Abstract
Multifunctional molecules are often employed as synthons in organic synthesis.
Development of new synthetic methodologies in which synthons are prepared is an
important subject of recent research in organic chemistry. Several methods have been
developed to obtain these precursors, which involve more tedious jobs or contain
circuitous routes. Generally the classical synthetic methodologies involve expensive
reagents and catalysts, which are not easily available and require harsh reaction
conditions. Thus there is a need to replace such reagents and catalysts. Recently there is
also a much greater demand on organic chemists for innovation of new mild synthetic
methodologies in view of the stipulations laid down by the environmental systems. The
threat to ecological and environmental synthesis due to the damages caused by the
chemicals has put forward a new area of the so called “Green Chemistry”.
Different improved processes are now being discovered to carry out the reactions
efficiently and conveniently with readily available inexpensive materials. During the
present study some important synthetic methodologies involving C-N or C-O bond
formation reactions and halogenation reactions have been developed by utilizing
heterogeneous as well as homogeneous catalysts. Some chemical reagents have also been
applied in novel ways for useful synthetic transformations. To discuss systematically, all
these investigations have been divided to two chapters (Chapter-I and Chapter-II).
Chapter-I: Development of new synthetic methodologies involving C-N
or C-O bond formation reactions
1. Synthesis of coumarins via Pechmann condensation using heterogeneous catalysts
Coumarins are ubiquitous in nature and have an important place in both natural and
synthetic organic chemistry. They are usually synthesized by several methods such as
Pechmann, Perkin, Knoevenagel, Reformatsky and Wittig reactions. We recently
observed that the synthesis of coumarins via Pechmann condensation can easily be
carried out with the heterogeneous catalysts, silica supported sodium hydrogen sulfate
(NaHSO4∙SiO2) and silica chloride. A phenol and ethyl acetoacetate underwent
i
Abstract
condensation in the presence of either of a catalyst under solvent free conditions to
produce the coumarin conveniently (Scheme IA).
OH
+
OEt
R
1
O
NaHSO4. SiO2 or
O
O
Silica Chloride
85 oC
0.5-3.5 h
O
R
45-93%
3
2
9 examples
Scheme IA
Several coumarins were successfully synthesized in high yields by following the above
method. The experimental simplicity, high yields, application of less costly
heterogeneous catalysts and absence of solvent are the advantages of the present
procedure. The method is environmentally benign.
2. Highly efficient, mild and chemo- and stereoselective synthesis of enaminones and
enamino esters using silica supported perchloric acid under solvent-free conditions
-Enaminones and -enamino esters are useful synthones for the synthesis of various
pharmaceuticals and bioactive heterocycles. They are the intermediates for the synthesis
of several aminoacids, aminols, peptides and alkaloids. Classically, -enaminones are
prepared by direct condensation of -dicarbonyl compounds with amines under reflux in
an aromatic solvent with azeotropic removal of water.
We have recently observed that silica supported perchloric acid (HClO4·SiO2) is a
highly efficient catalyst for the preparation of -enaminones and -enamino esters from
-dicarbonyl compounds by treatment with amines (Scheme IB).
ii
Abstract
O
HClO4 . SiO2
O
3
R2 + R NH2
R1
4
R3
NH O
Solvent-free
r.t., 5-14 min
5
R1
R2
90-99%
6
25 examples
Scheme IB
The method was found to be highly chemoselective. Amine attacks only at the ketone
carbonyl for both diketones and -ketoesters. The (Z)-selectivity was observed in the
products derived from acyclic diketones and -ketoesters but (E)-selectivity in the case of
5,5’-dimethyl-1,3-cyclohexadione.
The solvent-free conditions, mildness of the conversion, simple experimental
procedure, clear reaction profiles, high yields and chemo- and stereoselectivities, short
reaction times and reusability of the catalyst are the noteworthy advantages of the
protocol.
3. A highly chemoselective Boc protection of amines using sulfonic-acidfunctionalized silica as an efficient heterogeneous recyclable catalyst
The tert-butoxycarbonyl (Boc) group is one of the most useful functionalities for
protection of amines and amine derivatives. Different base-mediated reactions for Boc
protection of amines have been developed. Recently, some Lewis acids have also been
applied as catalysts for this purpose.
Here we have described a simple method for Boc protection of amines using sulfonicacid-functionalized silica as heterogeneous catalyst at room temperature (Scheme IC).
Selectivity of the method was extended by using a mixture of different amines (Scheme
ID).
iii
Abstract
(Boc)2O, Cat.
R1 NHR2
CH2Cl2, r.t.
5 min - 2 h
7
Cat.
R1 N(Boc)R2
SiO2
8
O
O Si
O
SO3H
Sulfonic-acid-functionalized silica
24 examples
Scheme IC
R2 NH2 + R3 NH2 + (Boc)2O
1
:
1
: 1
1
:
1
: 2
Cat., CH2Cl2
r. t., 5 min
R2 NHBoc + R3 NHBoc
85-99%
0-15%
99%
39-99%
(conversion from individual amine)
3 examples
Scheme ID
The protocol is highly chemoselective offering potential in different applications. The
method also has several other advantages such as simple experimental procedures, mild
reaction conditions, excellent yields of mono Boc protected amines and reusability of the
catalyst.
4. An efficient and convenient protocol for the synthesis of quinoxalines and
dihydropyrazines via cyclization-oxidation processes using HClO4·SiO2 as a
heterogeneous recyclable catalyst
Quinoxalines and pyrazines are important class of heterocycles in medicinal chemistry.
A number of methods have been developed for the synthesis of substituted quinoxalines
and dihydropyrazines (DHPs) involving condensation of 1,2-diamines with α-diketones,
1,4-addition of 1,2-diamines to diazenylbutenes, oxidation-traping of α-hydroxy ketones
with 1,2-diamines, cyclization-oxidation of phenacyl bromides and o-phenylenediamines
through solid-phase and oxidative coupling of epoxides with ene-1,2-diamines.
iv
Abstract
Recently, we investigated an efficient method for the synthesis of quinoxalines and
DHPs from α-bromo ketones and 1,2-diamines in the presence of silica supported
perchloric acid (HClO4·SiO2) at room temperature (Scheme IE).
R3
R3
2
H2 N
R
H2 N
R
N
3
R
R3
NH2
N
R1
12
O
NH2
1
HClO4. SiO2 R
70 - 93%
CH3CN, r. t.
13
20 - 35 min
R3 = -(CH2)4-, H
Br
9
R1 = aryl, alkyl
hetero aryl
N
R2
N
R2
2
10
HClO4. SiO2
R1
CH3CN, r. t.
15 - 60 min
80 - 95%
11
R2 = H, CH3
14 examples
Scheme IE
The mild reaction conditions, simple experimental procedure, clear reaction profiles
and reusability of the catalyst are notable advantages of the present method. To our
knowledge, this is the first report of the synthesis of quinoxalines and DHPs from 1,2diamines and α-bromo ketones using heterogeneous catalyst at room temperature.
5. A simple and efficient chemoselective benzyloxycarbonylation of amines in water
The protection of amines with benzyloxycarbonyl (Cbz) group is frequently used in
organic synthesis. The earlier methods reported for Cbz protection of amines are
associated with different drawbacks such as strongly basic conditions, low or high
temperatures, long reaction times, unsatisfactory yields and requirement of an organic
solvent.
Here we report a simple method for Cbz protection of amines by a treatment with CbzCl in water in the absence of any acid / base catalyst at room temperature (Scheme IF).
Cbz-Cl, Water
R1NHR2
r.t., 2 min - 1.5 h
14
28 examples
Scheme IF
v
R1N(Cbz)R2
71-99%
15
Abstract
The mild and eco-friendly reaction conditions, organic solvent free conversion,
interesting chemoselectivity in the case of two different amines as well as symmetrical
amines and amine in the presence of various functionalities and impressive yields are the
notable advantages of the method.
Chapter-II:
Development
of
synthetic
methodologies
involving
halogenation reactions
1. α-Bromination of carbonyl compounds using N-bromosuccinimide and
heterogeneous catalysts
-Bromination of carbonyl compounds is an important transformation in organic
synthesis as the -brominated products are useful synthetic intermediates. Previously
NBS has been utilized for α-bromination of carbonyl compounds using a radical initiator
[such as, azobisisobutyronitrile (AIBN) or dibenzyl peroxide (BPO)], or in strongly basic
media or in the presence of Mg(ClO4)2 or NH4OAc.
We have recently found that silica-supported sodium hydrogen sulfate (NaHSO4∙SiO2)
(Scheme IIA, Condition A) or sulfonic-acid-functionalized silica (Scheme IIA, Condition
B) is an efficient catalyst for α-bromination of carbonyl compounds using NBS.
Br
2
R
R1
O
R2
Condition A or
R1
Condition B
0.25 – 3h
16
O
10 – 99%
17
Condition A: NBS, NaHSO4∙SiO2, ether or CCl4
Condition B: NBS, sulfonic-acid-functionalized silica, ether or CCl4
40 examples
Scheme IIA
vi
Abstract
The present protocol is associated with several advantages such as mild reaction
conditions, short reaction times, excellent yields of monobrominated products, simple
experimental procedure and reusability of the catalyst. The used catalysts make the
process more eco-friendly compared to the homogeneous acid catalysts. A novel
important application of sulfonic-acid-functionalized silica is also discovered.
2. Regioselective nuclear bromination of aromatics and heteroaromatics with NBS
using sulfonic-acid-functionalized silica or ammonium acetate as a catalyst
Brominated arenes and heteroarenes are useful as pharmaceuticals, agrochemicals,
flame retardants and specialty chemicals. Several aryl and heteroaryl bromides are
potential antitumour, antibacterial and antioxidant agents. Earlier several methods for the
bromination of aromatics and heteroaromatics involving the utilization of NBS are
associated with certain drawbacks including long reaction time (NBS-SiO2), high
temperature (NBS-TBAB and NBS-HZSM-5) and complex experimental procedure
(NBS-HBF4·Et2O).
We have recently found that several activated arenes can easily be brominated with
NBS in the presence of sulfonic-acid-functionalized silica or ammonium acetate at room
temperature (Scheme IIB).
Ar - Br
Ar - H
Condition A or
or
or
HeteroAr - H Condition B HeteroAr - Br
1min - 3h
18 - 99%
19
18
Condition A: NBS, sulfonic-acid-functionalized silica, CH3CN-Et2O (1:3), r.t.
Condition B: NBS, ammonium acetate, CH3CN, r.t.
67 examples
Scheme IIB
vii
Abstract
The method is highly regioselective offering potential in various synthetic applications.
The mild reaction conditions, simple experimental procedure, rapid conversion and
excellent yields are notable advantages of the method.
3. A rapid and efficient stereoselective synthesis of (Z)- and (E)- allyl bromides form
Baylis–Hillman adducts using bromodimethylsulfonium bromide
The allyl halides prepared form Baylis–Hillman adducts have been used in the
synthesis of various natural and biologically active molecules and their analogues such as
α-methylidene-γ-butyrolactones, α-alkylidene-β-lactams and flavonoids. The direct
conversion of the Baylis–Hillman adducts into their corresponding halides has been
previously accomplished with different halogen-containing reagents including strong
acids (HBr/H2SO4, HI/H3PO4), organic acid halides (oxalyl chloride MsCl), HCA/PPh3,
Lewis acids (FeCl3, InCl3) and metallic (Na and Li) halides.
We have recently discovered that the Baylis–Hillman adducts can easily be converted
into the corresponding allyl bromides by treatment with bromodimethylsulfonium
bromide (Me2S+Br Br–) in acetonitrile at room temperature (Scheme IIC).
OH
EWG
R
+
Me2SBr Br
EWG
CH3CN, r.t.
0.3 - 3h
R
+
DMSO + HBr
83 - 99% Br
21
20
R = aryl, alkyl
EWG =
COOMe, COOEt, CN
15 examples
Scheme IIC
The method is characterized by mild reaction conditions, short conversion times, high
yields and excellent stereoselectivities [(Z)-configuration, when EWG = ester and (E)configuration in the case of EWG = CN].
viii
Abstract
4. Ammonium acetate catalyzed improved method for the regioselective conversion
of olefins into bromohydrins and bromoethers at room temperature
Selective vicinal functionalization of alkenes with the functional groups such as
hydroxy or alkoxy and halogen finds applications in various useful organic
transformations. The most common method for the preparation of halohydrins involves
ring opening of epoxides or cyclic sulfate by hydrogen halides or metalhalides.
We observed that olefins are rapidly converted into bromohydrins and bromoethers
using N-bromosuccinimede and catalytic amount of ammonium acetate (NH4OAc)
(Scheme IID).
OH
NBS,
NH
OAc
2 NBS, NH4OAc
4
R
R2
R
1
1
R
R
R1
H
O:Me
CO
(1:4)
ROH, r. t.
2
2
Br
Br
r. t.
5 - 20 min
22
17 - 94%
90 - 97%
4 - 45 min
23
24
R1, R2 = alkyl, aryl
R = alkyl
OR
2
18 examples
Scheme IID
The mild reaction conditions, simple experimental procedures, rapid conversion, clear
reaction profiles, excellent yields and high regioselectivity are the noteworthy advantages
of the present protocol.
5. An improved method for the regioselective conversion of olefins into iodohydrins
and iodoethers using NIS at room temperature catalyzed by ammonium acetate
Synthesis of bromohydrins has been reported directly from dilute aqueous solutions of
bromine. The preparation of iodohydrins using the same procedure is hampered by the
ready reversibility of the addition of hypoiodous acid. The preparation of iodohydrins
from alkenes also is reported by the use of N-iodosaccharin, H5IO6/NaHSO3, triodide ion,
ix
Abstract
N-iodoimide, dimethyldioxirane/CH3I, bis(pyridine)iodine(I)salts and iodine mediated by
clay.
Here we report the synthesis of iodohydrins and iodoethers form alkenes by treatment
with NIS in the presence of NH4OAc catalyst in water-acetone (1:4) at room temperature
(Scheme IIE).
OR
2
R1
R
I
92 - 98%
26
R = alkyl
OH
NIS,
NH
OAc
4
R
R2
1
1
R
R
H2O:Me2CO (1:4)
ROH, r. t.
I
r. t.
5 - 20 min
22
87 - 95%
5 - 25 min
25
R1, R2 = alkyl, aryl
NIS, NH4OAc
2
12 examples
Scheme IIE
The mild reaction conditions, interesting chemoselectivity and simple experimental
procedures are the noteworthy advantages of the present protocol.
6. Synthesis of β-chlorohydrins in water
The transformation of epoxides into halohydrins can be carried out with halogens,
hydrogen halides, and metal halides in organic solvents such as MeCN or CH2Cl2.
However, many of these methods are associated with several disadvantages, including
harsh reaction conditions, unsatisfactory yields and poor selectivity. Thus, an improved
protocol for the conversion of epoxides into the corresponding vicinal halohydrins is
essential.
We observed that the ring opening of epoxides can efficiently be carried out with TCT
(2,4,6-trichloro-1,3,5-triazine) in the presence of morpholine in H2O at room temperature
to form the corresponding β-chlorohydrins (Scheme IIF).
x
Abstract
Cl
N
N
Cl
O
27
Cl
HO
29
R'
R
N
Morpholine, H2O
r.t., 5-45 min
R
R'
Cl
or
Cl
R
R'
OH
28
81 99%
12 examples
Scheme IIF
The efficiency and the economic and environmental benefits of this reaction are the
notable features of our synthetic protocol.
Chapter-III: Studies on natural polycyclic compounds – Chemical
investigation on Pulicaria wightiana
Natural Products are increasingly gaining importance and attention from chemists and
pharmacologist alike. Many of the medicinal and biological agents used on a worldwide
basis are either natural products or derivatives of natural products. Natural product
chemistry is experiencing a dramatic evolution presently due to recent technological
development. Natural products have been the major source of medicines and much of the
world’s population still rely upon the remedies of natural product origin. The searching
for pharmacologically active agents obtained by screening natural sources such as plant
extracts has lid to the discovery of many clinically useful drugs those play a major role in
the treatment of human diseases. Several complex biologically promising molecules have
been isolated and characterized from different plant sources. However, nature continues
to offer unrivaled and virtually random structural diversity to produce various types of
bioactive compounds. Therefore the chemical investigation on medicinal plants have
always been given considerable importance. The plants not only continue to retain their
historical significance as important sources for development of new drugs, but also are
extremely useful as sources of lead compounds for structural modification and
optimization which can also be employed as specific probes in biochemical studies. Plant
xi
Abstract
derived compounds which have recently undergone development include the anticancer
agents such as taxol and camptothecin and the antimalarial drug artemisinin.
Inspired by the tends in the modern phytochemical research, the author has made a
modest effort to investigate on a medicinal plant, Pulicaria wightiana. In this thesis the
results of chemical investigation on this plant has been discussed. Chemical investigation
of the plant led to the isolation of some new polycyclic compounds along with several
reported known compounds. The isolation and structure elucidation of the constituents
have been discussed. The biological activities of some of the compounds have been
presented.
Chemical investigation on Pulicaria wightiana
Various species of Pulicaria are known for their medicinal properties. The metabolities
obtained from different species of Pulicaria are also chemically interesting. These
metabolities are of varied types, viz., sesquiterpenoids, diterpenoids, triterpenoids,
flavonoids, phenolic compounds and steroids.
The present investigation afforded three new clerodane diterpenoids, one new
benzofuranoid along with several known compounds. The structures of all the new
molecules have been confirmed by their 1D and 2D NMR (COSY, NOESY, HMBC and
HSQC) and MS spectroscopic studies. Antibacterial and antifungal activity of all the new
and some reported molecules have been studied. The structures of all the known
compounds were established from their detailed spectroscopic (IR, 1H NMR, some cases
13
C NMR and MS) data and by comparing the spectral values with those reported in
literature.
xii
Abstract
The following compounds have been isolated from the plant Pulicaria wightiana.
Compound
code
PWV-1
Compound name
Stigmasterol
Compound
nature
White crystals
PWV-2
β-Sitosterol
White solid
PWV-3
6-Benzofuran carboxylic acid-5-formyl methyl
ester
Methyl 15,16-epoxy-6α-hydroxy-3,13 (16),14clerodatrien-18-oate
Phyllemblin
Dark yellow
needles
Viscous mass
Methyl 6-oxo-3,13-clerodadien-15,16-olid-18oate
Pectolinarigenin
Colorless
crystals
Pale green
crystals
White solid
White solid
PWV-4
PWV-5
PWV-6
PWV-7
PWV-8
PWV-9
PWV-10
PWV-11
PWV-12
Isopimara-8(14),15-diene-7-keto-2α-ol
2β-(2-Methylbutanoyl)-3,13-clerodadien-15,16olid-18-oic acid
Methyl 6α-hydroxy-3,13-clerodadien-16,15olid-18-oate
Chrysin
White powder
First report from the
species
Known compound
New compound
First report from the
species
Known compound
Colorless
needles
Pale green
crystals
Viscous mass
First report from the
species
Known compound
White crystals
Known compound
Known compound
PWV-18
PWV-19
Methyl 6α-hydroxy-3,13-clerodadien-18-oate
Fraxetin
PWV-20
Gallic acid
PWV-21
Daucosterol
White powder
PWV-22
Bergenin
Colorless
crystals
PWV-16
First report from the
species
New compound
Pale yellow
powder
Viscous mass
Pale green
crystals
Viscous mass
Pale green
crystals
White powder
PWV-15
Known compound
Known compound
PWV-17
PWV-14
First report from the
species
First report from the
species
New compound
Viscous mass
Methyl 6,15-dihydroxy-3,13-clerodadien-15,16olid-18-oate
6α-Hydroxy-3,13-clerodadien-16,15-olid-18-oic
acid
Methyl 6α-hydroxy-3,13-clerodadien-15,16olid-18-oate
Methyl 6α,7α-dihydroxy-3,13-clerodadien15,16-olid-18-oate
6α-Hydroxy-3,13-clerodadien-15(16),4(7)diolide
Oxyanin B
PWV-13
Remarks
Known compound
New compound
First report from the
species
First report from the
species
First report from the
species
First report from the
species
All the isolated compounds have been examined (TLC experiments) to be present in
the original extract of the plant.
xiii
Abstract
H
H
H
H
H
H
HO
HO
PWV-2
PWV-1
O
O
H
O
H
MeO
HO
O
O
O
HO
OH
PWV-5
OH
CO2Me
PWV-3
PWV-4
O
H
OMe
O
HO
O
HO
H
O
CO2Me
MeO
OH
PWV-6
O
H
PWV-8
O
PWV-7
O
O
H
O
O
H
O
HO
O
O
CO2 H
OH
CO2Me
PWV-9
PWV-10
xiv
OH O
PWV-11
Abstract
O
OH
H
O
H
O
H
O
CO2 H
OH
CO2Me
PWV-13
PWV-14
OH
OH
CO2Me
PWV-12
O
O
H
H
OMe
O
O
O
MeO
OH
OH
OH
CO2Me
HO
OH
O
PWV-15
OH
OMe
O
O
PWV-17
PWV-16
H
O
O
O
O
MeO
HO
HO
OH
CO2Me
O
O
HO
OH
PWV-20
OH
PWV-19
PWV-18
OH
OH
MeO
H
OH
H
O
HO
HO
OH
OH O
H
HO
H
OH
O
PWV-22
O
OH
O
H
PWV-21
Thus the chemical investigation on Pulicaria wightiana offered four new compounds
along with several known compounds, some of which are reported first time from the
species.
xv