and easier work
2003, Bai et al. [22] reported microwave assisted synthesis of pyrazolone derivatives
under solvent free and catalyst
Shi and colleagues
condensation of aromatic aldehydes with 1
media using triethylbenzylammonium chloride (TEBA) as catalyst
Synthesis of Pyrazolones by Tandem Knoevenagel-Michael Reaction
118
-active molecules containing pyrazolone fragment
Now days, the pyrazolone derivatives have been paid much attention because
of their propitious biological activities such as antitumor, selective COX-2 inhibitory,
6]. Moreover, they are capable of prototropic tautomerism and
can be used as chelating agents for some metal ions and ligands [7-10]. 2,4
one derivatives including 4,4′-(arylmethylene)bis(3-methyl
ols) being used as gastric secretion stimulatory, antidepressant,
antibacterial and antifilarial agents [11-14]. In addition, they are also applied as
fungicides, pesticides, insecticides and dyestuffs [15-18].
Diverse approaches have been reported for the synthesis of
(arylmethylene)bis(3-methyl-1-phenyl-pyrazol-5-ols). First
chemical approach to these bispyrazolones involves the successive
phenyl-3-methylpyrazol-5-one (or 5-methyl-2-
one) and aryl aldehydes to afford the corresponding
arylidenepyrazolones followed by base promoted Michael reaction [19]. On the other
hand, they have been also reported to be prepared by one-pot tandem Knoevenagel
Michael reaction of arylaldehydes with two equivalents of 1-phenyl-3-methylpyrazol
variety of reaction conditions [20, 21].
assisted organic synthesis has attracted considerable attention
se it leads to decreased reaction time, increased yield and easier work
[22] reported microwave assisted synthesis of pyrazolone derivatives
under solvent free and catalyst free conditions.
Shi and colleagues [23] reported synthesis of these derivatives by
condensation of aromatic aldehydes with 1-phenyl-3-methylpyrazol-5-one in aqueous
media using triethylbenzylammonium chloride (TEBA) as catalyst (Scheme 3.II.1)
chael Reaction
active molecules containing pyrazolone fragment
Now days, the pyrazolone derivatives have been paid much attention because
2 inhibitory,
6]. Moreover, they are capable of prototropic tautomerism and
]. 2,4-Dihydro-
methyl-1-phenyl-
ols) being used as gastric secretion stimulatory, antidepressant,
]. In addition, they are also applied as
Diverse approaches have been reported for the synthesis of pyrazolone
ols). First
involves the successive
-phenyl-2,4-
one) and aryl aldehydes to afford the corresponding
]. On the other
pot tandem Knoevenagel-
methylpyrazol-
assisted organic synthesis has attracted considerable attention
se it leads to decreased reaction time, increased yield and easier work-up. In
[22] reported microwave assisted synthesis of pyrazolone derivatives
of these derivatives by
one in aqueous
(Scheme 3.II.1).
CHAPTER 3
Wang et al. [24
l-phenyl-5-pyrazolone with aromatic and aliphatic aldehydes in water at refluxing
temperature using sodium dodecyl sulfate (SDS) as the surfactant catalyst
3.II.2).
In 2008, Elinson and associates synthesized these derivatives using
electrolysis method [25].
Recently, the use of ceric ammonium nitrate has received considerable
attention as it is an inexpensive, non
providing excellent yields. K. Sujatha and group [
friendly method for the synthesis of 4,4
tandem Knoevenagel–
in water at ambient temperature and also illustrated its mechanism
Synthesized compounds further evaluated for in vitro antiviral activity a
des petits ruminant virus (PPRV).
CHAPTER 3 II: Synthesis of Pyrazolones by Tandem Knoevenagel
119
Scheme 3.II.1
[24] disclosed the environmentally friendly synthesis of 3
pyrazolone with aromatic and aliphatic aldehydes in water at refluxing
temperature using sodium dodecyl sulfate (SDS) as the surfactant catalyst
Scheme 3.II.2
008, Elinson and associates synthesized these derivatives using
electrolysis method [25].
Recently, the use of ceric ammonium nitrate has received considerable
attention as it is an inexpensive, non-toxic catalyst for various organic transformations
ing excellent yields. K. Sujatha and group [26] developed an efficient and eco
friendly method for the synthesis of 4,4′-(arylmethylene)bis(1H
–Michael reaction in presence of ceric ammonium nitrate (CAN)
in water at ambient temperature and also illustrated its mechanism
Synthesized compounds further evaluated for in vitro antiviral activity a
des petits ruminant virus (PPRV).
Scheme 3.II.3
Knoevenagel-Michael Reaction
] disclosed the environmentally friendly synthesis of 3-methyl-
pyrazolone with aromatic and aliphatic aldehydes in water at refluxing
temperature using sodium dodecyl sulfate (SDS) as the surfactant catalyst (Scheme
008, Elinson and associates synthesized these derivatives using
Recently, the use of ceric ammonium nitrate has received considerable
toxic catalyst for various organic transformations
6] developed an efficient and eco-
H-pyrazol-5-ols) by
Michael reaction in presence of ceric ammonium nitrate (CAN)
in water at ambient temperature and also illustrated its mechanism (Scheme 3.II.3).
Synthesized compounds further evaluated for in vitro antiviral activity against peste
CHAPTER 3 II: Synthesis of Pyrazolones by Tandem Knoevenagel-Michael Reaction
120
Natural biopolymers are attractive candidates in the search for solid support
and provide reusable and heterogeneous design for catalyst preparation and can be
efficiently used in organic reactions as it can be easily separated, reused and not
contaminated by the products. In this connection, Mosaddegh et al. [27] prepared an
inexpensive biopolymer-based catalyst cellulose sulfuric acid (CSA) and successfully
applied for synthesis of tandem Knoevenagel-Michael reaction (Scheme 3.II.4).
N
N
H3C
O
Ph
N
N N
N
ArH3C CH3
PhPh
Ar-CHO
OH HO
cellulose sulfuric acid
H2O/ethanol, reflux
+2
Scheme 3.II.4
K. Niknam and co-workers [28] developed supported silica-bonded S-sulfonic
acid (SBSSA) (Scheme 3.II.5) and employed as recyclable catalyst for the
condensation reaction of aromatic aldehydes with 3-methyl-l-phenyl-5-pyrazolone.
This condensation reaction was performed in ethanol under refluxing conditions
giving 4,4′-alkylmethylene-bis(3-methyl-5-pyrazolones) in 75–90% yields.
Scheme 3.II.5
The research of ionic liquids is developed at a booming speed during past
decade because of their properties such as practical nonvolatility, low melting point as
well as good electrochemical and thermal stability. Zang et al. [29] reported an
unexpected synthesis of 4-[(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-phenyl-
methyl]-5-methyl-2-phen-yl-1,2-dihydro-pyrazol-3-ones through the condensation
reaction of arylaldehydes and 3-methyl-1-phenyl-5-pyrazolone for the first time in the
presence of Brφnsted acidic ionic liquid [HMIM]HSO4 in refluxing ethanol (Scheme
3.II.6). Same group [30] reported this synthesis at ambient temperature with the aid of
ultrasound technique as it has been considered as a clean and useful protocol as
CHAPTER 3
compared to traditional methods because of the typical features such as accelerating
organic reactions, easier manipulation and being more convenient
Silica sulfuric acid
inexpensive, solid Brønsted acid catalyst. This heterogeneous catalyst can be easily
separated from the reaction media, has greater selectivity, recyclable, easier to handle,
more stable, nontoxic, and insoluble in organic solvents. Niknam and associate
utilised this silica sulfuric acid (SSA) for the condensation reaction of aromatic
aldehydes with 3-methyl
(Scheme 3.II.7).
In 2012, Niknam and colleagues
imidazolium hydrogen sulfate ([Sipmim]HSO
acid catalyst and applied for the synthesis of 4,4
pyrazolones) by tandem Knoevenagel
3.II.8).
CHAPTER 3 II: Synthesis of Pyrazolones by Tandem Knoevenagel
121
compared to traditional methods because of the typical features such as accelerating
organic reactions, easier manipulation and being more convenient (Scheme 3.II.6)
Scheme 3.II.6
Silica sulfuric acid (SSA) has been widely used as reusable, heterogeneou
inexpensive, solid Brønsted acid catalyst. This heterogeneous catalyst can be easily
separated from the reaction media, has greater selectivity, recyclable, easier to handle,
more stable, nontoxic, and insoluble in organic solvents. Niknam and associate
utilised this silica sulfuric acid (SSA) for the condensation reaction of aromatic
methyl-l-phenyl-5-pyrazolone in water-ethanol (1:1) at 70
Scheme 3.II.7
In 2012, Niknam and colleagues [32] envisaged N-(3-silicapropyl)
imidazolium hydrogen sulfate ([Sipmim]HSO4) (Fig. 3.II.3) as heterogeneous solid
pplied for the synthesis of 4,4′-alkylmethylene
pyrazolones) by tandem Knoevenagel-Michael reaction in refluxing e
Fig. 3.II.3 Synthesis of [Sipmim]HSO4 catalyst
Knoevenagel-Michael Reaction
compared to traditional methods because of the typical features such as accelerating
(Scheme 3.II.6).
reusable, heterogeneous,
inexpensive, solid Brønsted acid catalyst. This heterogeneous catalyst can be easily
separated from the reaction media, has greater selectivity, recyclable, easier to handle,
more stable, nontoxic, and insoluble in organic solvents. Niknam and associates [31]
utilised this silica sulfuric acid (SSA) for the condensation reaction of aromatic
ethanol (1:1) at 70 oC
silicapropyl)-N-methyl
as heterogeneous solid
alkylmethylene-bis(3-methyl-5-
in refluxing ethanol (Scheme
catalyst
CHAPTER 3 II: Synthesis of Pyrazolones by Tandem Knoevenagel-Michael Reaction
122
Scheme 3.II.8
A. Khazaei et al. [33] disclosed a green, simple and efficient method for the
synthesis of 4,4′-(arylmethylene)-bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s by the
condensation of 1-phenyl-3-methylpyrazol-5-one with aromatic aldehydes using 1,3-
disulfonic acid imidazolium tetrachloroaluminate {[Dsim]AlCl4} as new,
heterogeneous and reusable catalyst (Scheme 3.II.9).
Scheme 3.II.9
3.II.2 Present Work
The important advantage by the use of biosurfactants as a reaction media is to
eliminate the toxic organic solvents from organic synthesis. Biosurfactants act as
greener solvents for organic synthesis and are inexpensive as they are obtained from
renewable plant materials, non-toxic and easily biodegradable. They are surface active
and have ability to solubilise the sparingly soluble and practically insoluble organic
compounds in aqueous medium. Thus, it can replace chemical surfactants in organic
synthesis and serve as a green alternative to volatile organic solvents. This advatage is
more beneficial in the area of synthetic chemistry to carry out organic transformation
in aqueous medium.
In the present work, an operationally simple, inexpensive, efficient and
environmental friendly protocol for the synthesis of 4,4′-(arylmethylene)-bis(3-
methyl-1-phenyl-1H-pyrazol-5-ol)s using the 1 % biosurfactant solution in water at 80
°C has been reported (Scheme 3.II.10). It can be expected that these results will open
new perspectives for the use of biosurfactants in the field of synthetic organic
chemistry.
CHAPTER 3 II: Synthesis of Pyrazolones by Tandem Knoevenagel-Michael Reaction
123
Scheme 3.II.10
3.II.3 Results and Discussion
To optimize the reaction conditions, the reaction of 3-methyl-1-phenyl-5-
pyrazolone 1 (2 mmol) and 4-chlorobenzaldehyde 2 (1 mmol) was taken as model
reaction. To this added 5 mL (100 %) aqueous extract of Balanites Roxburghii fruit
and stirred at 80 oC in preheated oil bath. Initially Knoevenagel condensation
proceeded rapidly within two minutes to furnish 1:1 product i.e. orange coloured
arylidenepyrazolone which was converted to final white product through Michael step
within 30 minutes. On the completion of reaction as monitored by TLC, the reaction
mixture was diluted with cold water and product separated out. The filtration of
reaction mixture and washing with water and ethanol afforded the corresponding
product of high purity which displayed correct 1H NMR and 13C NMR spectra.
With these results in hand, we determined the optimum concentration for
maximum conversion of the reactants in water to give maximum yield of the product.
Thus the model reaction was carried out with various concentrations (% v/v) of
aqueous extract of Balanites Roxburghii fruit. After sufficient screening, we opted 1
% solution was efficient to catalyse the reaction. Constant yield of product as well as
constant pH of catalytic solution was observed in each case ranging from 100-1 %
indicating the buffering action of catalytic solution which renders for recyclability
performance of catalyst.
A controlled reaction conducted in water under identical conditions without
catalyst could not convert starting materials into quantitative amount of corresponding
product, despite the prolonged reaction times indicates role of biocatalyst is decisive
(Scheme 3.II.11).
NN
H3C
O
Ph
N
N N
N
ArH3C CH3
Ph Ph
Ar-CHO
OH HO
aq. fruit extract
80 oC+2 1
waterrefluxNo reaction
Scheme 3.II.11
N
N
H3C
O
Ph
N
N N
N
ArH3C CH3
Ph Ph
Ar-CHO
OH HO
aq. fruit extract
80 oC+
1 2 3
2 1
CHAPTER 3 II: Synthesis of Pyrazolones by Tandem Knoevenagel-Michael Reaction
124
After the optimization of concentration, a series of structurally diverse aryl
aldehydes were treated with 3-methyl-1-phenyl-5-pyrazolone in 1 % aqueous extract
at 80 oC temperature (Table 3.II.1). The reactions proceeded with this optimized
conditions within 20-60 minutes affording the desired products in excellent yields.
The aryl aldehydes bearing electron-donating as well as electron-withdrawing groups
underwent reactions successfully. In addition, heteroaromatic aldehyde such as
thiophene-2-aldehyde reacted efficiently furnishing anticipated product in good yield.
The method is also suitable for the sterically hindered 1-naphthaldehyde. Pure
products were obtained after recrystallization in ethanol which were then
characterised by their physical constants and spectral techniques. In IR spectrum of all
the compounds characteristic broad absorption in the region 2500-2600 cm-1 was
noticed for the H-bonded enolic OH and carbonyl absorption was absent indicating
that the pyrazolonyl group in all compounds exists in enol form [34].
Table 3.II.1 Tandem Knoevenagel-Michaela synthesis catalysed by aqueous extract
of Balanites roxburghii fruit
Sr. No.
Aldehyde Product Time (min)
Yield (%)
MP. oC [Lit.]c
1
15
90
170-171 [169-171]30
2
20
93
200-202 [203]34
CHO
N
NN
N
Ph PhOH HO
CHO
CH3
N
NN
N
Ph PhOH HO
CH3
CHAPTER 3 II: Synthesis of Pyrazolones by Tandem Knoevenagel-Michael Reaction
125
3
30
90
148-150 [148]34
4
20
92
235-236 [235-237]30
5
20
90
215-217 [214-217]30
6
25
88
215-217 [215]34
7
25
85
180-182 [182]34
CHO
OCH3
N
NN
N
Ph PhOH HO
OCH3
CHO
Cl
N
NN
N
Ph PhOH HO
Cl
CHO
Cl
N
NN
N
Ph PhOH HO
Cl
CHO
Br
N
NN
N
Ph PhOH HO
Br
CHO
F
N
NN
N
Ph PhOH HO
F
CHAPTER 3 II: Synthesis of Pyrazolones by Tandem Knoevenagel-Michael Reaction
126
8
25
83
218-220 [218-220]30
9
30
89
220-222 [221-222]30
10
50
86
151-153 [151-153]30
11
35
90
247-250
12
60
87
208-210
13
25
89
183-185
CHO
NO2
N
NN
N
Ph PhOH HO
NO2
CHO
NO2
N
NN
N
Ph PhOH HO
NO2
CHO
NO2
N
NN
N
Ph PhOH HO
NO2
CHO
CHO
N
NN
N
Ph PhOH HO
CHO
CHO
N
NN
N
Ph PhOH HO
S
CHO
N
NN
N
Ph PhOH HO
S
CHAPTER 3 II: Synthesis of Pyrazolones by Tandem Knoevenagel-Michael Reaction
127
aAll products were characterized by IR, 1H NMR, 13C NMR spectroscopy and elemental analysis technique. bIsolated yields. cLiterature values in parenthesis.
The exceptionally higher catalytic activity of biosurfactant can be related to its
ability to form micelles in water which turned the reaction mixture turbid. The
formation of micelles i.e. colloidal aggregates was confirmed on the basis of optical
microscopy (Fig. 3.II.4).
Fig. 3.II.4 Optical micrograph of reaction mixture
The role of micelle to catalyze the reaction can be explained as shown in Fig.
3.II.5. As the impact of micellar solution, reactants i.e. pyrazolone 1 and aldehyde 2
aggregates and pushed away from water molecules towards the hydrophobic core of
micelle which leads to the effective and efficient collision and the hydrophobic
interior of micelle removes water generated during the progress of reaction to give
corresponding Knoevenagel product 3. 3 react further with another molecule of
pyrazolone with shifting of equilibrium towards formation of desired product 4 with
excellent yield.
H O
RN
N
Ph
HO
+
..
...H+
NN
R
O
Ph
...H+NN OH
Ph
...
NN
Ph
R
N
N
PhOH
OH
-H2O -H2O
1
2 3 4
Fig. 3.II.5 Mechanistic picture of bispyrazolone formation
CHAPTER 3 II: Synthesis of Pyrazolones by Tandem Knoevenagel-Michael Reaction
128
To assess the reusability of biosurfactant, recycling experiments were carried
out with 4-chlorobenzaldehyde and 3-methyl-1-phenyl-5-pyrazolone as substrates
over the four reaction cycles. After each experiment, the aqueous solution of catalyst
was recovered by filtration, washed thoroughly with diethyl ether, concentrated and
then subjected to a new run with fresh reactants under identical reaction conditions.
As the aqueous solution of biosurfactant exhibited the constant pH because of the
buffering action, it showed remarkable ‘in-flask’ recyclability without change in yield
of product.
Characterisation of products:
4,4′-[(4-chlorophenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) (Table
3.II.1, Entry 5)
N
N N
N
H3C CH3
Ph PhOH HO
Cl
4.86
2.312.31
13.69
N
N N
N
H3C CH3
Ph PhOH HO
Cl
33.1
11.811.8
1H NMR 13C NMR
In IR spectrum (Fig. 3.II.6) characteristic broad absorption peak exhibited for
H-bonded enolic OH group at 2553 cm-1 and C=C vibrations appeared at 1598 cm-1.
In 1H NMR spectrum (Fig. 3.II.7) sharp singlet at δ 2.31 ppm observed for six
protons of two methyl groups and methine proton noticed as sharp singlet at 4.86
ppm. Six aromatic protons exhibited doublet at 7.18 ppm, four protons at 7.37 ppm in
the form of triplet followed by remaining four protons in the form of doublet. A broad
peak noticed at 13.69 ppm which corresponds to one OH proton. In 13C spectrum
(Fig. 3.II.8) peak observed at 11.8 ppm for two symmetric methyl carbons while
methine carbon noticed at 33.1 ppm. All aromatic carbons appeared in aromatic
region at δ 120.9, 125.6, 128.2, 128.8, 129.1, 131.5, 137.6, 140.7 and 145.9 ppm.
4,4′-[(2-formyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) (Table 3.II.2,
Entry 11)
CHAPTER 3 II: Synthesis of Pyrazolones by Tandem Knoevenagel-Michael Reaction
129
N
N N
N
H3C CH3
Ph PhOH HO
CHO2.342.34
4.96
9.92
13.80
N
N N
N
H3CCH3
Ph PhOH HO
CHO11.9
33.5
11.9192.6
1H NMR 13C NMR
In IR spectrum (Fig. 3.II.9) characteristic broad absorption peak exhibited for
H-bonded enolic OH group at 2552 cm-1 and C=C vibrations appeared at 1598 cm-1
while carbonyl frequency appeared at 1688 cm-1. In 1H NMR spectrum (Fig. 3.II.10)
sharp singlet at δ 2.34 ppm observed for six protons of two methyl groups and
methine proton noticed as sharp singlet at 4.96 ppm. A triplet at 7.18 ppm observed
for two aromatic protons followed by other triplet for four aromatic protons at 7.37
ppm. One aromatic proton also resonated in the form of triplet at 7.45 followed by
doublet at 7.57 for one proton. Six aromatic protons exhibited triplet at 7.67 ppm.
Aldehydic proton observed at 9.92 ppm along with a broad peak at 13.80 ppm which
corresponds to one OH proton. In 13C spectrum (Fig. 3.II.11) peak observed at 11.9
ppm for two symmetric methyl carbons while methine carbon noticed at 33.5 ppm.
All aromatic carbons appeared in aromatic region at δ 104.7, 120.9, 125.7, 127.8,
128.5, 128.9, 129.1, 133.8, 136.5, 137.6, 143.5, 146.1 and 157.6 ppm while carbonyl
carbon appeared at 192.6 ppm confirming the formation of correct structure of the
product.
4,4′-[(2-thienyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) (Table 3.II.1,
Entry 13)
N
N N
N
H3C CH3
Ph PhOH HO
S 2.32
5.04
2.32
13.88
N
N N
N
H3C CH3
Ph PhOH HO
S 11.8
30.7
11.8
1H NMR 13C NMR
IR spectrum (Fig. 3.II.12) exhibited characteristic broad absorption peak for
H-bonded enolic OH group at 2600 cm-1 and for C=C vibrations at 1595 cm-1. In 1H
CHAPTER 3 II: Synthesis of Pyrazolones by Tandem Knoevenagel-Michael Reaction
130
NMR spectrum (Fig. 3.II.13) sharp singlet at δ 2.32 ppm observed for six protons of
two methyl groups and methine proton noticed as sharp singlet at 5.04 ppm. One
aromatic proton resonated in the form of doublet at 6.74 ppm followed by singlet for
one proton at 6.84 ppm. Three aromatic protons appeared as triplet at 7.17-7.22
followed by second triplet for four protons at 7.37-7.41 ppm. Remaining four protons
appeared as doublet at 7.70-7.73 along with broad peak at 13.88 ppm for OH proton.
In 13C spectrum (Fig. 3.II.14) peak observed at 11.8 ppm for two symmetric methyl
carbons while methine carbon noticed at 30.7 ppm. All aromatic carbons appeared in
aromatic region at 120.8, 124.0, 124.9, 125.7, 126.9, 128.9, 145.7, 147.6 ppm
respectively.
3.II.4 Conclusion
In summary, our synthetic pathway complies with several key requirements of
green chemistry principles such as elimination of organic solvents, practically nil
waste, simple work-up procedure and non-toxic, safer reaction medium along with
excellent recyclability of biosurfactant. Importance of promiscuity concept in
biocatalysis is noteworthy, since it not only highlights the existing catalysts, but may
provide novel and practical synthetic pathways which are not currently available.
3.II.5 Experimental Section
Solvents and reagents were commercially sourced from Sigma Aldrich and
Spectrochem and used without further purification. Melting points were determined in
an open capillary and are uncorrected. Infrared spectra were obtained on Perkin Elmer
FT-IR spectrometer. The samples were examined as KBr discs ~5 % w/w. 1H NMR
and 13C NMR spectra were recorded on Bruker Avon 300 spectrometer using DMSO-
d6 as solvent and TMS as internal reference. Elemental analysis was carried out using
Uro EA 3000 Vectro model. Optical micrograph was taken using ordinary light
microscope (Leica DM 2000) under 100 × magnifications.
General procedure for synthesis of 4,4′-(arylmethylene)-bis(3-methyl-1-phenyl-1H-
pyrazol-5-ol)
In 100 mL round bottom flask 3-methyl-l-phenyl-5-pyrazolone or 5-methyl-2-
phenyl-2,4-dihydro-3H-pyrazol-3-one (2 mmol) and aldehyde (1 mmol) were placed
in 5 mL catalytic biosurfactant solution and stirred at 80 oC temperature in oil bath till
the completion of reaction as indicated by TLC. The solid products were separated by
CHAPTER 3 II: Synthesis of Pyrazolones by Tandem Knoevenagel-Michael Reaction
131
simple filtration. Crude products were then washed with water and then recrystallised
from ethanol. All synthesized compounds were confirmed by physical constants and
characterized by spectral analysis. The physical and spectroscopic data are in
consistent with the proposed structures and literature data.
Spectral data of representative compounds:
4,4′-(phenylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) (Table 3.II.1,
Entry 1) Pale yellow solid; mp 170-172 °C.
IR (KBr): υ = 2620 (OH), 1615, 1489, 780 cm-1. 1H NMR (300 MHz, DMSO-d6): δ = 2.30 (s, 6H, CH3), 4.98 (s, 1H, CH), 7.12-7.16
(m, 1H, ArH), 7.21-7.25 (m, 6H, ArH), 7.38-7.42
(t, 4H, ArH), 7.58-7.62 (d, 4H, ArH) ppm. 13C NMR (75 MHz, DMSO-d6): δ = 12.0, 33.5, 121.3, 126.4, 126.5, 127.7, 128.7,
129.5, 137.4, 142.5, 146.8 ppm.
Elemental Analysis requires: C, 74.29; H, 5.54; O, 7.33; N, 12.84 %.
(C27H24O2N4): found: C, 74.31; H, 5.55; O, 7.38; N, 12.78 %.
4,4′-[(1-naphthyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) (Table
3.II.1, Entry 12) White solid; mp 208-210 °C.
IR (KBr): υ = 2585 (OH), 1608, 1544, 1497, 784 cm-1. 1H NMR (300 MHz, DMSO-d6): δ = 2.32 (s, 6H, CH3), 5.52 (s, 1H, CH), 7.33-7.42
(m, 17H, ArH) ppm. 13C NMR (75 MHz, DMSO-d6): δ = 12.2, 31.4, 106.0, 120.5, 123.7, 125.4, 125.5,
126.1, 126.2, 127.4, 129.0, 129.1, 129.1, 131.2,
134.1, 137.0, 137.7, 146.1, 158.8 ppm.
Elemental Analysis requires: C, 76.52; H, 5.39; O, 6.58; N, 11.51 %.
(C31H26O2N4): found: C, 76.48; H, 5.35; O, 6.60; N, 11.53 %.
132
Fig. 3.II.6 IR spectrum of 4,4'-[(4-chlorophenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)
133
Fig. 3.II.7 1H NMR spectrum of 4,4'-[(4-chlorophenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)
134
Fig. 3.II.8 13C NMR spectrum of 4,4'-[(4-chlorophenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)
135
Fig. 3.II.9 IR spectrum of 4,4'-[(2-formyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)
136
Fig. 3.II.10 1H NMR spectrum of 4,4'-[(2-formyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)
137
Fig. 3.II.11 13C NMR spectrum of 4,4'-[(2-formyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)
138
Fig. 3.II.12 IR spectrum of 4,4'-[(2-thienyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)
139
Fig. 3.II.13 1H NMR spectrum of 4,4'-[(2-thienyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)
140
Fig. 3.II.14 13C NMR spectrum of 4,4'-[(2-thienyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)
CHAPTER 3: Synthesis of Pyrazolones by Tandem Knoevenagel-Michael Reaction
141
3.II.7 References
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Oda, Y. Yamazaki, M. Nishikawa, S. Takemura, T. Doi, Y. Yoshinori, M.
Ohkuchi, U. S. Patent 983,928, 2003.
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Heterocycl. Chem., 2002, 39, 869; (b) X. H. Liu, P. Cui, B. A. Song, P. S.
Bhadury, H. L. Zhu, S. F. Wang, Bioorg. Med. Chem., 2008, 16, 4075; (c) E.
Akbas, I. Berber, Eur. J. Med. Chem., 2005, 40, 401; (d) P. Schmidt, K.
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R. W. Hartmann, T. Sergejew, G. L. Grun, D. Ledergerber, J. Med. Chem.,
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Djung, M. G. Natchus, B. De, L. C. Hsieh, S. C. Xu R. L. Walter, M. J.
Mekel, S. A. Heitmeyer, K. K. Brown, K. Juergens, Y. O. Taiwo, M. J.
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