Abstract
ABSTRACT
Introduction:
Oxygen and nitrogen containing heterocycles are getting immense
importance in the area of pharmaceuticals and agrochemicals. Pesticides belong
to agrochemical area, which includes insecticides, fungicides, rodenticides,
herbicides and fumigants. Among pesticides, insecticides are widely used
chemicals by Indian farmers to control various diseases caused by different
insects. Indiscriminate usage of pesticides in the fields is causing resistance
development by insects resulting lower yields of the crops. Ultimately the farmer is
at receiving end with enormous financial loss. To overcome this problem an
intense research is currently in progress to develop pyrethroids, nicotinoids where
the usage of chemical is at gross level; however, the insect based diseases are
well controlled. This is the emerging area with a lot of potential and there is a need
to synthesize a new class of pyrethroids, nicotinoids and subjected to bioevaluation in order to find a promising candidate.
The broad objective of the present investigation is concerned with making a
systematic and extensive study on the synthesis of Nicotinoids, pyrethroids,
pyrano/furo fused quinolines and azabicyclo[2,2,2]octane derivatives and their bioevaluation. The programme of work is accomplished and formated into a thesis
entitled "DESIGN, SYNTHESIS OF NOVEL ISOXAZOLE DERIVATIVES, QUINOLINES & AZA
BICYCLO [2,2,2] OCTANE HETEROCYCLES AND THEIR BIOLOGICAL ACTIVITY "
Chapter-I, covers literature update on insecticides; includes the organo
phosphorous compounds, chlorinated pyrethroids, nicotinoids, pyrazoles, pyrroles,
pyridazines, isoxazoles and synthetic pyrethroids. Chapter-II deals with the
synthesis of isoxazole nicotinoids. The synthesis of cyclopropane containing
pyrethroids and non-cyclopropane pyrethroids is well documented in chapter-III.
Chapter-IV, deals with the imino Diels-Alder reaction involving the preparation of
pyrano and furo quinolines. Chapter-V, describes the synthesis of aza bicyclo
[2,2,2] octane derivatives. Chapter-VI, deals with the studies on bioactivity of the
compounds prepared in the present investigation.
I
Abstract
The research work covered under each chapter has been briefly outlined
below.
CHAPTER-I
Insecticides belong to pesticides and their application is mainly to target
pests/insects
harmful
to
various
crops
and
mankind.
They
include
organochlorines, organophosphates, carbamates, pyrethroids, nicotinoids and
various heterocycles like pyrazoles, pyrroles, quinazolines etc,. A detailed
literature coverage of earlier and existing insecticides is described in this chapter.
Some of the commercially well known products are outlined below.
H
Cl
C
Cl
O H3C
Cl
H3CO
C
Cl
Cl
P
O
C
C
O CONHCH 3
NHCH 3
O
OCH 3
DDT
H
Monocrotophos
N
Cl
N
O
Cl
O
carbaryl
NO 2
H
N
F O
NH
O
CN
Cypermethrin
Cl
F
N
Imidacloprid
H
N
Cl
O
Diflubenzuron
CHAPTER II
Synthesis of isoxazole Neo-nicotinoids:
The present chapter demonstrates the synthesis of isoxazole containing
new heterocyclic compounds and tests their insecticidal activity.
The salient feature of our strategy involves initial conversion of
acetophenones into methyl 5-phenyl substituted isoxazole-3-carboxylate using
dimethyloxalate, hydroxylaminehydrogensulphate in methanol. The isoxazole ester
is further transformed into alcohol and then converted to chloride. The chloro
fragment is coupled with the other moiety 2-nitroimineimidazole to obtain novel
II
Abstract
insecticidal heterocyclic compounds. The structure of the compounds are well
characterized by the spectroscopic methods like IR, 1HNMR,
13C
NMR, Mass,
elemental analysis and also by X-ray analysis. The details of the strategy adopted
to synthesise novel heterocyclic compounds are given in Scheme 1.
In order to generalize and show the versatility of the reaction, different
substituted acetophenones are prepared and tested for the reactions and they
underwent smooth transformation to give final products in quantitative yields.
O
O
COOMe
CH 3 COOMe
R
O
N
COOMe (NH2-OH)2 H2SO4
R
R
NaOMe
MeOH
1 (a-k)
O
MeOH
COOMe
2 (a-k)
NaBH4 THF
AlCl3 Reflux
O
CH2Cl
R
K2CO3
HN
Acetonitrile
CsCl
O
O
N
NH
N
4 (a-k)
N
SOCl2, DMF
heptane
0
65-80 C
CH2OH
R
3 (a-k)
NO 2
N
N
R
NH
N
5(a-k)
NO2
a = H, b = 4-Cl, c = 4-Br, d = 4-F, e = 4-CH3, f = 4-OCH3, g = 4-Isobutyl,
h = 3-OCH3, i = 3-Cl, j = 2-OCH3, k = 2-Cl
Scheme 1
CHAPTER III
The synthesis of cyclopropane containing isoxazoles and non-cyclopropane
isoxazoles retaining the active functional groups like dimethyls at C 2 and
stereochemistry at C3 positions is well documented in chapter-III. The completed
work is conveniently divided into two sections.
III
Abstract
Section A: Synthesis of new series of cyclopropane pyrethroids:
The present work is initiated with the condensation of optically pure
cyclopropane containing acid fragment with the heterocycle moiety containing
alcohol similar to cypermethrine and cyhalothrin. The synthon (methyl 5-phenyl
substituted isoxazole-3-carboxylate) which was prepared and covered in chapter II
is utilized further and converted to aldehyde (2) using sodium bis(2methoxyethoxy)aluminum hydride (Red-Al) at -70˚C in toluene. The other moiety,
optically pure acid part is converted into acid chloride using thionyl chloride in
hexane. The acid chloride (3/4) and aldehyde was coupled via insitu generation of
cyanohydrin by using NaCN and DABCO as PTC in dichloroethane and target
molecule is obtained. The coupling product is obtained in diastereomeric pairs,
which could not be separated by column chromatography. The details of reaction
is depicted in scheme 2.
In order to study the versatility of the above series of reactions, we have
synthesized various aldehydes by changing the constituent R groups and
prepared a series of new molecules. They are tested for larvicidal activity.
O
N
COOMe
R
O
Red-Al in Toluene
Toluene, -70 0C
N
CHO
R
1
2
NaCN, 0-5 0C, 'R
DABCO
''R
Dichloroethane, water
N
'R
''R
O
CN
3. R' = R'' = Cl (cypermethric acid)
4. R' = Cl, R'' = CF3 (cyhalothric acid)
R = H, 4-CH3, 4-F, 4-OCH3, 4-Cl, 2-OCH3, 2-Cl, 3-OCH3, 3-Cl
IV
O
3 and 4
O
O
5 and 6
Scheme 2
Cl
R
Abstract
Section B: Synthesis of non-cyclopropane pyrethroids:
In continuation of our studies on structure modifications in the alcohol moiety of
pyrethroids 5 [(R,S)Cyano(5-aryl-3-isoxazole)methyl(1R)-cis-3-(2,2-dichlorovinyl) 2,2-dimethyl cyclopropanecarboxylate] and 6 [(R,S)Cyano(5-aryl-3-isoxazole)
methyl(1R)-cis-3-(2-chloro-3,3,3-trifluro-1-propenyl)-2,2-dimethylcyclopropane-1car boxylate] as discussed in the section A of chapter-III, we have adopted
alternate strategies to achieve the final target molecule of noncyclopropane
isoxazoles.
The
S-acid
[(2S)-2-(4-chlorophenyl)-3-methylbutanoicacid]
is
converted into acid chloride (7) and treated with aldehyde and obtained desired
product (8) in good yield (scheme 3). All the compounds prepared in this section
are screened for their activity.
O
N
COOMe
R
O
Red-Al in Toluene
Toluene, -70 0C
N
CHO
R
1
2
Cl
NaCN, 0-5 0C,
DABCO
Cl
Dichloroethane, water
N
O
7
O
O
Cl
CN
O
R
8
R = H, 4-CH3, 4-F, 4-OCH3, 4-Cl, 2-OCH3, 2-Cl, 3-OCH3, 3-Cl
Scheme 3
CHAPTER IV
Zirconium tetrachloride mediated imino Diels-Alder Reactions: Synthesis of
pyrano and furo [3,2-c] quinolines.
Natural products containing pyrano and furoquinoline moieties are widely
distributed in nature and found to be associated with a wide range of biological
activities such as psychotropic, antiallergic, anti-inflammatory, estrogenic activities.
Hence, efforts are directed towards the synthesis of these compounds by imino
V
Abstract
Diels-Alder reaction catalyzed by a Lewis acid from N-benzylideneanilines and
nucleophilic olefins. We have used ZrCl4 as a green catalyst for imino Diels-Alder
reaction and reported here for the first time.
Here we describe the synthesis and characterization of mono and disubstituted pyrano and furoquinolines 3, 4, 6, 7, 8, 9, 10, 11 and 12, 13 for the first
time by the application of the imino Diels-Alder reaction using ZrCl4 as a new
catalyst. This procedure is simple, efficient and has general application for the
synthesis of pyrano and furo [3,2-c] quinolines starting from respective Nbenzylideneanilines
as
dienes
and
3,4-dihydro-2H-pyran
(DHP)
or
2,3-
dihydrofuran (DHF) as dienophiles to yield pyrano or furo quinolines respectively.
Reaction of N-benzylideneanilines (1a-k) with DHP or DHF in the presence of
ZrCl4 (10 mol%) in DCM at ambient temperature resulted in the formation of endo
(3a-k) and exo (4a-k) pyrano and furoquinolines in 72-97% yield
9
R
R
N
O
ZrCl4 , RT
[ ]n
CH2Cl2
60-180 min
+
1
O
7
HN
10b
4a
R
O1
H
HN
+
10b
2
4a
3
[ ]
n
5
H
H
R'
2
H
7
2
[ ] 3
n
5
10
8
H
1
H
n=0
n=1
R'
9
10
8
R'
3
4
Scheme 4
The structures of the final products are characterized by IR, ‫׀‬H NMR,
13C
NMR, Mass spectroscopic data, elemental analysis and X-ray crystallography
studies.
Interestingly, the di-substituted 3-chloro-4-fluoro-N-benzylideneaniline (5)
and DHP (2a) under the present reaction conditions yielded four isomers 6, 8, 10,
and 12 in the ratio 50: 15: 18: 17 respectively in an overall yield of 69% (Scheme
5) containing a large excess of the endo isomer. It is for the first time that all four
isomers are isolated in pure state from the reaction mixture by column
chromatography and characterized unequivocally by
VI
‫׀‬H
NMR spectra and
Abstract
reported. As observed in the case of DHP, DHF (2b) also acted as a good
dienophile in reaction with 3-chloro-4-fluoro-N-bezylideneaniline (5) to obtain the
expected mixture of four isomers in the ratio of 60: 12: 17: 11 in 93% yield. All the
four compounds (7, 9, 11, 13) are new and the structures assigned are in
consonance with the ‫׀‬HNMR spectra.
F
F
Cl
Cl
H
H
O
O
HN
H
H
[ ]n
HN
H
H
[ ]n
F
Cl
O
+
N
[ ]n
ZrCl4 (10 mol%)
CH2Cl2 , RT
90-180 min
6 (n=1)
7 (n=0)
8 (n=1)
9 (n=0)
F
F
5
Cl
H
Cl
H
n=1 (a)
n=0 (b)
O
O
HN
2
H
H
[ ]n
10 (n=1)
11 (n=0)
HN
H
H
[ ]n
12 (n=1)
13 (n=0)
Scheme 5
It
is noteworthy to mention that exo and endo isomers (6, 7, 8, 9, 10, 11, 12,
13) of compounds are reported for the first time and the structures unambiguously
assigned using IR, ‫׀‬HNMR,
13CNMR,
Mass spectroscopic data, elemental analysis
and X-ray crystallography.
In order to generalize and show the versatility of the reaction, different
substituted imines are prepared and condensed with DHP and DHF to obtain
diastereomerically pure final products in quantitative yields.
VII
Abstract
CHAPTER V
Zirconiumtetrachloride mediated imino Diels-Alder Reactions: Synthesis of
aza bicyclo [2, 2, 2] octane derivatives. (imine acting as dienophile):
The imino Diels-Alder reaction has emerged as a powerful tool for the
synthesis of nitrogen containing heterocycles.
In the present chapter the use of cyclic α, β-unsaturated ketone
(cyclohexene-2-one) as diene in imino Diels-Alder reaction catalyzed by zirconium
tetrachloride furnished cycloaddition products. N-benzylideneanilines, prepared
according to the reported procedure, reacted with cyclohexene-2-one in the
presence of zirconium tetrachloride
(10 mol%) in dichloromethane at ambient
temperature, resulted in the formation of new compounds 3a, 4a, 5a in the ratio 45:
2: 18 respectively in an overall yield of 65% (scheme 6). The compounds 3a, 4a,
5a are unequivocally characterized by 1D and 2D NMR spectroscopic techniques,
including HSQC and HMBC analysis.
R'
O
R
N
R
R
ZrCl4 (10 mol%)
+
N
CH2Cl 2 , RT , 6Hrs
R'
+
N
R'
2
R
3 a-e
+
N
O
R'
R
1a-e
R'
4 a-e
N
O
R'
5 a-e
Scheme 6
Unlike 1a-e, when imine 1f-g derived from benzyl amine, is used as substrate
(scheme 7) in presence of ZrCl4 (10 mol %), the reaction proceeded smoothly at
ambient temperature to furnish exclusively a single product 4f-g in 30-35% yield
Table 1 (entry f-g). These products are new and characterized by spectroscopic
data (IR, 1HNMR, 13CNMR, MS).
VIII
Abstract
R
R
R'
O
N
ZrCl4 (10 mol%)
+
N
CH2Cl 2 , RT , 8Hrs
O
R'
R'
4 f-g
1 f-g
Scheme 7
A probable reaction mechanism is depicted in scheme 8
OH
Ph
N
+
Ar
Ph
Ar
HN
H
Ph
N
Ar
N
Ar
N
O H
Ar
Ph
Ph
O
5a
H
Ph
Ar
N
Ar
O
4a
H3O+
H
Ph
N
Ar
Ar
N
Ph
3a
Scheme 8
In order to generalize and show the versatility of the reaction, different
substituted imines are prepared and tested for the above mentioned reactions and
they underwent smooth transformation to give final products in quantitative yields.
The reaction of imine with cyclopentenone in presence of ZrCl4 found that there is
no product formation.
IX
Abstract
CHAPTER VI
The compounds prepared in chapter II, III, IV and V are subjected to activity
screening and some of the compounds showed promising activity against fourth
instar larvae of Culex quinquefasciatus and tetrahydroquinolines have been tested
for anti bacterial activity using Bacillus subtilis, Psudomonas aeruginosa,
Aspergillus niger, Alternaria radicinia as test species
Conclusion:
The research programme covered in this thesis is demonstrated to synthesize well
targeted molecules adopting various strategies and each compound is screened
for activity in order to find its potency to identify a lead molecule, which is prone to
become a drug.
X