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Abstract
“Design and Synthesis of Some Biologically Active Aryl Alkanoic Acid
Derivatives and Development of Novel Synthetic Methodologies”
The thesis has been presented as five chapters. Chapter-I deals with
general introduction on the synthesis of arylacetic acids, -hydroxy arylacetic
acid (mandelic acid) derivatives as well as their biological activity, and the novel
routes for the synthesis of dihydropyrimidines (DHPMs) and Michael addition
reactions on indole as well as on aliphatic amines. Chapter-II explains about the
synthesis of arylacetic acids and derivatives. Chapter-III is presented as three
sections, the section–A deals with the synthesis of -hydroxy arylacetic acid
(mandelic acid) and its derivatives, section–B describes about the synthesis and
biological activity of mandelic acid derived hybrid benzimidazoles, section–C
comprises the synthesis and anti-tubercular activity of hybrid mandelic acid
derived 3-bromo benzoic acid molecules. Chapter-IV comprises the new protocol
for the synthesis of dihydropyrimidines (DHPMs) by cyclocondensation of an
aldehyde, urea and -keto ester using bismuth (III) triflate at ambient
temperature in acetonitrile. Chapter-V constitute a two sections, the section-A
describes the new procedure for Michael addition of indoles at C-3 position by
using Bi(OTf)3 as catalyst in acetonitrile as solvent. The section-B deals with the
aza-Michael addition reaction of aliphatic amines catalyzed by bismuth triflate.
CHAPTER I. General Introduction and Current Status of the Work:
CHAPTER II. A Facile Synthesis of Arylacetic Acid Derivatives via
Willgerodt-Kindler Reaction
Aryl alkanoic acids are versatile intermediates used extensively in
synthetic
organic
chemistry,
predominantly
as
building
blocks
in
pharmaceuticals, insecticides, pesticides, perfume industries and they are
showing broad range of biological activity. i.e. antibacterial, analgesic, virucidal,
prostaglandin synthetase response. They are used as important intermediates in
the synthesis of benzamido, phenylacetamido and phenyl benzodioxinones
I
derivatives. Most of the aryl alkanoic acids are used as NSAIDs and construction
of β-lactam antibiotics.
NSAIDs
O
OH
OH
OH
O
O
O
MeO
Naproxen
Fenoprofen
O
O
OH
HN
Cl
Ibuprofen
MeO
OH
OH
HN
Cl
Cl
O
N
O
F
Indomethacin
Cl
Lumiracoxib
Diclofenac
-lactam antibiotics:
S
O
O
H2N
HN
NH 2
N
S
HN
O
N
O
N
HO2C
Penicillins (ampiclllin)
N
N
N
H3CO
CH 3
COOH
SO3H
O
H2N
S
NH 2
Monobactams (carumonam)
S
O
O
O
O
COOH
HN
O
HN
N
S
N
OAc
O
COOH
Cefalosporins (cefotaxime)
Cephalosporin
The importance of these compounds, prompted to develop a novel route
for the synthesis of a variety of substituted arylacetic acids. The present
procedure is an efficient synthesis of arylacetic acid derivatives via WillgerodtKindler reaction from acetophenone or substituted acetophenone, sulfur,
II
morpholine and p-toluene sulphonic acid under Phase Transfer Catalytic
conditions using triethyl benzyl ammonium chloride (BTEACl or TEBA) as a
phase transfer catalyst produced the corresponding products in good to excellent
yield.
O
+ S +
R
O
p-TSA
R
120-130oC
NH
N
O
S
NaOH
100oC, 5 h
TEBA
ONa
OH
R
HCl
R
O
O
R = H, OH, OCH3, Cl, Br, NH2, Ph, NO2
CHAPTER III.
This chapter presented as three sections, section-A, section-B and section-C.
Section-A: An Efficient Synthesis of Mandelic acid Derivatives via Cannizzaro
Reaction
-hydroxy arylacetic acid (mandelic acid) and their derivatives are
biologically active and display a wide range of physiological effects. The
multiple functionalities within the molecule allow for a wide range of
biochemical
transformations
to
be
carried
out.
condensation and substitution, thus explaining
Oxidation,
reduction,
the biological activity.
Application of mandelic acids in the production of -lactam antibiotics, some of
the very diverse applications of mandelic acid its derivatives are as follows. They
are used as precursor for ligands in asymmetric catalysis, additives in cosmetics,
corrosion inhibitors, detergent additives, antiplaque agents, additives in the
molding of concrete, insect repellants, additive in electroplating, antifungal
agents urinary antiseptics, anti-inflammatory, anti-tubercular, anti-oxidant, anti
spasmodic, anti-cholinergic, anti-tumor, anti-HIV etc.
III
p-hydroxy mandelic acid, commonly known as pisolithin B, is an
antifungal antibiotic, isolated from the extracellular metabolite mixture of the
mycorrhizal fungus pisolithus tinctorius.
OH
H
O H
H O
HO
HO
HO H O
O
O
HO
O
H
Goniopypyrone
Goniofufurone
CH 3
H3C N
N
O
H
O
OH
Br
H
OH
O
O
O
O
HOMOATROPINE METHYL BROMIDE
SCOPALAMINE
O
OH
O
OH
O
N
CH 3
Br
Br
O
N
H3C CH 3
MEPENZOLE (CANTIL)
CLIDINIUM BROMIDE (QAUARAZAN)
Only a limited number of synthetic methods are available in the literature
for the synthesis of α-hydroxy arylacetic acid (mandelic acid) and derivatives.
The present work deals about an intramolecular cannizzaro reaction, can
be effectively catalyzed by In(OTf)3 producing α-hydroxy arylacetic acids
directly in good yield from aryl methyl ketones. As a preliminary test reaction
studied the one-pot oxidation-cannizzaro reaction of acetophenone in a 3:1
mixture of dioxane/H2O, SeO2 and In(OTf)3 (2 mol%) added and the resulting
IV
suspension was stirred at 90 0C for 14 hrs to obtain the corresponding α-hydroxy
arylacetic acid in excellent yield.
O
OH
R
In(OTf)3,SeO2
dioxane/H2O
90 0C, 14 hrs
R1
R
CO 2H
R1
R = R1 = H, OH, Cl, Br, OCH3, CH3, NO2
Section-B. Synthesis and Biological Activities of Mandelic Acid Derived
Hybrid Benzimidazole Molecules as a New Class of Antimicrobial and
Anti-inflammatory Agents:
The benzimidazole nucleus is an important heterocyclic ring and
derivatives are of wide interest because of their diverse biological activity and
clinical applications. This ring system is present in numerous antiparasitic,
fungicidal, anthelemintic and anti-inflammatory drugs. Some benzimidazole
nucleosides, particularly 5,6-dichlorobenzimidazole-1--D-ribofuranoside (DRB)
and its 2-substituted derivatives show activity against human cytomegalovirus.
It
is
also
known
that
5,6-dinitrobenzimidazole
can
substitute
5,6-
dimethylbenzimidazole in the vitamin B12 molecule in Corynebacterium diphteriae
and
2-trifluorobenzimidazoles
are
potent
decouplers
of
oxidative
phosphorylation in mitochondria.
2-aminobenzimidazole is one of the most important known nitrogen
heterocycle has been recently recognized as a useful building block for the
synthesis of a wide variety of substituted benzimidazoles for better
chemotherapeutic agents.
A new hybrid series of N1-(1H-benzo[d]imidazol-2-yl)-2-hydroxy-2(substituted) phenylacetamide (4a-g) were envisaged resulting from the
combination of 2-aminobenzimidazole (3) and substituted mandelic acids (2a-g)
as seen, would result in compounds with potent antimicrobial and antiinflammatory activities.
V
In the present study, substituted mandelic acids (2a-g) were prepared
according to the procedure presented in section A of this chapter,
2-aminobenzimidazole (3) was allowed to condense with the above prepared
substituted mandelic acids (2a-g) in the presence of Ph3P/DCM/NBS to obtain
the
desired
new
series
of
N1-(1H-benzo[d]imidazol-2-yl)-2-hydroxy-2-
(substituted) phenylacetamide (4a-g or compound-I to compound-VII).
OH
N
R
Ph3P/DCM/NBS
CO 2H + H2N
Pyridine, rt.
N
H
R1
2a-g
R1
O
R
OH
3
N
N
H
N
H
4a-g
R = R1 = H, OH, Cl, Br, OCH3, CH3
ANTIMICROBIAL ACTIVITY:
The modern era of antimicrobial chemotherapy began in 1929 with
Fleming’s discovery of powerful bactericidal substance penicillin, and Domagk’s
discovery of synthetic sulfonamides with broad antimicrobial activity in 1935.
In the 1940’s World War II as surplus amount of antibacterial agents were
required. Penicillin was isolated, purified and injected into animal, where it was
found to cure infections.
The present section describes about the antimicrobial and antiinflammatory activities. For antimicrobial activity, the following bacteria and
fungi were studied by disc diffusion method. Ciprofloxacin 50 μg/ml and
ketoconazole 50 μg/ml were used as standards.
1. Bacillus cereus ATCC 11778 (Gram +ve)
2. Staphylococcus aureus ATCC 155 (Gram +ve)
3. Klebsiella pneumoniae ATCC 29665(Gram -ve).
4. Escherichia coli mutant ATCC 25922(Gram –ve)
5. Aspergillus niger ATCC 9029 (fungi)
6. Candida albicans ATCC 2091 (fungi)
VI
The in vivo anti-inflammatory activity of the synthesized compounds were
evaluated by carrageenan induced acute paw oedma in rats taking carrageenan
as control and indomethacin as standard.
Section-C. Synthesis and Biological Activities of Mandelic Acid Derived
Hybrid Bromobenzoic Acid Molecules as a New Class of Anti-tubercular
Agents:
Mycobacterium tuberculosis, causes tuberculosis (TB), a slow growing
bacterium evolved from soil bacterium more than ten thousand years ago. The
history of M. tuberculosis is very old as the fragments of the spinal column from
Egyptian mummies 2400 BC show definite pathological signs of tubercular
decay. Exact pathological and anatomical description of the disease appeared in
the 17th century. In 1882, Robert Koch’s scientific brilliance led to the discovery of
M. tuberculosis as the causative agent of the disease. Different means of TB
curtailment were developed from time to time. In the 19th century, a French
bacteriologist Calmette together with Guerin created the Bacilli Calmette-Guerin
(BCG) vaccine. Even though relatively ineffective, it is still in widespread use. In
the 20th century, during World War II, came the final breakthrough of
chemotherapy the greatest challenge to the bacterium that had threatened
humanity for thousands of years.
A new hybrid series of N'1-(3-bromobenzoyl)-2-hydroxy-2-(substituted)
phenylethanohydrazide were envisaged resulting from the combination of 3bromobenzoic acid and substituted mandelic acid hydrazides as seen, would
result in compounds with potent antitubercular activity.
VII
OH
OH
R
OH
O
1
R
R
EtOH/DCE
H+, reflux
O
1
R
N2H4.H2O/EtOH
reflux
2a-g
1a-g
Br
OH
OEt
O
OH
Cl
Pyridine, reflux
R
R1
H
N
O
R
H
N
NH 2
O
1
R
3a-g
O
Br
N
H
5a-g
R = R1 = H, OH, Cl, Br, OCH3, CH3
ANTITUBERCULAR ACTIVITY:
In the present study, a new series of N'1-(3-bromobenzoyl)-2-hydroxy-2(substituted) phenylethanohydrazide were synthesized and found to possess anti
tubercular activity. The compounds tested for anti tubercular activity, which
showed significant anti tubercular activity. The anti tubercular activity was
determined against standard strain H37Rv and with 2 human strains of
mycobacterium tuberculosis. The in vitro anti tubercular activity of the
compounds were evaluated on Lowenstein-Jensen medium. The minimum
inhibitory concentrations (MIC) of the compounds were also determined by agar
streak dilution method.
CHAPTER IV. A Novel Approach for the Synthesis of 3,4-Dihydropyrimidine
-2 (1H)-Ones via Three-Component Biginelli Reaction:
The 3,4-Dihydropyrimidine-2(1H)-Ones (DHPMs) exhibit a pharmacological profile to dihydropyrimidine (DHP) calcium channel modulators of the
nefidipine and much activity has been observed in this area throughout the
1980’s and 1990’s.
Several functionalized dihydropyrimidines have been found to exhibit a
wide spectrum of biological effects including antiviral, antitumar, antibacterial
and anti-inflammatory activities. Moreover, several natural products with
interesting biological activities containing the dihydropyrimidine-5-carboxylate
core have been isolated from marine sources.
VIII
O
NH
O2N
Ph
E
R
E
N
H
N
MeO2C
R1
CO 2Me
N
H
M
H2N
R1
NH
6
H
N
O
H
H
+
O
N
Me
N
H
N
H
(CH 2)6CH 3
O
3
NH 2
+
E = ester, amide, acyl
Ph = substituted phenyl
R, R1 = alkyl
The
present
procedure
describes
about
the
synthesis
of
dihydropyrimidine-2(1H)-ones catalyzed by bismuth (III) triflate in the threecomponent condensation reaction, is an efficient and improved modification of
Biginelli reaction.
R
O
X
O
R
NH2 +
H + H2N
1
O
O
2
2 mol% Bi(OTf)3
2
1
R
R
CH3CN, rt
1-4 hrs
3
R2
NH
1
R
N
H
X
4
CHAPTER V. An Efficient Method for Heteroatom Nucleophilic Addition to
Electron-Deficient Olefins via Michael Addition Reaction:
This chapter is presented as two sections section-A and section-B
Section A: A New and Efficient Route for the Synthesis of 3-Substituted
Indole Derivatives.
Indoles particularly have been the subject of great research interest owing
to their appearances in the structures of complex biologically active compounds.
The development of indole chemistry began in the mid-nineteenth century with
intensive research on the dye indigo.
Indole chemistry continued to be an important in the dye industry until
the beginning of the twentieth century when newer dyes supplanted the indoles.
A brief decline in indole research then occurred. But in the 1930’s the discovery
that many alkaloids contain the indole nucleus led to a notable revival. During
IX
this period recognition of the essential amino acid tryptophan and the plant
growth hormone heteroauxin as indole derivative added stimulus to this
research. Many important methods of indole synthesis were developed in order
to synthesis these moieties and their analogs.
O2S
NHMe
O
N
H
H3C
NMe 2
N
H
CH 3 CO 2H
Sumatriptan
Etodolac
Me
N
O
O
N
N
H3C
O
N
H3C
N
H
Tropisetron
Ondansetron
The present study, a development of novel method for the synthesis of
indole derivatives by C-alkylation using bismuth (III) triflate. It was found that
the treatment of indole with , -unsaturated compounds in the presence of
catalytic amount of bismuth triflate in acetonitrile afforded 3-alkylated indole in
high yields.
R3
O
+
N
R
R1
2
R
R2
5 mole% Bi(OTf)3
3
R
CH3CN, r t
O
N
R
R1
H
R = H,CH2 Ph
R1 = H, CH3
R2 = CH3, Ph, OCH3,Ph C CH
R3 = Ph, H
R2 = R3 = (CH 2)2 , (CH )
2 3
Section B: A Novel Protocol for the Synthesis of β-Amino Carbonyl
Compounds From Aza-Michael Reaction
The aza-Michael reaction is an important reaction in organic chemistry
especially for the synthesis of heterocycles, containing ,-amino carbonyl unit.
X
-Amino carbonyl compounds are versatile synthetic intermediates for the
synthesis of a variety of biologically important natural products, antibiotics, amino alcohols, chiral auxiliaries, and other nitrogen-containing compounds.
These compounds also find wide applications in fine chemicals and
pharmaceuticals. This has led to the development of novel synthetic
methodologies for β-amino carbonyl compounds. The Mannich reaction is one of
the classical methods for the construction of this functionality.
OH
O
Br
HN
HN
O
O
O
O
N
O
O
O
O
O
NH
HN
N
H
Cl
O
OCH 3
O
Cryptophycin
Jasplakinolide
The present work demonstrates the remarkable catalytic effect of bismuth
triflate for this transformation. It was found that the treatment of pyrrolidine
with methyl acrylate in the presence of 2 mol% of bismuth triflate in anhydrous
acetonitrile at ambient temperature to obtain the product methyl-(3-pyrrolidine)propionate in high yield.
OMe
O
N
H
Bi(OTf)3, CH3CN
r.t
XI
N
CH2 CH2 CO2Me