SYNTHESIS AND BIOLOGICAL STUDYOF

PYRAZOLES, AMINO-PYRIMIDINES AND

JJTU MALONONITRILES DERIVED FROM
CYCLIC IMIDES
THESIS
SUBMITTED TO THE
SHRI JAGDISH PRASAD JHABARMAL
TIBREWALA UNIVERSITY,
FOR THE DEGREE
OF

DOCTOR OF PHILOSOPHY
IN

CHEMISTRY
Year -2016
 TITLE
SYNTHESIS AND BIOLOGICAL STUDYOF
PYRAZOLES, AMINO-PYRIMIDINES AND
MALONONITRILES DERIVED FROM CYCLIC IMIDES

Name of scholar : Ravindra Shenfadu Dhivare

Registration Number : 15712276
Subject : Chemistry
Guide : Dr. Rajendrasingh Yadav
Co-Guidance of : Dr. Rajput Shankarsing Sardarsing

Year: 2016
The Thesis Has Been Divided Into The Following
Points

Abstract
Introduction
Justification
Literature Survey
Objective of the plan work
Chapter wise Synthesis & Results
Concluding Remarks
Future Scope
 ABSTRACT

Formylation is a fundamental route of organic synthesis

subsequently the formation of aldehyde which plays an
intermediate role. The formyl chalcones are very important
intermediates and building blocks widely employed in the synthesis
of diverse pyrazole and pyrimidine systems. Bis-chalcones are the
synthestic and naturally occurring flavonoids present in the variety
of food stuffs. These are recently focused as a pharmacological,
medicinal, and several synergistic groups of biological activities.
Chalcone based pyrazoles and pyrimidines show the wide range of
applications in medicines. Pyrimidino-pyrazoles are being studied
in the combact against cancer so on. Malononitriles is a versatile
active methylene group used as initial constituent in the synthesis
of nitrile groups in the Knoevenagel condensation reaction of cyclic
imides by eco-friendly route. All the compounds in the research
scheme were synthesized by conventional and microwave
synthetic methods.
 ABSTRACT Cont.…

The synthesis of N-phenyl-pyrrolidine-2, 5-dione (2a-j) and N-

phenyl-piperidine-2, 6-dione (4a-j) has been developed. The
method involves in the first step; the treatment of substituted
anilines and succinic anhydrides in benzene which form N-
phenylcarbamoyl propanoic acid and then further cyclization with
acetyl chloride. Some of N-phenyl succinimides and N-phenyl
glutarimides are so far unknown. All these synthesized cyclic
imides may by use for preparation of various heterocyclic systems
such as chalcones, pyrazoles, pyrimidines and malononitriles. The
development of bis-chalcone (5a-j and 7a-j) involves in the
treatment of cyclic imides and vanillin in neutral alumina in
microwave solvent free method. Correspondingly the synthesis of
pyrazole (6a-j and 8a-j) derivatives has been obtained by the
treatment of substituted chalcones and hydrazine hydrate with
neutral alumina.
 ABSTRACT Cont.…

Similarly the substituted amino-pyrimidines (9a-j and 10a-j) were

also prepared by bis-chalcones and guanidine nitrate with neutral
alumina in microwave solvent free synthesis. As a final point the
Knoevenagel condensation of malononitrile derivatives (11a-j and
12a-j) was consistently prepared thru the same method by using
cyclic imides and di-cyanomethane in presence of neutral alumina.
All the synthesized compounds were found reasonable
antibacterial activities counter to Bacillus subtilis gram +ve and
Escherichia coli gram -ve bacterial strains. Likewise they showed
significant to good activities against fungal strains Candida
albicans and Aspergillus niger. Out of these, some of the
compound exhibited synergistic antifungal activities.
 INTRODUCTION

The science of assembling heterocyclic ring has made

enormous strides in recent years. The proper arrangement of
such assemblies has general novel molecular species.
Heterocycles provide the various beneficial resource routes for
the construction of the heterocyclic systems in various kinds of
synthetic policies including aldol-condensation, cyclo-addition,
cyclo-condensation and molecular-rearrangement so on
 INTRODUCTION Cont….

The chemistry of chalcones created the challenges of scientific

studies all over the globe. They are especially remarkable for their
biological, pharmaceutical and industrial relevance due to their multi-
coloured characteristics. Basically they are benzylidene-
acetophenones but they are popularly known as “Chalcone”
specified by the scientist S.V. Kostanecki and J. Tambor in the year
1899. Aldol-condensation is the significant variety of scheme
available for the synthesis of chalcones. Various naturally occurring
antibiotics and amino-chalcones possess their biological activity
which exist an unsaturated carbonyl group. Chalcones were
illustrated by their tenure structure along with two aromatic rings.
 INTRODUCTION Cont….

Pyrazole is a simple aromatic five membered ring compound has

very important class of heterocycles due to its biological and
pharmacological activities which exhibit an anti-inflammatory,
herbicidal, plant growth regulating, fungicidal, bactericidal, anti-
pyretic and protein kinase inhibitors. In the crop production
chemistry, there is a great significance of pyrazole derivatives due
to their biological potency amongst herbicidal, fungicidal and
insecticidal action found with their stroke of synthetic routes and
the mode of action. Pyrazole derivatives can be used as an
inhibitor action in blood platelet aggregation in recent times and
also very important in the field of enzyme inhibition. The types of
pyrazole nucleus are,
 INTRODUCTION Cont….

Pyrimidine is the most important and essential diazine which is

useful for all types of life processes on the mother earth. It
occupies a great role in the heterocyclic compounds because of
its therapeutic, pesticidal, insecticidal and fungicidal actions. It
also possesses good pharmacological properties. Almost all the
derivatives of pyrimidine based chalcones demonstrated excellent
anti-microbial activities.
 INTRODUCTION Cont….

Malononitrile (MDN) is vital and prevalently acknowledged reagent

which is helpful for the heterocyclic synthesis. It shows versatile
moiety and its reactivity is broadly spread in chemical, biological,
medicinal and industrial fields due to its pesticidal, fungicidal,
pharmaceutical, dyestuff making, charge transfer, semiconductor,
organic conductor and electrochemical transformation activities. A
malononitrile derivative also gives remarkable stability and electrical
properties which is well suitable to organic conductors for the
charge transfer development systems. Due to its electron
withdrawing groups; it is also efficient electron acceptors for the
semiconductor devices. Hence, the malononitrile builds a significant
chemical property in medicinal research and chemical synthesis.
The malononitrile nucleuses are;
 INTRODUCTION Cont….

Cyclic-imides are the part of cyclic amide ring compounds which

is having the molecular structure -CO-V(R)-CO- imide ring and
are hydrophobic as well as neutral in nature but they can traverse
the biological membranes. Some general structures of cyclic
imides are;
 JUSTIFICATION

Rationale – The main validating aim of the present research is to

demonstrate the importance of the organic synthesis and its
scope with the numerous properties against biological, medicinal,
pharmacological, agriculture as well as industrial fields. By
interpreting the endurance of current situation; here the
researcher is going to prepare some of the important compounds
such as pyrazoles, amino-pyrimidines and malononitriles
derivatives from chalcones and expecting to examine their
biological activities.
LITERATURE
SURVEY

1 Gilchrist T. L. reported of new and improved methods of aromatic building

(1999) blocks of heterocycles by ring compounds

2 Doan T.N., Dao reported chalcones i.e. synthetic flavonids

T.T. (2011)

3 Shibata S. Anti-tumorigenic Chalcones, Stem Cells

(1994)

4 Jamal H. et al. Chalcones: Differential effects on glycogen contents of

(2009) liver, brain and spinal cord in rats

5 Sharma B. et al. Chalcones a New Class of Potential Non- Azo Dyes

(2010)

6 Werner et al. A Convenient Synthesis of 4-Aminoaryl Substituted Cyclic

(2003) Imides

7 Prado et al. Biological evaluation of some selected Cyclic Imides:

(2004) Mitochondrial Effects and in vitro Cytotoxicity
LITERATURE
SURVEY Cont…
8 Kolyamshin N-Aryl-2-dialkylaminosuccinimides
O.A., Danilov
V.A. (2004)
9 Shetgiri N.P., Synthesis and antimicrobial activity of some succinimides
Nayak B.K.
(2005)
10 Guevara-Salazar The Electronic Influence on the Active Site-Directed
et al. (2007) Inhibition of Acetylcholinesterase by N-aryl-Substituted
Succinimides
11 Wang et al. Efficient Synthesis of 4,5-Disubstituted-3-toluenesulfonyl
(2008) Glutarimides Application to the Formal Synthesis of
Mappicine Ketone
12 Michalska et al. Glutarimide: A Carrier Transporting Drug Through Cell
(2000) Membranes
13 Corradi et al. New “Green” Approaches to the Synthesis of Pyrazole
(2007) Derivatives

14 Radi S. Synthesis and Preliminary Biological Activity of Some New

(2010) Pyrazole Derivatives as Acyclonucleoside Analogues
 LITERATURE
SURVEY Cont…
14 Bole S.B. Synthesis and biological evaluation of novel pyrazole
(2011) derivatives as urease inhibitors

15 Yuvaraj S. Analysis and Antibacterial Evaluation of Pyrazole Derivative

(2009)

16 Sharma R.N. Synthesis, Characterization, and Biological activities of

(2010) Some New Arylazopyrazoles
17 Solankee et al. Chalcones, pyrazolines and aminopyrimidines as
(2009) antibacterial agents
18 Mohebbi S. "Synthesis route-based hit identification approach" as a tool
(2011) in medicinal chemistry and its application in investigating
the anti-proliferative and antimicrobial effects of 2-
aminopyrimidine derivatives
19 Nofal Z.M. Synthesis of new pyrimidine derivatives with evaluation of
(2011) their anti-inflammatory and analgesic activities
20 Suneel Kumar Synthesis and characterization of some novel Pyrimidines
K.(2011) via Aldol Condensation
 LITERATURE
SURVEY Cont…

21 Singh K. et al. 2-Aminopyrimidine based 4-aminoquinoline anti-plasmodial

(2012) agents, Synthesis, biological activity, structure-activity
relationship and mode of action studies
22 Sharma V. & Synthesis and biological activity of some 2-amino-4,6-
Sharma K.V. substituted-diarylpyrimidines: reaction of substituted
(2011) chalcones with guanidinium carbonate
23 Kim B.R. et al. Efficient Synthesis of 4,5,6-Trisubstituted-2-
(2009) aminopyrimidines
24 El-Zahar M.I. Synthesis, Antitumor Activity and Molecular Docking Study
(2011) of Novel Benzofuran-2-yl Pyrazole Pyrimidine Derivatives
25 Sidhu et al. Chemoselective reaction of malononitrile with imine-ones
(2010) and antifungal potential of products
26 Helmy N.M. et A route to dicyanomethylene pyridines and substituted
al. benzonitriles utilizing malononitrile dimer as a precursor
(2011)
27 Bhuiyan et al. Microwave assisted knoevenagel condensation: synthesis
(2012) and antimicrobial activities of some arylidene-
malononitriles
 LITERATURE
SURVEY Cont…
28 Ameta K.L. et al. Synthesis of some novel chalcones and their facile one-pot
(2011) conversion to 2-aminobenzene-1, 3-dicarbonitriles using
malononitrile
29 Deng H. et al. Discovery of 2-(4-Methylfuran-2(5H)-ylidene)malononitrile
(2011) and Thieno[3,2-b]thiophene-2-carboxylic Acid Derivatives
as G Protein-Coupled Receptor 35 (GPR35) Agonists
30 Hosni H.M. and Anti-Inflammatory and Analgesic Activities of some newly
Abdulla M.M. Synthesized Pyridinedicarbonitrile and
(2008) Benzopyranopyridine Derivatives
31 Rajput S.S. Synthesis and Characterization of Bis-Heteroyclic
(2012) Derivatives of 1-(3-Chlorophenyl)-Pyrrolidine-2, 5-Dione
32 Kumar R. Synthesis and Biological Evaluation of some Novel
(2008) Analogue of p-Hydroxyaniline
33 Rajput A.P. and Synthesis, Characterization and Microbial Screening of
Girase P.D. Pyrazoline Derivatives of 2, 6-Dichloro-1-(N-Substituted
(2011) Phenyl)-1, 4-Dihydropyridine-3, 5-Dicarbaldehyde
34 Rajput A.P. and Synthesis of 2, 5-dichloro 3, 4-diformyl (N-substituted
Bhadane S.J. phenyl) pyrroles and their synthetic utility
(2012)
 RESEARCH OBJECTIVES

1) To prepare N-substituted phenyl-succinimides and

glutarimides from succinic anhydride and glutaric
anhydride using substituted aniline and their
characterization.
2) To synthesize prazoles from N–phenyl-succinimides and
glutarimides and scrutinize their characterization.
3) To synthesize amino-pyrimidines from N–phenyl-
succinimides and glutarimides and examine their
characterization.
4) To synthesize the malononitrile derivatives from N–phenyl-
succinimides and glutarimides and assess their
characterization.
5) The entire synthesized compound series will be tested for
their biological potencies.
MATERIALS AND METHODS

Synthesis of Cyclic Imides

Synthesis of Chalcone Derivatives from imides
Synthesis of pyrazole derivatives
Synthesis of Amino-pyrimidines
Synthesis of Malononitriles
Characterization of all of the compounds
Biological Activities of all synthesized derivatives
MATERIALS AND METHODS
 CHAPTER-3

SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL

ACTIVITIES OF N-PHENYL SUCCINIMIDE AND N-PHENYL
GLUTARIMIDE DERIVATIVES
A comprehensive literature review discloses that the chemistry of
N-substituted phenyl succinimides and glutarimides have not been
studied significantly. To achieve our aim we have developed
efficient and economical two step synthesis followed by acid
intermediates by using succinic anhydride and glutaric anhydride
as a starting compounds for the construction of N-substituted
phenyl succinimides and glutarimides. In this method Succinic
anhydride or glutaric anhydride was treated with substituted
aromatic primary amines in presence of benzene which gives acid
intermediates. The acid intermediates further refluxed with acetyl
chloride furnished N-substituted phenyl succinimides (2a-j) and N-
phenyl glutarimides (4a-j) as visualized in (Scheme-I).
CHAPTER-3 Cont.…..
CHAPTER-3 Cont.…..

The researcher has developed the convenient method for the

synthesis of N-phenyl succinimide & Glutarimide derivatives.
The experimental method is demonstrated in the fig.
HCl fumes
Escape

10 mmole
NH2

O
O NH OH

O O
O
O N O

10 mmole After dried

completely
then reflux O
30 ml next step Cl

90 mmole
Refluxed at 90-110 ºC up to 15 - 20 minutes for both conditions
CHAPTER-3 Cont.…..

To accomplish the research objective benzene (10 mmole) was

added in succinic anhydride and heated under reflux with
constant stirring for 15 to 20 minutes till the solution becomes
clear. Into this solution the primary aromatic amines and α-
napthyl amine ‘A’ (10 mmole) in 5 ml benzene was slowly
poured with constant stirring for 15 to 20 minutes till the
solution becomes homogenized. Upon evaporation of benzene
the whitish amorphous powder of 3-(N-phenyl or
napthylcarbamoyl) propanoic acid 1a-j was obtained.

The mixture of 3-(N-phenyl or napthylcarbamoyl) propanoic

acid 1a-j and acetyl chloride (90 mmole) was refluxed with
constant stirring at the temperature 90-110 ºC for 15 to 20
minutes till the complete evolution of HCl gas. The mixture was
then became cool at room temp accomplished the solid
products 2a-j. Thus the crude product was washed 2 to 3 times
by lukewarm distilled water and filtered off; the resulting solids
were recrystallized from ethanol (Scheme–Ia).
CHAPTER-3 Cont.…..

NH2 NHCOCH2CH2COOH
O
O O
N
Acetyl
Benzene Chloride
O +
Reflux Reflux
90-110 ºC 90-110 ºC
® ®
S O A 1a-j
®
2a-j
® , a = -H, b = -4Br, c = -4Cl, d = -4CH3, e = -4OCH3,
f = -4F, g = -4NO2, h = -phenyl, i = -3Cl,-4F, j = -2,4,5Cl

Scheme -Ia: Preparation of N-phenyl Succinimides

CHAPTER-3 Cont.…..

Physical Characteristics of 2a-j

Product
Sr. Substituted Compound Molecular Practical M.P. Range
M.W. Colour
No. Aniline Code Formula Yield (ºC)
(Crude)
Cream
1 -H 2a C10H9NO2 175.06 79.91% 154-156 ºC
White
2b Whitish
2 4-Br C10H8BrNO2 254.08 89.78% 174-176 ºC
Brown
2c Whitish
3 4-Cl C10H8ClNO2 209.63 76.60% 159-161 ºC
Lavender
2d
4 4-CH3 C11H11NO2 189.21 62.73% 150-152 ºC
Cream
2e
5 4-OCH3 C11H11NO3 205.21 78.91% 160-162 ºC
Brown
2f
6 4-F C10H8FNO2 193.17 62.90% 176-178 ºC
Brownish
2g Cream
7 4-NO2 C10H8N2O4 220.18 88.86% 219-221 ºC
Yellow
2h Dark
8 α-Napthyl C14H11NO2 225.24 99.11% 148-150 ºC
Lavender
2i Pinkish
9 3-Cl,4-F C10H7ClFNO2 227.62 84.60% 158-160 ºC
White
2j Pure
10 2,4,5-Cl C10H6Cl3NO2 278.52 75.56% 196-198 ºC
White
CHAPTER-3 Cont.…..

O NH2 NHCO(CH2)3COOH
O N O

Acetyl
Benzene Chloride
O +
Reflux Reflux
90-110 ºC 90-110 ºC
® ®
G O A ®
3a-j 4a-j
® , a = -H, b = -4Br, c = -4Cl, d = -4CH3, e = -4OCH3,
f = -4F, g = -4NO2, h = -phenyl, i = -3Cl,-4F, j = -2,4,5Cl
Scheme -Ib: Preparation of N-phenyl Glutarimides
CHAPTER-3 Cont.…..

Physical Characteristics of 4a-j

Product
Sr. Substituted Compound Molecular Practical M.P. Range
M.W. Colour
No. Aniline Code Formula Yield (ºC)
(Crude)
Cream
1 -H 4a C11H11NO2 189.21 77.92% 120-122 ºC
Colour
Whitish
2 4-Br 4b C11H10BrNO2 268.11 82.94% 144-146 ºC
Brown
Faint
3 4-Cl 4c C11H10ClNO2 223.66 86.70% 123-125 ºC
Lavender
Marble
4 4-CH3 4d C12H13NO2 203.24 77.07% 179-181 ºC
Colour

5 4-OCH3 4e C12H13NO3 219.24 76.66% 138-140 ºC

Brownish

6 4-F 4f C11H10FNO2 207.2 76.35% 119-121 ºC

Brownish
Cream
7 4-NO2 4g C11H10N2O4 234.21 84.01% 168-170 ºC
Yellow
Dark
8 α-Napthyl 4h C15H13NO2 239.37 83.61% 153-155 ºC
Lavender
Whitish
9 3-Cl,4-F 4i C11H9ClFNO2 241.65 91.30% 104-106 ºC
Brown
Pure
10 2,4,5-Cl 4j C11H8Cl3NO2 292.55 85.73% 138-140 ºC
White
CHAPTER-3 Cont.…..

Spectral Analysis of 2a-j & 4a-j

These title derivatives were characterized by their spectral analysis. Elemental
analysis the series of these compounds were found closely around the given
ranges of C: 57.83, H: 3.59, N: 2.50. These compounds in its IR spectrum
observed and showed the frequency bands at 1800 cm-1 to 1665 cm-1 typical
range for cyclic anhydride carbonyl carbon groups, bands between 3000 cm -1 to
2800 cm-1 for –CH2−CH2− and –CH2−CH2−CH2− stretching for cyclic group,
array frequency bands at 1350 cm-1 to 1300 cm-1 for cyclic imine groups, bands
at 1650 cm-1 to 1450 cm-1 three peaks for aromatic ring and a single band of Ar-
Br between 1075 cm-1- 1030 cm-1, Ar-Cl between 1035 cm-1- 1100 cm-1, Ar-F
between 1250 cm-1- 1100 cm-1, Ar-NO2 between 1550 cm-1- 1500 cm-1, Ar-OCH3
between 1350 cm-1- 1100 cm-1 in the starting substituted phenyl succinimides
was found, verified and confirmed the formation of cyclic imides. The 1HNMR
spectrum of the compounds 2a-j and 4a-j in CDCl3 solvent showed typical
signals of aromatic (7.16-7.36 δ) multiplets 4H atoms, napthyl group (7.30-8.03
δ) multiplet signals of seven protons and imide group signal (2.94 δ) four
protons. Based on these data the probable structures of 2a-j and 4a-j were
predicted.
CHAPTER-3 Cont.…..

Spectra of 2a-j
CHAPTER-3 Cont.…..

Spectra of 4a-j
CHAPTER-3 Cont.…..

Antimicrobial Activities of N-Phenyl Succinimide and N-

Phenyl Glutarimide Series: 2a-j & 4a-j

Antibacterial Activities of

2a-j & 4a-j

CHAPTER-3 Cont.…..

Antimicrobial Activities of N-Phenyl Succinimide and N-

Phenyl Glutarimide Series: 2a-j & 4a-j

Antifungal Activities of

2a-j & 4a-j

CHAPTER-3 Cont.…..

Result & Discussion of 2a-j & 4a-j

The compounds 2a-j and 4a-j were found moderately active against
gram +ve Bacillus subtilis and gram -ve Escherichia coli bacterial
strains. In the same way only a few compounds 2a, 2f, 2i were showed
significant potency against Aspergillus niger and Candida albicans
fungal strains and compound 2j was found moderate activity against
Candida albicans.
CHAPTER- 4

SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL

ACTIVITIES OF PYRAZOLE DERIVATIVES
Pyrazole derivatives have concerned a great deal of consideration on
account of their wide range of application in biological, pharmaceutical and
medicinal domains. To accomplish the objective we have designed
ecofriendly, efficient and economical solvent free synthesis followed by
chalcone intermediates. The substituted bis-chalcones 5a-j and 7a-j were
prepared initially irradiation of substituted phenyl succinimides (2a-j) and
glutarimides (4a-j) with vanillin using neutral alumina in microwave.
Subsequently to accomplish the pyrazole synthones, the afforded
chalcones were reacted with hydrazine hydrates in presence of neutral
alumina in solvent free microwave condition furnishes the (6a-j) and (8a-j)
compounds foreseen in the (Scheme-II).
CHAPTER- 4 Cont.…..
 CHAPTER- 4 Cont.…..

Material Method: Melting points were noted and uncorrected by open-glass

capillaries. IR spectra in (KBr pallets) were note down via Shimadzu FṮIṞ꞉8400Ṡ
and ATR Brucker alpha FṮ-IṞ spectrophotometer. 13C NMR and 1H NMR spectras
were monitored on 500.13 MHz, 400 MHz and 125.77 MHz by Brucker
spectrophotometer. The reactions were monitored by TLC executed by using pre
coated silica-gel aluminium plates with mixture of diethyl ether and ethyl acetate
7:3 proportion or benzene. All the compounds 5a-j, 6a-j, 7a-j and 8a-j were
synthesized in the domestic microwave oven Electrolux Nutrition in hours from the
corresponding commercially available 4-hydroxy-3-methoxy benzaldehyde
(vanillin), hydrazine hydrate, neutral alumina (Al2O3) and ethanol as shown in the
fig.
 CHAPTER- 4 Cont.…..

General Procedure for the Synthesis of Bis-chalcones by using N-Phenyl

Succinimides 5a-j:

The bis-chalcones (5a-j) are synthesized by the mixture of 5 mmole of

phenyl substituted succinimides (2a-j) and 10 mmole of 4-hydroxy-3-
methoxy-benzaldehyde (V) in 2 gm of neutral Al2O3 under microwave
assisted solvent free conditions at 640W powers for 5-8 minutes. The
afforded coloured compounds were recovered and recrystallized by ethanol
(Scheme – IIa) CH3 H3C
O O

CHO
HO OH
O O MW
N
Neutral Al2O3
1 + 2 O O
N
640W
OCH3 5-8 min
OH
® V
2 a-j
5 a-j ®
® , a = -H, b = -4Br, c = -4Cl, d = -4CH3, e = -4OCH3,
f = -4F, g = -4NO2, h = -phenyl, i = -3Cl,-4F, j = -2,4,5Cl

Scheme -IIa: (3Z,4Z)-3,4-bis-(-4-hydroxy-3-methoxy-benzylidene)-N-phenyl-pyrrolidine-2,5-dione (5a-j)

 CHAPTER-4 Cont.…..

Physical Characteristics of 5a-j

MW
Sr. Substituted Compd Molecular Pr. M.P. Range Product Colour
No. Aniline Code Formula Yield (ºC) (Crude)

-H 5a C26H21NO6 443.45 84.56% 112-114 ºC White Crystals

1

5b 522.34
2 4-Br C26H20BrNO6 97.59% 91-93 ºC Whitish Brown
5c 477.89 Whitish Brown
3 4-Cl C26H20ClNO6 94.93% 109-111 ºC
5d 457.47 Whitish Yellow
4 4-CH3 C27H23NO6 68.28% 99-101 ºC
5e 473.47 Muddy White
5 4-OCH3 C27H23NO7 71.48% 108-110 ºC
5f 461.44 Dark Yellow
6 4-F C26H20FNO6 64.62% 148-150 ºC
5g 488.45 Dark Yellow
7 4-NO2 C26H20N2O8 84.42% 152-154 ºC
5h 493.51 Dark Brown
8 α-Napthyl C30H23NO6 83.26% 89-91 ºC
5i 495.88 Pinkish
9 3-Cl,4-F C26H19ClFNO6 74.39% 98-100 ºC
5j 546.78 Whitish Yellow
10 2,4,5-Cl C26H18Cl3NO6 71.06% 137-139 ºC
 CHAPTER- 4 Cont.…..

General Procedure for the Synthesis of Bis-chalcones by using N-Phenyl

Glutarimides 7a-j:

The bis-chalcones (7a-j) are synthesized by the mixture of 5 mmole of phenyl

substituted glutarimides (4a-j) and 10 mmole of 4-hydroxy-3-methoxy-
benzaldehyde (V) in 2 gm of neutral Al2O3 under microwave assisted solvent
free conditions take place on 640W powers for 3-6 minutes. The afforded
coloured compounds were recovered by and recrystallized by ethanol as shown
in the scheme – IIc.
CH3 CH3
O O
CHO MW

O N O 640W HO O N O OH
3-6 min
+ 2
Neutral Al2O3
OCH3
OH
®
® V
4a-j 7a-j
® , a = -H, b = -4Br, c = -4Cl, d = -4CH3, e = -4OCH3,
f = -4F, g = -4NO2, h = -phenyl, i = -3Cl,-4F, j = -2,4,5Cl

Scheme -IIc: (3Z,5Z)-3,5-bis(4hydroxy3methoxybenzylidene)-N-phenyl-piperidine-2,6dione (7a-j)

 CHAPTER-4 Cont.…..

Physical Characteristics of 7a-j

MW
Sr. Substituted Compd Molecular Pr. M.P. Product Colour
No. Aniline Code Formula Yield Range(ºC) (Crude)

-H 7a C27H23NO6 457.47 79.91% 78-80ºC Pale Yellow

1

7b 536.37
2 4-Br C27H22BrNO6 94.37% 94-96ºC Dark Yellow
7c 491.92
3 4-Cl C27H22ClNO6 82.25% 76-78ºC Dark Yellow
7d 471.5
4 4-CH3 C28H25NO6 83.98% 95-97ºC Yellow
7e 487.5
5 4-OCH3 C28H25NO7 69.41% 68-70ºC Brown
7f 475.47
6 4-F 27H22FNO6 90.84% 85-87ºC Yellow
7g 502.47
7 4-NO2 C27H22N2O8 78.33% 93-95ºC Yellow
7h 507.53
8 α-Napthyl C31H25NO6 91.74% 88-90ºC Brown
7i 509.91
9 3-Cl,4-F C27H21ClFNO6 82.23% 74-76ºC Dark Yellow
7j 560.81
10 2,4,5-Cl C27H20Cl3NO6 83.03% 103-105ºC Yellowish white
CHAPTER-4 Cont.…..

Spectral Analysis of 5a-j & 7a-j

These intermediate derivatives were characterized by their spectral analysis.
Elemental analysis series of these compounds were found closely around the
given ranges of C: 57.83, H: 3.59, N: 2.50. These compounds in its IR spectrum
observed and showed the frequency bands at 1800 cm-1 to 1665 cm-1 typical
range for cyclic anhydride carbonyl carbon groups, a single band found
between 3100 cm-1 to 3000 cm-1 for =CH stretching for cyclic group, ranges the
frequency broad band at 3600 cm-1 to 3200 cm-1 for aromatic alcohol group,
bands at 1650 cm-1 to 1450 cm-1 for aromatic ring three peaks and a single band
of Ar-Br between 1075 cm-1- 1030 cm-1, Ar-Cl between 1035 cm-1- 1100 cm-1, Ar-
F between 1250 cm-1- 1100 cm-1, Ar-NO2 between 1550 cm-1- 1500 cm-1, Ar-
OCH3 between 1350 cm-1- 1100 cm-1 in the intermediary substituted chalcones
were found, verified and confirmed the formation of bis-chalcones. The 1HNMR
spectrum of the compounds 5a-j and 7a-j in CDCl3 and DMSO-d6 solvents
showed the signals typical of aromatic (6.80-7.42 δ) multiplets 8H atoms and
=CH group, methoxy group (3.86 δ) singlet signal of three protons and aromatic
alcoholic -OH group signal (9.77 δ) singlet for a single proton. Founded these
data the possible structures of 5a-j and 7a-j were confirmed.
CHAPTER-4 Cont.…..

Spectra of 5a-j
CHAPTER-4 Cont.…..

Spectra of 7a-j
CHAPTER-4 Cont.…..

Antimicrobial Activities of Bis-chalcones: 5a-j & 7a-j

Antibacterial Activities of

5a-j & 7a-j

CHAPTER-4 Cont.…..

Antimicrobial Activities of Bis-chalcones 5a-j & 7a-j

Antifungal Activities of

5a-j & 7a-j

 CHAPTER- 4 Cont.…..

General Procedure for the Synthesis of Bi-pyrazoles by using Bis-

chalcones derived from N-phenyl succinimides 6a-j:

The pyrazole (6a-j) derivatives were synthesized by the mixture of 2 mmole of

bis-chalcones (5a-j) and 4 mmole of hydrazine hydrate in 2 gm of neutral Al 2O3
under microwave assisted solvent free conditions on 640 W powers for 4-7
minutes. The afforded coloured compounds were recovered by ethyl acetate
and recrystallized by ethanol (Scheme – IIb)
CH3 H3C HO OH
O O
O O
H3C CH3
HO OH
MW
O O Neutral Al2O3 HN NH
N
2 NH2NH2.H2O N N N
640W
4-7 min

5 a-j
®
® , a = -H, b = -4Br, c = -4Cl, d = -4CH3, e = -4OCH3, 6 a-j ®
f = -4F, g = -4NO2, h = -phenyl, i = -3Cl,-4F, j = -2,4,5Cl
Scheme -IIb: (3Z,4Z)-3,4-bis-(4-hydroxy-3-methoxy-benzylidene)-7-(N-phenyl)-3,3a,3b,4,5,7-
hexahydro- 2H-pyrrolo[2,3-c,5,4-c] dipyrazole (6a-j)
CHAPTER-4 Cont.…..

Physical Characteristics of 6a-j

Comp
Sr. Substituted Molecular Pr. M.P. Range Product Colour
d
No. Aniline Formula MW Yield (ºC) (Crude)
Code

1 -H 6a C26H25N5O4 471.51 91.48% 172-174ºC Yellowish brown

2 4-Br 6b C26H24BrN5O4 550.4 60.36% 207-209ºC Brownish yellow

3 4-Cl 6c C26H24ClN5O4 505.95 95.61% 194-196ºC Brown chilly

4 4-CH3 6d C27H27N5O4 485.53 78.83% 197-199ºC Yellow

5 4-OCH3 6e C27H27N5O5 501.53 67.87% 179-181ºC Dark yellow

6 4-F 6f C26H24FN5O4 489.5 88.88% 202-204ºC Yellow

7 4-NO2 6g C26H24N6O6 516.51 92.63% 173-175ºC Yellow

8 α-Napthyl 6h C30H27N5O4 521.57 96.52% 128-130ºC Brown

9 3-Cl,4-F 6i C26H23ClFN5O4 523.94 76.15% 177-179ºC Pale Yellow

10 2,4,5-Cl 6j C26H22Cl3N5O4 574.84 84.66% 169-171ºC Pale Yellow

 CHAPTER- 4 Cont.…..

General Procedure for the Synthesis of Bi-pyrazoles by using Bis-

chalcones derived from N-Phenyl Glutarimides 8a-j:

The pyrazole (8a-j) derivatives were synthesized by the mixture of 2 mmole of

afforded bis-chalcones (7a-j) and 4 mmole of hydrazine hydrate in 2 gm of
neutral Al2O3 under microwave assisted solvent free conditions on 640W powers
for 3-6 minutes. The afforded coloured compounds were recovered by ethyl
acetate and recrystallized by ethanol (Scheme – IId)
HO OH
CH3 CH3
O O
O O H3 C CH3

HO O N O OH MW
HN NH
2 NH2NH2 . H2O
N N N
Neutral Al2O3
640W
® 3-6 min
7a-j

8a-j ®
® , a = -H, b = -4Br, c = -4Cl, d = -4CH3, e = -4OCH3,
f = -4F, g = -4NO2, h = -phenyl, i = -3Cl,-4F, j = -2,4,5Cl

Scheme -IId: (3Z,4Z)-3,4-bis-(4-hydroxy-3-methoxy-benzylidene)-7-(1-phenyl)-3,3a,3b,4,5,7-hexahydro-

2H- piperidine-[2,3-c,5,4-c] dipyrazole (8a-j)
CHAPTER-4 Cont.…..

Physical Characteristics of 8a-j

Sr. Substituted Compd Molecular Pr. M.P. Range Product Colour

No. Aniline Code Formula MW Yield (ºC) (Crude)

1 -H 8a C27H27N5O4 485.53 82.57% 151-153ºC Yellow granules

2 4-Br 8b C27H26BrN5O4 564.43 78.01% 157-159ºC Yellow granules

3 4-Cl 8c C27H26ClN5O4 519.98 75.37% 155-157ºC Yellow

4 4-CH3 8d C28H29N5O4 499.56 81.04% 158-160ºC Yellow

5 4-OCH3 8e C28H29N5O5 515.56 82.81% 148-150ºC Greenish muddy

6 4-F 8f C27H26FN5O4 503.52 75.20% 152-154ºC Pale Yellow

7 4-NO2 8g C27H26N6O6 530.53 83.01% 147-149ºC Yellow

8 α-Napthyl 8h C31H29N5O4 535.59 84.96% 149-151ºC Greenish brown

9 3-Cl,4-F 8i C27H25ClFN5O4 537.97 87.26% 148-150ºC Pale Yellow

10 2,4,5-Cl 8j C27H24Cl3N5O4 588.87 76.53% 144-146ºC Dark yellow

CHAPTER-4 Cont.…..

Spectral Analysis of 6a-j & 8a-j

Elemental analysis series of these compounds were found much close
around the given ranges of C: 57.83, H: 3.59, N: 2.50. These compounds in
its IR spectrum observed and showed the frequency band at 3400 cm-1 to
3100 cm-1 typical range for the presence of primary amine (−NH) groups,
ranges the frequency broad band at 3600 cm-1 to 3200 cm-1 for aromatic
alcohol group, bands at 1650 cm-1 to 1450 cm-1 for aromatic ring three peaks
and a single band of Ar-Br stuck between 1075 cm-1- 1030 cm-1, Ar-Cl
between 1035 cm-1- 1100 cm-1, Ar-F between 1250 cm-1- 1100 cm-1, Ar-NO2
between 1550 cm-1- 1500 cm-1, Ar-OCH3 between 1350 cm-1- 1100 cm-1 in
the confirmatory pyrazoles nucleus were found, proved and validated the
formation of bi-pyrazoles. The 1HNMR spectrum of the compounds 6a-j and
8a-j in CDCl3 and DMSO-d6 solvents showed the signals typical of aromatic
(6.71-8.04 δ) multiplets 8H atoms, a single peak observed in the presence of
–NH group (8.60 δ) singlet 1H, singlet signal of –CH group of 1H (4.53 δ),
singlet of –CH2 value (3.40 δ) two protons, methoxy group (3.84 δ) singlet
signal of three protons and aromatic alcoholic −OH group signal (9.73 δ)
singlet for a single proton. 13C NMR spectral values 55.99, 110.55, 115.95,
123.91, 125.97, 130.88, 148.45, 150.33 and 161.03 also observed.
Detecting these validated data the possible structures of 6a-j and 8a-j were
confirmed.
CHAPTER-4 Cont.…..

Spectra of 6a-j
CHAPTER-4 Cont.…..

Spectra of 8a-j
CHAPTER-4 Cont.…..

Antimicrobial Activities of Bi-pyrazoles: 6a-j & 8a-j

Antibacterial Activities of

6a-j & 8a-j

CHAPTER-4 Cont.…..

Antimicrobial Activities of Bi-pyrazoles 6a-j & 8a-j

Antifungal Activities of

6a-j & 8a-j

CHAPTER-4 Cont.…..

Result & Discussion of 6a-j & 8a-j

The compounds 5a-j, 6a-j, 7a-j and 8a-j were found considerable active
against gram +ve Bacillus subtilis and gram -ve Escherichia coli bacterial
strains. Similarly the compounds 5a-j and 7a-j showed superior activity
and compound 6i and 8j showed moderate activity against Candida
albicans fungal strain and 6c and 8j showed moderate activity against
Aspergillus niger.
 CHAPTER- 5

SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL ACTIVITIES OF

AMINO-PYRIMIDINES DERIVED FROM N-PHENYL SUCCINIMIDES
By considering the versatile application of pyrimidines in biological and
medicinal fields, it was planned to synthesize the new substituted amino-
pyrimidine derivatives with the hope to get potential antimicrobial agents.
To attain the target work substituted bis-chalcones derived from N-phenyl
succinimides were treated with guanidine nitrate forms the final amino-
pyrimidines respectively as shown in the Scheme - III.
 CHAPTER- 5 Cont.…..

General Procedure for the Synthesis of Amino-pyrimidines by using Bis-

chalcones derived from N-Phenyl Succinimides 9a-j:
The researcher has developed the convenient ecofriendly microwave method
used for the synthesis of amino-pyrimidine derivatives. To achieve the research
objective amino-pyrimidine (9a-j) derivatives were synthesized by the mixture of
2 mmole of afforded bis-chalcones (5a-j) and 4 mmole of guanidine nitrate in 2
gm of neutral Al2O3 under microwave assisted solvent free conditions on 640W
power for 4-7 minutes. The afforded coloured compounds were recovered by
ethyl acetate and recrystallized by ethanol (Scheme – IIIa)
CH3 H3C OH OH
O O O O
H3 C CH3

HO OH

O O MW 640W
N N N
Neutral Al2O3 4-7 min
NH H 2N N N N NH2
2
H2 N NH2 .HNO3

5 a-j
®

® , a = -H, b = -4Br, c = -4Cl, d = -4CH3, e = -4OCH3, 9 a-j ®

f = -4F, g = -4NO2, h = -phenyl, i = -3Cl,-4F, j = -2,4,5Cl
Scheme -IIIa: 9-(N-phenyl)-4,5-(2","'-methoxyphenol)-9H-1,3,6,8,9-penta-azo-fluorene-2,7-diamine (9a-j)
CHAPTER-5 Cont.…..

Physical Characteristics of 9a-j

Sr. Substituted Compd Molecular Pr. M.P. Product Colour

No. Aniline Code Formula MW Yield Range(ºC) (Crude)

1 -H 9a C28H23N7O4 521.53 92.30% 179-181ºC White

2 4-Br 9b C28H22BrN7O4 600.42 79.66% 117-119ºC Wheat

3 4-Cl 9c C28H22ClN7O4 555.97 76.81% 104-106ºC Dark Yellow

4 4-CH3 9d C29H25N7O4 535.55 80.45% 108-110ºC Wheat

5 4-OCH3 9e C29H25N7O5 551.55 67.88% 105-107ºC Whitish

6 4-F 9f C28H22FN7O4 539.52 81.34% 114-116ºC Yellow

7 4-NO2 9g C28H22N8O6 566.52 55.83% 113-115ºC Pale Yellow

8 α-Napthyl 9h C32H25N7O4 571.59 100-102ºC Dark Brown

9 3-Cl,4-F 9i C28H21ClFN7O4 573.96 83.50% 117-119ºC White

10 2,4,5-Cl 9i C28H20Cl3N7O4 624.86 73.71% 149-151ºC White

 CHAPTER- 6

SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL ACTIVITIES OF

AMINO-PYRIMIDINES DERIVED FROM N-PHENYL GLUTARIMIDES
In view of the multipurpose application of pyrimidines in pharmacological,
biological medicinal arenas and in our work continuance for the synthesis of
amino-pyrimidines, it was deliberated to synthesize the new substituted
amino-pyrimidine derivatives with the confidence to get potential
antimicrobial agents. To attain the target work substituted bis-chalcones
derived from N-phenyl glutarimides were treated with guanidine nitrate forms
the final amino-pyrimidines respectively as shown in the Scheme - IV.
 CHAPTER- 6 Cont.…..

General Procedure for the Synthesis of Amino-pyrimidines by using

Bis-chalcones derived from N-Phenyl Glutarimides 10a-j:
The researcher has developed the convenient ecofriendly microwave method
used for the synthesis of amino-pyrimidine derivatives. To achieve the research
objective amino-pyrimidine (10a-j) derivatives were synthesized by the mixture
of 2 mmole of afforded bis-chalcones (7a-j) and 4 mmole of guanidine nitrate in
2 gm of neutral Al2O3 under microwave assisted solvent free conditions on
640W power for 4-7 minutes. The afforded coloured compounds were recovered
by ethyl acetate and recrystallized by ethanol (Scheme – IVa)
OH OH
CH3 CH3
O O
O O H3 C CH3

HO N OH
MW 640W N N
Neutral Al2O3 4-7 min
NH H 2N N N N NH2
2
® H2 N NH2 .HNO3
7 a-j

® , a = -H, b = -4Br, c = -4Cl, d = -4CH3, e = -4OCH3, 10 a-j ®

f = -4F, g = -4NO2, h = -phenyl, i = -3Cl,-4F, j = -2,4,5Cl
Scheme -IVa: 9-(N-phenyl)-4,5-(2","'-methoxyphenol)-9H-1,3,6,8,9-hexa-azo-fluorene-2,7-diamine (10a-j)
 CHAPTER-6 Cont.…..

Physical Characteristics of 10a-j

Substitute
Sr. Compd Molecular Pr. M.P. Range Product Colour
d
No. Code Formula MW Yield (ºC) (Crude)
Aniline

1 -H 10a C29H25N7O4 535.55 80.45% 89-91ºC Dark Yellow

2 4-Br 10b C29H24BrN7O4 614.45 76.54% 99-101ºC Dark Yellow

3 4-Cl 10c C29H24ClN7O4 570.00 83.03% 88-90ºC Yellow

4 4-CH3 10d C30H27N7O4 549.58 79.12% 108-110ºC Yellow

5 4-OCH3 10e C30H27N7O5 565.58 67.25% 88-90ºC Yellowish Brown

6 4-F 10f C29H24FN7O4 553.54 80.00% 91-93ºC Dark Yellow

7 4-NO2 10g C29H24N8O6 580.55 70.68% 123-125ºC Pale Yellow

8 α-Napthyl 10h C33H27N7O4 585.61 64.60% 103-105ºC Dark Brown

9 3-Cl,4-F 10i C29H23ClFN7O4 587.99 72.60% 84-86ºC Yellow

10 2,4,5-Cl 10j C29H22Cl3N7O4 638.89 72.10% 128-130ºC White

CHAPTER-5 & 6 Cont.…..

Spectral Analysis of 9a-j & 10a-j

Elemental analysis series of these compounds were found much close
around the given ranges of C: 57.83, H: 3.59, N: 2.50. These compounds in
its IR spectrum observed and showed the frequency band at 3400 cm-1 to
3100 cm-1 typical range for the presence of primary amine (−NH) groups,
ranges the frequency broad band at 3600 cm-1 to 3200 cm-1 for aromatic
alcohol group, bands at 1650 cm-1 to 1450 cm-1 for aromatic ring three peaks
and a single band of Ar-Br stuck between 1075 cm-1- 1030 cm-1, Ar-Cl
between 1035 cm-1- 1100 cm-1, Ar-F between 1250 cm-1- 1100 cm-1, Ar-NO2
between 1550 cm-1- 1500 cm-1, Ar-OCH3 between 1350 cm-1- 1100 cm-1 in
the confirmatory pyrazoles nucleus were found, proved and validated the
formation of bi-pyrazoles. The 1HNMR spectrum of the compounds 6a-j and
8a-j in CDCl3 and DMSO-d6 solvents showed the signals typical of aromatic
(6.71-8.04 δ) multiplets 8H atoms, a single peak observed in the presence of
–NH group (8.60 δ) singlet 1H, singlet signal of –CH group of 1H (4.53 δ),
singlet of –CH2 value (3.40 δ) two protons, methoxy group (3.84 δ) singlet
signal of three protons and aromatic alcoholic −OH group signal (9.73 δ)
singlet for a single proton. 13C NMR spectral values 55.99, 110.55, 115.95,
123.91, 125.97, 130.88, 148.45, 150.33 and 161.03 also observed.
Detecting these validated data the possible structures of 6a-j and 8a-j were
confirmed.
CHAPTER-5 & 6 Cont.…..

Spectra of 9a-j
CHAPTER-5 & 6 Cont.…..

Spectra of 10a-j
CHAPTER-5 & 6 Cont.…..

Antimicrobial Activities of Amino-pyrimidines: 9a-j

Antibacterial Activities of

9a-j
CHAPTER-5 & 6 Cont.…..

Antimicrobial Activities of Amino-pyrimidines: 10a-j

Antibacterial Activities of

10a-j
CHAPTER-4 Cont.…..

Antimicrobial Activities of Amino-pyrimidines 9a-j & 10a-j

Antifungal Activities of

9a-j & 10a-j

CHAPTER-5 & 6 Cont.…..

Result & Discussion of 9a-j & 10a-j

Results: The compounds 9a-j were found adequate results practicing

against gram +ve Bacillus subtilis and gram -ve Escherichia coli bacterial
strains. In the same way these compounds exhibited the significantly
superior antifungal activity against Aspergillus niger and Candida
albicans fungal strains.

Results: The compounds 10a-j attained the reasonably active against

gram +ve Bacillus subtilis and gram -ve Escherichia coli bacterial strains.
Similarly some of these compounds validated the synergistic antifungal
activity against Candida albicans and Aspergillus niger fungal strains.
 CHAPTER- 7

SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL ACTIVITIES

OF MALONONITRILE DERIVATIVES
A wide-ranging literature review discloses that the chemistry of
malononitrile have not been explored extensively. Various synthetic
practices were reported for the synthesis of malononitrile derivatives but
the majority of the processes experience from limitations such as
availability of the precursors, multi-steps, lengthy reaction conditions,
tolerance of functional group and comparatively low yield. The chemical
and pharmacological importance and inconvenient and inefficient
procedures encouraged us to develop a short, candid and inexpensive and
ecofriendly route for the construction of malononitrile derivatives. Thus, we
planned to synthesize the novel malononitrile derivatives from substituted
N-phenyl succinimides and N-phenyl glutarimides as a final target
visualized in the Scheme – V.
CHAPTER- 7 Cont.…..
 CHAPTER- 7 Cont.…..

General Procedure for the Synthesis of Malononitriles by using N-Phenyl

Succinimides 11a-j:

The researcher has developed the convenient ecofriendly microwave method

used for the synthesis of malononitrile derivatives. To achieve the research
objective malononitriles (11a-j) derivatives were synthesized by the mixture of
2 mmole of afforded N-phenyl succinimides (2a-j) and 4 mmole of
dicyanomethane in 2 gm of neutral Al2O3 under the microwave assisted solvent
free conditions on 640W power for 4-7 minutes. The afforded brownish and
coffee coloured compounds were recovered and recrystallized by ethanol.
(Scheme – Va)
N
NC CN
O O C MW
N N
Neutral Al2O3 NC CN
+ 2 HC
2
640W
C 4-7 min
N
2 a-j ® 11 a-j ®

® , a = -H, b = -4Br, c = -4Cl, d = -4CH3, e = -4OCH3,

f = -4F, g = -4NO2, h = -phenyl, i = -3Cl,-4F, j = -2,4,5Cl
Scheme -Va: 2-(5-dicyanomethylene-N-phenyl-pyrrolidin-2-ylidene)-malononitrile (11a-j)
 CHAPTER-7 Cont.…..

Physical Characteristics of 11a-j

Sr. Substituted Compd Molecular Pr. M.P. Range Product Colour

No. Aniline Code Formula MW Yield (ºC) (Crude)

1 -H 11a C16H9N5 271.28 55.55% 138-140 ºC Dark Brown

2 4-Br 11b C16H8BrN5 350.17 45.71% 130-132ºC Brown

3 4-Cl 11c C16H8ClN5 305.72 65.57% 105-107ºC Brownish yellow

4 4-CH3 11d C17H11N5 285.3 59.29% 113-115ºC Whitish brown

5 4-OCH3 11e C17H11N5O 301.3 26.91% 118-120ºC Brownish yellow

6 4-F 11f C16H8FN5 289.27 47.05% 129-131ºC Brownish yellow

7 4-NO2 11g C16H8N6O2 316.27 28.48% 160-162ºC Brownish yellow

8 α-Napthyl 11h C20H11N5 321.33 72.89% 80-82ºC Violet

9 3-Cl,4-F 11i C16H7ClFN5 323.71 63.46% 143-145ºC Yellowish white

10 2,4,5-Cl 11j C16H6Cl3N5 374.61 53.47% 175-177ºC White

 CHAPTER- 7 Cont.…..

General Procedure for the Synthesis of Malononitriles by using N-Phenyl

Glutarimides 12a-j:

To achieve the research objective malononitriles (12a-j) derivatives were

synthesized by the mixture of 2 mmole of afforded N-phenyl glutarimides (4a-j)
and 4 mmole of dicyanomethane in 2 gm of neutral Al2O3 under the microwave
assisted solvent free conditions on 640W power for 4-7 minutes. The afforded
brownish and coffee coloured compounds were recovered and recrystallized by
ethanol. (Scheme – Va)

C MW NC CN
O N O N
Neutral Al2O3
+ 2 HC
2 CN CN
640W
C 4-7 min
N
4 a-j ® 12 a-j ®
® , a = -H, b = -4Br, c = -4Cl, d = -4CH3, e = -4OCH3,
f = -4F, g = -4NO2, h = -phenyl, i = -3Cl,-4F, j = -2,4,5Cl

Scheme -Vb: 2-(6-dicyanomethylene-N-phenyl-piperidin-2-ylidene)-malononitrile (12a-j)

 CHAPTER-7 Cont.…..

Physical Characteristics of 12a-j

Sr. Substituted Compd Molecular Pr. M.P. Range Product Colour

No. Aniline Code Formula MW Yield (ºC) (Crude)

1 -H 12a C17H11N5 285.3 61.40% 97-99ºC Coffee

2 4-Br 12b C17H10BrN5 364.2 35.71% 133-135ºC Whitish mud

3 4-Cl 12c C17H10ClN5 319.75 74.60% 80-82ºC muddy

4 4-CH3 12d C18H13N5 299.33 48.49% 164-166ºC Cream

5 4-OCH3 12e C18H13N5O 315.33 40.95% 107-109ºC Lavender mud

6 4-F 12f C17H10FN5 303.29 67.65% 119-121ºC Yellowish

7 4-NO2 12g C17H10N6O2 330.3 28.78% 115-117ºC Brown mud

8 α-Napthyl 12h C21H13N5 335.36 28.05% 95-97ºC Dark violet

9 3-Cl,4-F 12i C17H9ClFN5 337.74 54.89% 91-93ºC Brown

10 2,4,5-Cl 12j C17H8Cl3N5 388.64 38.65% 109-111ºC Cream

CHAPTER-7 Cont.…..

Spectral Analysis of 11a-j & 12a-j

The malononitrile derivatives were characterized by their spectral analysis.
Elemental analysis the series of these compounds were found closely nearby
given default ranges of C: 57.83, H: 3.59, N: 2.50. The IR spectrum observed of
these compounds which showed the frequency bands at 2300 cm-1 to 2100 cm-
1
typical range for nitrile C≡N group, bands between 3000 cm-1 to 2800 cm-1 for
–CH2−CH2− and –CH2−CH2−CH2− stretching for cyclic group, ranges the
frequency bands at 1350 cm-1 to 1300 cm-1 for cyclic imine groups, bands at
1650 cm-1 to 1450 cm-1 three peaks for aromatic ring and a single band of Ar-Br
between 1075 cm-1- 1030 cm-1, Ar-Cl between 1035 cm-1- 1100 cm-1, Ar-F
between 1250 cm-1- 1100 cm-1, Ar-NO2 between 1550 cm-1- 1500 cm-1, Ar-OCH3
between 1350 cm-1- 1100 cm-1 in the substituted malononitriles was found,
verified and confirmed the formation of malononitriles. The 1HNMR spectrum of
the compounds 11a-j and 12a-j in CDCl3 and DMSO-d6 solvents showed the
representative signals of aromatic (7.02-7.58 δ) multiplets 5H atoms, napthyl
group (7.30-8.03 δ) multiplet signals of seven protons and imide group signal
(2.28 δ) multiplet two protons of 11a-j and multiplet signals 2H (1.81 δ) in 12a-j.
13
C NMR detected the values 16.90, 20.57, 24.66, 32.77, 39.80, 39.97, 40.15,
112.50, 118.99, 124.36, 125.39, 131.01 and 173.10 and the molecular weight of
11b also confirmed by HRMS. Based on these data the probable structures of
11a-j and 12a-j were predicted.
CHAPTER-7 Cont.…..

Spectra of 11a-j
CHAPTER-7 Cont.…..

Spectra of 12a-j
CHAPTER- 7 Cont.…..

Antimicrobial Activities of Malononitriles: 11a-j & 12a-j

Antibacterial Activities of

11a-j & 12a-j

CHAPTER-7 Cont.…..

Antimicrobial Activities of Malononitrile 11a-j & 12a-j

Antifungal Activities of

11a-j & 12a-j

CHAPTER- 7 Cont.…..

Result & Discussion of 11a-j & 12a-j

Results: The compounds 11a-j and 12a-j were found moderately active
against gram +ve Bacillus subtilis and gram -ve Escherichia coli bacterial
strains. Similarly these compounds exhibited the significantly superior
antifungal activity against Aspergillus niger and Candida albicans fungal
strains.
 CHAPTER- 8

CONCLUDING REMARKS AND FUTURE SCOPE

Chapter wise conclusions:
Chap-3: Synthesis, Characterization and Biological Activities of
N-Phenyl Succinimide and N-Phenyl Glutarimide Derivatives

The synthesized compounds 2a-j and 4a-j were evaluated in–vitro

antimicrobial activities by using gram +ve Bacillus subtilis and gram -ve
Escherichia coli bacterial strains. Similarly antifungal, activity against
Aspergillus niger and Candida albicans fungal strains. Almost all the
compounds indicated moderate antibacterial activities and significant
antifungal activities equated with standard drug. These synthones were used
as a title compounds for further preparation of chalcones, pyrazoles,
pyrimidines and malononitrile derivatives.

Some of N-phenyl succinimides and N-phenyl glutarimides

are so far unknown. All these synthesized cyclic imides
may by use for preparation of various heterocyclic
systems such as chalcones, pyrazoles, pyrimidines so on.

CONCLUSION
 CHAPTER- 8 Cont.…..

Chap-4: Synthesis, Characterization and Biological Activities of Pyrazole

Derivatives
CONCLUSION
Overall method for the synthesis of bis-chalcones 5a-j and 7a-j has been
developed by using different substituted phenyl succinimides and glutarimides
with di-substituted aromatic aldehyde vanillin in the solvent-free microwave
method. Correspondingly further treatment on bis-chalcones with hydrazine
hydrate gave substituted pyrazoles 6a-j and 8a-j. Bis-chalcones and pyrazoles
both were screened their antimicrobial activities. As a result, they showed
moderate to good activities against Bacillus subtilis and Escherichia coli strains.
Similarly some bis-chalcones showed superior antifungal activities bu only few
pyrazoles showed good antifungal activities against Candida albicans and
Aspergillus niger strains.

1. Over-all method for the synthesis of bis–chalcone derivatives has been

developed. The method consists of the treatment of afforded cyclic imides and
vanillin in neutral alumina in microwave solvent free method.
2. Correspondingly the synthesis of pyrazole derivatives has been obtained by
the treatment of substituted chalcones and hydrazine hydrate with neutral
alumina.
3. The ecofriendly microwave method can be used for the preparation of
different substituted heterocyclic synthones.
 CHAPTER- 8 Cont.…..

Chap-5 & 6: Synthesis, Characterization and Biological Activities of

Amino-Pyrimidines derived from N-phenyl Sucinimides.

Substituted amino-pyrimidines 9a-j and 10a-j was synthesized from bis-chalcones

and guanidine nitrate by eco-friendly rout of the microwave irradiated solvent-free
method. These synthones were evaluated in vitro antimicrobial activities against
Bacillus subtilis and Escherichia coli with different concentrations found
considerable activity. Similarly they exhibited significantly synergistic antifungal
activity against Candida albican and Aspergillus niger strains as compared to
standard drugs.
1) General method for the synthesis of substituted amino-pyrimidines
was developed which consists of the treatment of afforded
bis-chalcones and guanidine nitrate with neutral alumina in
microwave solvent free synthesis.
2) The amino-pyrimidines formed 9a-j so far novel synthones
and might be used for the preparation of innumerable heterocyclic
schemes such as Schiff’s bases and condensation products so on.
3) Common method for the synthesis of substituted amino-pyrimidines
was prepared by consisting treatment of synthesized bis-chalcones
derived from N-phenyl glutarimides and guanidine nitrate
with neutral alumina in microwave solvent free method.
4) These amino-pyrimidines may be used for the synthesis
CONCLUSION
of various heterocycles.
 CHAPTER- 8 Cont.…..

Chap- 7: Synthesis, Characterization and Biological Activities of

Malononitrile Derivatives

At the end of all the sections, malononitrile 11a-j and 12a-j derivatives were
developed by the title compounds with the mixture of dicyanomethane in
microwave method. These synthesized active methylene malononitrile
analogs were evaluated against the same bacterial and fungal strains. Almost
all the compounds showed moderately active against bacterial strains but
superior and synergistic activity showed on fungal strains.

1. A general method for the properties of malononitrile

derivatives 11a-j and 12a-j has been developed.
2. The compounds 11a-j and 12a-j may be used for
properties of various heterocyclic syntheses.

CONCLUSION
FUTURE
SCOPE
The contents of this thesis are research centered by continuing testimony and the views
of the heterocyclic synthesis group. There is a considerable amount of activities in the
area of the development of eco-friendly and sophisticated chemical synthesis. There are
a number of syntheses and novel synthones with their antimicrobial activities were
successfully reported in the current situations. Here the researcher was developed some
novel heterocyclic compounds and screened their biological activities as well as put the
future scope of these newly synthesized compounds.
1) The different substituted N-phenyl succinimides may be used for the synthesis of heterocyclic
analogs.
2) The substituted N-phenyl glutarimides may be used for the development of heterocyclic
derivatives.
3) These cyclic imides may be used as stiffning agent in the production of vulcanized rubber.
4) Chalcones from succinimides may be used for the synthesis of novel heterocyclic synthones.
5) Chalcones derived from glutarimides may be used for the preparation of the novel hetero
compounds.
6) Pyrazoles derived fro the chalcones may be used for the different and new heterocyclic
synthesis.
7) Some of these pyrazoles can also be used for making the dyes or pigments in dye industries.
8) Amino-pyrimidines from the chalcones may be used for the preparation of different types of
heterocyclic analogs.
9) Some amino-pyrimidine derivatives might be suitable for the fungicides and fungal infection
against human being due to their greater potency towards fungi species.
10) Malononitrile derivatives derived from the succinimides and glutarimides may be used for the
development of novel heterocyclic and cyano groups.
ANY
QUESTION
Prepared By,
Name of scholar : Dhivare Ravindra S.
Registration Number: 15712276
Subject : Chemistry