CHAPTER 3 Section-I Synthesis of 2-Arylideneindane -1,3 ...shodhganga.inflibnet.ac.in/bitstream/10603/44933/9/... · condensation of ethyl acetate and dimethyl phthalate (Scheme 3.I.11)

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



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


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



philic addition of

active methylene compounds like malononitrile, barbituric acid, Meldrum’s acid,

to carbonyls followed by dehydration to


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



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


(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).


chemistry and highly pronounced pharmacological properties



] reported condensation of aromatic aldehydes with active

acid in water

] were successful in carrying out uncatalysed


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


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.


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


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


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


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).


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


nthesized compounds

cyanoacetylindole

as active methylene compound employing triphenylphosphine catalyst at room

used further to react with DMS


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


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).


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


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


Scheme 3.I.12


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


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



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


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


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


ganic transformations using biosurfactant as catalyst and reaction



mentally friendly. In present work, as the source of biosurfactant, we

Balanites roxburghii i.e. Hingota because of its high natural


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



Sapindus trifoliatus fruits [49].

Fig. 3.I.5 Structure of saponin


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


atalyst and reaction



of biosurfactant, we

because of its high natural


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




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)


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


97

Fig. 3.I.7 Coloured products

h these results in hand, we determined the optimum concentration for


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



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



carried out the model reaction using sodium dodecyl sulphate (SDS). Both reactions

proceeded same with respect to time and yield. As natural surfactant is


concentration of SDS by dilution, greatly affected the yield of product.


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


determined the optimum concentration for


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



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



phate (SDS). Both reactions

ield. As natural surfactant is recyclable



catalyst gave no corresponding product, despite the prolonged reaction

eries of structurally diverse aryl

indanedione in 1 % aqueous extract at ambient


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.


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


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


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.


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.


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


114

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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


heterocycles constitute the largest portion of chemical entities,


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


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


especially antipyretic and analgesic drugs. It is also used in the colorimetric

determination of phenols.

Knoevenagel-Michael Reaction

Michael Reaction


heterocycles constitute the largest portion of chemical entities,


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


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)


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


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


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).


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].


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


] 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


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).


121


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



more stable, nontoxic, and insoluble in organic solvents. Niknam and associate


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



(Scheme 3.II.6).

reusable, heterogeneous,



more stable, nontoxic, and insoluble in organic solvents. Niknam and associates [31]


ethanol (1:1) at 70 oC

silicapropyl)-N-methyl

as heterogeneous solid

alkylmethylene-bis(3-methyl-5-

in refluxing ethanol (Scheme

catalyst


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.


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


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


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


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


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


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


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)


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


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


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

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Documents

CHAPTER 3 Section-I Synthesis of 2-Arylideneindane -1,3 ...shodhganga.inflibnet.ac.in/bitstream/10603/44933/9/... · condensation of ethyl acetate and dimethyl phthalate (Scheme 3.I.11)