Abstract
ABSTRACT
The thesis entitled “Synthesis and Biological Evaluation of New
Heterocyclic
compounds
and
Development
of
New
Synthetic
Methodologies” is divided in to six Chapters. Chapter 1 contains an over view of
the pesticides, heterocyclic compounds and phasetransfer catalyst. Chapter 2
provides synthesis of new thiadiazolyl derivatives containing imidazolidin
taxophore akin to imidacloprid. Chapter 3 describes the synthesis of new
isoxazolyl triazole derivatives as fungicides. Chapter 4 is divided into Section A
and Section B that describes the preparation and use of new phasetransfer
catalyst and the preparation of novel 2-isoxazolyl benzimidazole derivatives
respectively. Chapter 5 contains Section A and Section B dealing respectively on
one pot synthesis of 2,3-dihydropyrimidinone derivatives (Biginelli compounds)
and the preparation of 1,5-benzodiazepine derivatives. Chapter 6 describes
studies on the biological activity of new heterocyclic compounds reported in this
thesis.
CHAPTER 1: Introduction
This introductory chapter will attempt to bring out some of the highlights of
heterocyclic compounds particularly of pesticidal importance and the significance
of phase transfer and other catalysis in the area of organic chemistry, from
literature. This chapter reviews the history, importance and classification of
pesticides and discusses briefly about their economic importance in the farming
sector. The crop protection chemicals widely used in agriculture to control various
pests are classified as insecticides, fungicides, rodenticides, herbicides and
fumigants depending upon their mode of activity. Among pesticides, insecticides
are widely used chemicals to control various diseases caused by different insects.
Nitrogen, oxygen and sulfur containing heterocyclic compounds are key
building blocks used to develop compounds of biological or medicinal interest to
chemists. A vast number of nitrogen containing heterocyclic building blocks have
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Abstract
applications in pharmaceuticals and agrochemical research and drug discovery.
Heterocyclic compounds also have a practical use as components in dyes,
antioxidants, copolymers, bases, and ligands.
The
present
work
explains
synthesis
of
thiadiazole,
isoxazole,
benzimidazole, dihydropyrimidinones, and benzodiazepine derivatives, and their
biological importance such as insecticidal and fungicidal properties. An attempt
has been made to bring out the importance of phase transfer catalysis.
CHAPTER 2: Synthesis of new thiadiazolyl derivatives containing imidazolidin taxophore akin to imidacloprid
This chapter deals with the synthesis of 1,2,3-thiadazolyl imidazole
derivatives as neo nicotinoid insecticides. This study relates in essence to N-(4aryl-5-1,2,3-thiadiazolylmethyl)-2-nitroiminoimidazoline
derivatives.
Retro
synthetic analysis of target molecules requires appropriately substituted propio
and valerophenones as starting materials for 1,2,3-thiadiazole derivatives and 2nitroimino imidazole as an intermediate. The semicabzones of propio and valerophenone (2a-k) are cyclised with thionyl chloride to obtain 5-alkyl-4-aryl-1,2,3thiadiazole (3a-k), which is further transformed into 1-oxo-2-1-[1-(4-aryl-1,2,3thiadiazol-5-yl)methyl/propyl]-tetrahydro-1H-2-imidazolyliden-1-hydraziniumolate
(6a-p). The sequence of synthetic methodology is depicted in Scheme 1.
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Abstract
NH-NH-CONH 2
O
NH2-NH-CO-NH2.HCl
NaOAc
DMF
R
R1
N N
S
SOCl2
R
R
R1
1a-k
R1
2a-k
3a-k
NBS / CCl4
peroxide
N N
S
R
1
R
N
NH
N
6a-k
N N
S
K2CO3 / CH3CN
R
HN
NO 2
1
NH
R
N
4a-k
NO 2
5
Br
R = H, 4-Cl, 4-Br, 4-F, 4-OMe, 3-Br, 2-Cl. R1 = H, C2H5.15 Compounds
Scheme 1
The formation and characterization of unusual compound (6 l-p) obtained in the
condensation
of
4-aryl-5-(1-bromopropyl)-1,2,3-thiadiazole
with
2-nitroimine
imidazole is described (Scheme 2).
N N
S
R
+
Br
HN
NH
N
K2CO3
CH3CN/ heat
+ R
R
NH
N
NO 2
CH 3
4g-k
N N
S
N N
S
CH 3
6 g-k
5
N
N
CH 3
NO 2
NH
N
NO 2
6 l-p
Scheme 2
CHAPTER 3: Synthesis of isoxazolyltriazole derivatives as fungicides
With a view to obtaining biologically active isoxazole derivatives containing
triazole moiety, synthesis of a series of compounds have been conceived and the
synthetic strategy is described in the Scheme 3. The triazole moiety has been
found to be an important taxophore to exhibit fungitoxic properties inhibiting the
cell wall synthesis and also known as C-14 demethylation inhibitor (to act as
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Abstract
fungicide). Most of the exploited azole fungicides contain an aromatic ring system,
and to the best of the author’s knowledge no compound with isoxazole
heterocyclic moiety has so for been synthesized and studied for their fungitoxic
properties.
O
O
COOEt
CH 3 COOEt
R
R
NaOMe
MeOH
7a-k
O
8a-k
O
COOEt (NH2-OH)2 H2SO4
R
MeOH
Transesterification
N
COOMe
9a-k
NaBH4
AlCl3 ,THF
Reflux
O
O
N
CH2Cl
R
N
K2CO3
HN
Acetonitrile
N
N
SOCl2, DMF
Heptane
0
65-80C
CH2OH
R
11a-k
10a-k
12
O
N
N
N
N
R
R = H, 2-Cl, 2-OMe, 3-Cl, 3-OMe, 4-Me, 4-Cl, 4-Br, 4-F, 4-OMe, 2,4-diOMe.
13a-k
Scheme 3
The target molecule 5-aryl-3-(4H-1,2,4-triazol-4-yl methyl) isoxazole (13ak) is prepared by N-alkylation of 1H-1,2,4-triazole (12) with 5-aryl-3-chloromethylisoxazole under mild basic conditions using different bases in polar solvent
(Scheme 5). The yields obtained are in the range of 80-90 %. The possibility of
formation of C-4 alkylated product is ruled out based on the unequivocal
characterization of the product using spectral data.
O
N
HN
CH 2Cl +
R
11a-k
N
N
O
K2CO3, CH3CN
Reflux
12
N
N
N
R
13a-k
R = H, 2-Cl, 2-OMe, 3-Cl, 3-OMe, 4-Me, 4-Cl, 4-Br, 4-F, 4-OMe, 2,4-diOMe.
Scheme 4
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N
Abstract
CHAPTER 4:
Section A: Preparation of new phasetransfer catalyst and its applications
Many of the industrially and economically important organic chemical
intermediates
and
biologically
significant
compounds
require
in
their
production/process the use of high yielding procedures with little or no pollution.
Phase transfer catalysis permits or accelerates reactions between ionic
compounds and water insoluble organic substrates by transferring the ionic
compounds into organic medium in the form of ionic pairs. A need arose to search
for developing a new and simple quaternary ammonium salt, such that the same
may be used as a phase transfer catalyst in the ongoing some of the process
development work under taken at IICT. In view of this a simple N-butyl-N,Ndimethyl--phenylethyl ammonium bromide catalyst has been prepared and its
utility as phase transfer catalyst in various organic transformations is exploited
and the results are reported in this chapter.
The compound N-butyl- N,N-dimethyl--phenylethylammonium bromide
(16) was prepared starting from -phenyl ethyl amine (14) by using formic acid
and formaldehyde to get N,N-dimethyl- -phenylethylamine (15) followed by
reaction with n-butyl bromide (Scheme 5).
CH 3
H
14
NH 2
CH 3
CH 3
N
CH 3
HCHO/HCOOH
Heat
15
CH 3
n-BuBr
Heat
Br
16
CH 3
CH 3
-N
CH 3
Scheme 5
This catalyst is used in esterification reactions of esfenvalarate and cypermethrin,
oxidation of aryl carbinols and alkylation of phenols
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Abstract
Section B: Preparation of 2-isoxazolyl benzimidazole derivatives
Some of the benzimidazole derivatives containing a heterocyclic moiety at
2-position are thiabendazole (17) and cambendazole (18) which are commercially
important.
N
i-PrOCOHN
N
S
N
H
N
N
S
N
H
Cambendazole (18)
Thiabendazole (17)
The present work aims to synthesize novel 2-isoxazolyl substituted benzimidazoles using N-butyl-N,N-dimethyl--phenylethylammonium bromide (16) as
the catalyst. Retro synthetic analysis of target molecules requires appropriately
substituted 5-aryl-3-isoxazol carbaldehyde (19a-i) as an active intermediate. The
sequence of synthetic methodology is depicted below (Scheme 6) and each step
of synthesis has been discussed in detail. The reaction of o-phenylenenediamine
(OPDA) and 5-aryl-3-isoxazolecarbaldehyde at reflux temperature of 1,2dichloroethane in the presence of 10 mol % of catalyst for 3-4 hours to give title
compounds (21a-m).
O N
O N
COOMe
R1
R1
NH 2
CHO
+
Reduction
R
9 a-i
NH 2
20
19a-i
Catalyst / DCE
reflux, 3-4 h.
O N
R1
H
N
N
21 a-m
R1 = H, 2-Cl, 3-Cl, 3-OMe, 4-Me, 4-Cl, 4-Br, 4-F, 4-OMe. R = H, OMe.
Scheme 6
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R
Abstract
Chapter 5: Development of new synthetic methodologies: ZrCl4 catalyzed
reactions
Zirconium tetrachloride is a relatively weak Lewis acid, and used as
catalyst in Friedal-Crafts reaction, Diels-Alder reactions, asymmetric Diels-Alder
reactions, [2+2]-adduct formation and in intramolecular cyclisation. This Lewis
acid is used as an efficient catalyst in the preparation of dihydropyrimidinones and
1,5-benzodiazepine derivatives.
Section A: One pot synthesis of 2,3-dihydropyrimidinone derivatives
(Biginelli compounds)
Dihydropyrimidinones (Biginelli compounds) exhibits a diverse range of
biological activities such as calcium channel blockers, anticarcinogenic, antiinflammatory activity etc.
The reaction of benzaldehyde (22), ethylacetoacetate (23) and urea (24) in
the presence of 10 mol % zirconium (IV) chloride in refluxing ethanol gave the
corresponding dihydropyrimidinone (25a-m) in 90% yield. This one pot synthesis
is novel in the sense that it preserves the simplicity of Biginelli’s one-pot reaction
and improves the yields to an extent of 83-96 % dihydropyrimidinones (Scheme
7).
O
R-CHO + H C
3
22
OEt
23
O
X
O
ZrCl4
+ H2N
NH 2
24
Ethanol
, 4-6 h
R
EtO
H3C
NH
N
H
X
25a-m
Scheme 7
It is interesting to note that when ethyl trifluoro acetoacetate (26) is used as
a -ketoester in this synthesis hexahydro pyrimidine (27), (scheme 33) considered
vii
Abstract
to be an intermediate in the Biginelli reaction, has been isolated in very good
yields (Scheme 8).
R
O
R-CHO + F3C
22
O
O
OEt
+ H2N
26
H
EtOOC
NH 2
ZrCl4
NH
HO
Ethanol
, 4-6 h
F3C
24
N
H
O
27n-o
Scheme 8
Section B: Preparation of 1,5-benzodiazepine derivatives
The benzodiazepine nucleus has been recognized as an important
pharmacophore. The present work is mainly designed to synthesize a variety of
new
2,3-dihydro-1H-1,5-benzodiazepine derivatives (30a-p) using symmetrical
and unsymmetrical diamines (28) and substituted ketones (29) to obtain number
of 1,5-benzodiazepine derivatives. Our continued interest in exploitation of
zirconium tetrachloride as a catalyst, made us to use of the catalyst in the
condensation reaction of ketones with o-phenyl- enediamine to obtain various 1,5benzodiazepine derivatives in very good yields. Formation of regioisomers and
their structural elucidation in case of substituted o-phenylene diamines based on
NMR study is discussed in detail (Scheme 9).
1
R
O
NH 2
+
R
NH 2
28
2
2R
CH 3
ZrCl4
DCE, reflux
30-180 min
1
2
H R
N
CH 3
R
N
R
30a-p
29
Scheme 9
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R2
Abstract
O2N
H
N
R2
CH 3
N
R2
H3CO
H
N
R2
CH 3
N
R2
When R =H and R1 = OCH3
When R = No2 and R1 =H
Chapter 6: Biological activity studies
The compounds prepared in Chapter 2, 3 and 4 are subjected to
insecticidal activity screening and some of the compounds showed promising
activity against fourth instar larvae of Culex quinquefasciatus. The fungicidal
activity studies of isoxazolyl triazoles showed moderate acivity against various
fungi like Aspergillus niger, Chrysosporium tropicum and Rhizopus oryzae. The
antibacterial activity studies of benzimidazole derivatives are under progress.
Conclusion:
The research programme described in this thesis demonstrates the
synthesis of new chemical entities adopting various strategies and the
compounds are screened for pesticidal activity in order to find a lead molecule for
a specified biological activity. The preparation of new phase transfer catalyst and
its utilization in various organic reactions is reported for the first time. The
preparation
of
biologically
important
dihydropyrimidinones
and
1,5-
benzodiazepines using ZrCl4 in one-pot reaction and the characterization of some
of the new regioisomers is significant.
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