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Chapter VI
CHAPTER VI
Summary and Conclusions
CHAPTER I
DBU: A highly efficient catalyst for one pot synthesis of substituted 4H-benzo[g]
chromenes, 4H-pyrans and pyrano[2,3-d]pyrimidines in aqueous medium
One pot multicomponent reactions (MCRs) offer significant advantages over
conventional linear type syntheses. Developing MCR protocols in water is an active
area of research. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) with a pKa = 12 has been
used as an organic base for organic reactions. Therefore, we have investigated the
application of DBU for different MCRs. This chapter is divided into three parts.
I.1: DBU catalysed synthesis of 4H-benzo[g]chromenes in water
In this part, we report the synthesis of 4H-benzo[g]chromenes catalyzed by DBU in
water. The reaction conditions were optimized by attempting reactions of 4nitrobenzaldehyde (1.0 mmol), malononitrile (1.5 mmol) and 2-hydroxynaphthalene-
1,4-dione (1.0 mmol) in water in presence of different catalysts e.g., KOH, K2CO3,
NH4Cl, L-proline, TBAH, Et3N, Et2NH, piperidine and DBU. The best results were
obtained by refluxing the components in water in the presence of DBU (10 mol%) as
catalyst. Reactions of other aromatic aldehydes also yielded the corresponding 2-amino4-aryl-5,10-dioxo-5,10-dihydro-4H-benzo[g]chromene-3-carbonitriles
in
excellent
yields under optimized conditions. Promising results were also obtained when
malononitrile was replaced with ethyl cyanoacetate (eq. 1).
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Chapter VI
I.2: DBU catalysed synthesis of 4H-pyrans in water
The scope of the above protocol was examined for three component condensation of 4-
nitrobenzaldehyde (1.0 mmol), malononitrile (1.0 mmol) and ethyl acetoacetate (1.0
mmol) in the presence of 10 mol% of DBU under reflux. Ethyl 6-amino-5-cyano-2-
methyl-4-(4-nitrophenyl)-4H-pyran-3-carboxylate was obtained in 5 min. Subsequently,
a series of differently substituted ethyl 6-amino-4-aryl-5-cyano-2-methyl-4H-pyran-3carboxylates were prepared in high yields from different aromatic aldehydes under
otherwise identical conditions (eq. 2).
I.3: DBU catalysed synthesis of pyrano[2,3-d]pyrimidines in water
The protocol employed for the synthesis of 4H-benzo[g]chromenes and 4H-pyrans was
further explored for the condensation of aldehydes (1.0 mmol), malononitrile (1.0
mmol) and heterocycle based 1,3-diketone i.e. 1,3-dimethyl barbituric acid (1.0 mmol)
in aqueous media under reflux in the presence of 10 mol% of DBU. A wide range of
diversely substituted aromatic aldehydes underwent this three component cyclo-
condensation reaction with malononitrile and 1,3-dimethyl barbituric acid to produce
corresponding 7-amino-5-aryl-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]
pyrimidine-6-carbonitriles in high yields (eq. 3).
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CHAPTER II
Synthesis of novel benzo[a]pyrano[2,3-c]phenazine and benzo[a]chromeno[2,3-c]
phenazine derivatives via four component domino protocol and their
photophysical studies
Phenazine based compounds are abundant amongst natural products and possess myriad
of biological functions. Fluorescent phenazine derivatives are also used as photosensitizers in photodynamic therapy (PDT). Therefore, we have attempted the synthesis
of novel pyrano and chromeno fused phenazine derivatives. The photophysical studies
of novel benzo[a]pyrano[2,3-c]phenazine derivatives have also been investigated. This
chapter is divided into three parts.
II.1: Synthesis of novel benzo[a]pyrano[2,3-c]phenazine derivatives
In this part, we report a new one pot four component, convergent, expedient sequential
protocol for the synthesis of 1-aryl-1H-benzo[a]pyrano[2,3-c]phenazin-3(2H)-ones by
the reaction of 2-hydroxynaphthalene-1,4-dione (1.0 mmol), 1,2-phenylenediamines
(1.0 mmol), aromatic aldehydes (1.0 mmol) and Meldrum’s acid (1.0 mmol) in glacial
AcOH at 70°C in excellent yields (eq. 4).
The synthesis was attempted by different acid catalysts namely p-TSA, H2SO4, HCl,
InCl3 and Gl. AcOH in different solvents and at different temperatures. The protocol is
environmentally benign and has high atom-economy.
II.2: Synthesis of benzo[a]chromeno[2,3-c]phenazine derivatives
In this part, the above optimized sequential four component domino methodology was
further extended for the condensation of cyclic 1,3-diketones having active methylene
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group like cyclohexane-1,3-dione, 5-methylcyclohexane-1,3-dione and 5,5-dimethyl
cyclohexane-1,3-dione instead of Meldrum’s acid in glacial AcOH at 70°C. The
reactions yielded corresponding benzo[a]chromeno[2,3-c]phenazine derivatives in high
yields (Scheme 1).
Scheme 1
The structure of one of the phenazine derivative namely, 3,12-dimethyl-16-(3,4,5-
trimethoxyphenyl)-2,3,4,16-tetrahydro-1H-benzo[a]chromeno[2,3-c]phenazin-1-one has
been established by single crystal X-ray crystallographic study.
II.3: Photophysical studies of novel benzo[a]pyrano[2,3-c]phenazines
The spectral characteristics of the compounds such as absorption maxima (λabs,
max),
emission maxima (λem, max), extinction coefficient (ε) and Stokes shift were measured in
chloroform. All the compounds, showed three absorption bands, a strong band I in the
region of 275-290 nm and two weak bands II and III in the region of 380-430 nm.
Moreover, when these compounds were excited at 280 nm (λmax), all exhibited strong
photoluminescent emissions with the maximum emission peaks varying from 428 to
449 nm. The influence of solvents of different polarity such as hexane, chloroform,
ethyl acetate, N,N-dimethylformamide, dimethylsulphoxide and methanol on the
absorbance and fluorescence spectra of benzo[a]pyranophenazines derivatives was also
examined. The fluorescence spectra underwent significant red shift upon increasing
solvent polarity, whereas no such significant shift is observed in absorption spectra by
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varying the solvent polarity. It implies that the ground-state energy distribution is not
affected to a great extent. The Lippert-Mataga plot of the Stokes shift as a function of
orientation polarizability (∆f ) shows a good linear relationship, suggesting that specific
solute-solvent interactions are involved, which is known to consist of several effects
i.e., dipole-dipole interactions and dipole induced dipole interactions.
The synthesized benzo[a]pyrano[2,3-c]phenazine derivatives also act as good pH
indicators in the range of 6.5-13. The colour change in the pH range 6.5-13 of these
compounds was extremely sharp, clear and reversible. Addition of alkali to 1-(4-
fluorophenyl)-11-methyl-1H-benzo[a]pyrano[2,3-c]phenazin-3(2H)-one showed visual
colour change from pale yellow (pH=6.5) to pink (pH=13). This colour change in
benzo[a]pyrano[2,3-c]phenazine derivatives with addition of dilute alkali solution
(NaOH) is probably due to the hydrolysis of the lactone ring. The hydrolysis-cyclisation
of lactones is a reversible reaction. Therefore, the synthesized benzo[a]pyrano[2,3-c]
phenazine derivatives can act as new pH chemosensors.
CHAPTER III
TSIL catalyzed synthesis of novel naphthoquinone-urazole hybrids and evaluation
of their antioxidant and in vitro anticancer activity
Quinones, including 1,4-naphthoquinones and 1,2-naphthoquinones are ubiquitous in
nature and several well-known anticancer drugs used to treat solid tumours possess a
quinonoid structure. Their structural properties have been linked to the stimulation of
oxidative stress and alkylation of cellular nucleophiles in cancer cells. Urazole (1,2,4triazolidine-3,5-dione) moiety exhibits biological functions such as anticonvulsant,
antifungal, herbicidal, hypolipidemic and insecticidal. 1-Acyl and 1,2-diacyl-1,2,4triazolidine-3,5-diones are known to be effective cytotoxic agents in both murine and
human cancer cell lines. Therefore, we decided to attempt synthesis of naphthoquinoneurazole hybrids. In this chapter, we report synthesis of novel naphthoquinone-urazole
hybrids and evaluation of their antioxidant and in vitro anticancer activities. This
chapter is divided into two parts.
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III.1: Synthesis of novel naphthoquinone-urazole hybrids using task specific ionic
liquid
The synthesis of naphthoquinone-urazole hybrids was achieved by linking
naphthoquinone and urazole moieties through aldehydes as linkers. The reactions of
aromatic aldehyde (1.0 mmol), 2-hydroxynaphthalene-1,4-dione (1.0 mmol) and 4-
phenylurazole (1.0 mmol) were attempted with a variety of catalysts e.g., InCl3, CAN,
CeCl3, La(OTf)3, Gl. AcOH, HCl, p-TSA, H2SO4 and [bmim]HSO4 under different
conditions. Reactions carried out in ionic liquid [bmim]HSO4 (10 mol%) at 60°C gave
the desired products in high yields. [bmim]HSO4 acted both as catalyst and medium in
these reactions (eq. 5).
III.2: Evaluation of antioxidant and in vitro anticancer activity of naphthoquinoneurazole hybrids
Radical scavenging activity of the synthesized compounds was examined using DPPH
(2,2-diphenyl-1-picrylhydrazyl) assay and compared with BHT (butylated hydroxy
toluene) as standard. The disappearance of DPPH was measured spectrophotometrically
at 517 nm using BHT as standard. 0.025 µM/mL, 0.05 µM/mL, 0.1 µM/mL, 0.2
µM/mL and 0.4 µM/mL solutions of 1-((aryl)(3-hydroxy-1,4-dioxo-1,4-dihydro
naphthalen-2-yl)methyl)-4-phenyl-1,2,4-triazolidine-3,5-diones
were
prepared
in
chloroform and % radical scavenging activity was calculated. All the naphthoquinone-
urazole hybrids showed high DPPH radical scavenging activity, comparable to the
standard BHT. Generally compounds having high antioxidant activity also show good
anticancer activity. Therefore, these naphthoquinone-urazole hybrids were also
screened in vitro for anticancer activity against five human cancer cell lines i.e. breast
(T47D), colon (HCT-15), ovary (PA-1), liver (HepG2) and lung (NCI H-522) at a
concentration of 1 ×10-5 M. 3-Bromo, 2-methyl, 2-naphthyl and 3-methyl substituted
naphthoquinone-urazole hybrids were most active. Therefore, these compounds which
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exhibited good anticancer activity against various cell lines were further studied and
their IC50 values were determined.
CHAPTER IV
An efficient and convenient approach for the synthesis of novel pyrazolo[1,2-a]
triazole-triones by glacial acetic acid catalyzed three component condensation and
evaluation of their antimicrobial activities
Nitrogen-containing heterocycles having a urazole (1,2,4-triazolidine-3,5-diones)
moiety are important as they are part of natural and non-natural products, many of
which having a variety of biological activities. They are also utilized in the production
of polymeric materials. Pyrazolo[1,2-a]triazole-triones having urazole substructure are
reported for their antifungal properties. Therefore, we have attempted synthesis of some
novel pyrazolo[1,2-a]triazole-triones and evaluated their antimicrobial and antifungal
activities.
IV.1: Synthesis of novel pyrazolo[1,2-a]triazole-triones
In this chapter, we report glacial AcOH catalyzed synthesis of novel 7-aryl-2phenyldihydropyrazolo[1,2-a][1,2,4]triazole-1,3,5(2H)-triones by one pot condensation
of aldehydes, Meldrum’s acid, and 4-phenylurazole. Reactions were attempted with
different catalysts such as p-TSA, H2SO4, CAN, Et3N, L-proline, La(OTf)3 and Gl.
AcOH under different conditions. However, best results were obtained when aldehyde
(1.0 mmol), Meldrum’s acid (1.0 mmol) and 4-phenylurazole (1.0 mmol) were heated
in presence of 20 mol% of glacial AcOH at 80°C. Glacial acetic acid served both as
catalyst and medium. A wide range of aromatic aldehydes bearing electronwithdrawing as well as electron-donating groups underwent the reactions smoothly
under the optimized reaction conditions to give the desired pyrazolo[1,2-a]triazole-
triones in high yields (eq. 6).
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Bis-condensation product was obtained when the reaction was attempted with
terephthaldehyde. The structure of 7-(2-chlorophenyl)-2-phenyldihydropyrazolo[1,2-a]
[1,2,4]triazole-1,3,5(2H)-trione was also established by X-ray crystallography. The
reactions have been proposed to be proceeding via Knoevenagel condensation followed
by Michael addition with concomitant loss of acetone and carbon dioxide.
IV.2: Evaluation of antimicrobial activities of pyrazolo[1,2-a]triazole-trione derivatives
The synthesized pyrazolo[1,2-a]triazole-trione derivatives were screened for their
antibacterial and antifungal activities. The compounds possessed variable antibacterial
activity against Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis) and
antifungal activity against Aspergillus niger and A. flavus. However, the compounds did
not exhibit any activity against Gram-negative bacteria (Escherichia coli, Pseudomonas
aeruginosa). Among all the tested compounds, 7-(2,4-dichlorophenyl)-2-phenyl
dihydropyrazolo[1,2-a][1,2,4]triazole-1,3,5(2H)-trione showed good antibacterial and
antifungal activity.
CHAPTER V
Lanthanum triflate catalyzed rapid oxidation of 1,2-diols, α-hydroxyketones and
alcohols with urea-hydrogen peroxide (UHP) in ionic liquid
Urea-hydrogen peroxide (UHP) has been reported as an inexpensive oxidizing agent
and requires a co-catalyst to exhibit its oxidizing potential for various substrates. We
have investigated the potential of UHP as an oxidizing agent in the presence of
lanthanum triflate in [bmim]BF4 for the oxidation of 1,2-diols, α-hydroxy ketones and
alcohols.
In this chapter, we have reported a simple procedure for the oxidation of 1,2-diols to
1,2-diketones, α-hydroxyketones to 1,2-diketones and
alcohols to corresponding
carbonyl compounds with UHP in the presence of 10 mol% of La(OTf)3 in [bmim]BF4
at 70°C. The reaction conditions were optimized by model reaction of hydrobenzoin
with UHP and different catalysts in ionic liquids by changing the molar ratios and
temperature. Reaction with 1:2 molar ratio of substrate:UHP with 10 mol% of La(OTf)3
in [bmim]BF4 gave benzil in 90% yield in 60 min at 70°C. Subsequently a variety of
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Chapter VI
hydrobenzoins and aliphatic 1,2-diols were oxidized to the corresponding 1,2-diketones
in high yields under these conditions (eq. 7).
The application of UHP as an oxidant for the oxidation of α-hydroxyketones in
[bmim]BF4 was also investigated. α-Hydroxyketones also underwent oxidation using
1:2 molar ratio of substrate:UHP with 10 mol% La(OTf)3 in [bmim]BF4 at 70°C to give
the corresponding 1,2-diketones in high yields (eq. 8).
The efficiency of this method was further evaluated for oxidation of alcohols. A variety
of alcohols both aromatic and aliphatic could be oxidized to the corresponding carbonyl
compounds in high yields with UHP in presence of La(OTf)3 in [bmim]BF4. Diaryl
alcohols required higher molar equiv. of UHP for completion of reaction (eq. 9).
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