MICROWAVE ASSISTED AND

CHARACTERIZATION OF
4’-SUBSTITUTED SPIRANES

A.AARTHI (Register number – 19HCH01)

A.AARTHI (Register number – 19HCH01)
M.Phil., CHEMISTRY
M.Phil., CHEMISTRY
PG & RESEARCH DEPARTMENT OF CHEMISTRY
PG & RESEARCH DEPARTMENT OF CHEMISTRY
SEETHALAKSHMI RAMASWAMI COLLEGE
SEETHALAKSHMI RAMASWAMI COLLEGE
TIRUCHIRAPPALLI, TAMIL NADU, INDIA
TIRUCHIRAPPALLI, TAMIL NADU, INDIA
INTRODUCTION
• Constructing the carbon framework or skeleton of
the desired molecule
• Introducing, removing or transforming functional
groups in a fashion that achieves the functionality
of the desired compound.
• Exercising selective stereocontrol at all stages in
which centers of stereoisomerism are created or
influenced.
• A successful synthesis must produce the desired
product in reasonable amount, it should be as
short and efficient as possible.
 A two or three-step sequence is usually better than a six or
seven step procedure, even if the individual step yields are better
in the longer route.
 Recovery or recycling of expensive reagents and catalysts is
often desirable.
 The term atom efficiency has been coined to reflect the latter
point.
 For a given target molecule, several different reaction
sequences may serve to accomplish its synthesis. Indeed, new
synthetic routes to known compounds continue to be reported,
particularly as new reactions are developed and applied to difficult
transformations.
 Evaluating the quality and efficacy of these diverse procedures
involves consideration of all the above.
 HETEROCYCLIC SPIRO
COMPOUNDS
Synthesis of heterocyclic compounds is of great
interest in synthetic organic chemistry because of their
existence in drugs, biologically active molecules and in
many natural products such as vitamins, hormones,
antibiotics and alkaloids.
 The spiro-atom is a quaternary carbon and they are
generally called as spiranes. Spiro compounds provide
unique preparative challenges as whether each ring
contributing to its structure is unique or identical or
whether they are carbocyclic or heterocyclic owing to
the practical implications of tetra-functionalizing
character of the central spiro atom (often with four
different groups) and the unique aspects of chirality.
Spiroaromaticity in organic chemistry refers to a
special case of aromaticity in which conjugation is
interrupted by a single spiro atom.
Though this spiro center disrupts the continuous
overlap of p-orbitals, traditionally thought to be a
requirement for aromaticity.
 Spirocompounds have considerable thermodynamic
stability and many of the spectroscopic,magnetic, and
chemical properties associated with aromatic
compounds are still observed for such compounds.
 MICROWAVE ASSISTED
ORGANIC SYNTHESIS
 In the new millennium, Industrial chemistry is
adopting the concept of green chemistry to meet the
synthetic challenges of protecting human health and
environment while maintaining commercial visibility.
 A most important aspect is the replacement of
volatile organic solvents from the reaction medium
with possible substitution by non-volatile or
recyclable alternatives,
 Among the emerging important tools the use of
Microwaves as alternative source of energy is
becoming an alternative especially under the solvent
It is an environmentally friendly technology since it can
reduce or eliminate the use of solvents. Since products
are often produced in pure form with microwaves, use
of solvents and chromatographic methods in
purification can also be reduced.
Microwave
assisted
reaction

Orga
nic Organic
Water
synth solvents

esis

Solid
state
 AIM AND SCOPE
Heterocyclic ring systems of spiro indoline pyrrolidine
nucleus

Spiro indoline pyrrolidine

Unique non-polar core units of many
Biologically active
structure naturally occurring
pharmaceutical molecules possess
And rigid chiral
applications significant
structure pharmacological activities
The
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 3’-benzoyl-4’-phenyl-5’-(piperazine-1-
ylmethyl)spiro[indoline-3,2’-pyrrolidine]-2-
one.
 3’-benzoyl-4’-(p-tolyl)-5’-(piperazine-1-
ylmethyl )spiro[indoline-3,2’-pyrrolidine]-2-
one.
 3’-benzoyl-4’-(4-methoxyphenyl)-5’-
(piperazine-1-ylmethyl)spiro[indoline-3,2’-
pyrrolidine]-2-one.
 3’-benzoyl-4’-(4-bromophenyl)-5’-(piperazine-
1-ylmethyl)spiro[indoline-3,2’-pyrrolidine]-2-
one.
 ToTo discover and
characterize effective
analyse
To carry out the
therapeutic molecu
agents lar
with
the newly synth esized
docking studies to p red ict the
minimum
copmpoun side effects
ds with and
their
predomin ant binding mod es
melting point, FT-IR, ¹H-NMR
ofmaximum potential
the ligand with protein .
and ¹³C NMR.
actions.
EXPERIMENTAL METHODS
Synthesis of 3’-benzoyl-4’-
substituted Spiranes
Mixture of isatin, 2-(piperazine-1-yl) ethanamine
Aryl substituted chalcones
Sulphated yttria as catalyst

Using Methanol as a solvent

Under Microwave irradiation at 220w, 80oC for 10 min
Extracted with ethyl acetate (30 ml).The organic layer was washed with brine
solution, dried with anhydrous sodium sulfate and concentrated in vacuo .

The residue was purified by column chromatography with hexane–ethyl acetate

(8:2) mixture to get
3'-benzoyl-4'-phenyl-5'-(piperazin-1-ylmethyl) spiro[indoline-3,2'-
pyrrolidin]-2-one
 3'-benzoyl-4'-phenyl-5'-(piperazin-1-ylmethyl)
spiro[indoline-3,2'-pyrrolidin]-2-one
3'-benzoyl-5'-(piperazin-1-ylmethyl)-4'-(p-tolyl)
spiro[indoline-3,2'-pyrrolidin]-2-one
3'-benzoyl-4'-(4-methoxyphenyl)-5'-(piperazin-1-
ylmethyl) spiro[indoline-3,2'-pyrrolidin]-2-one
3'-benzoyl-4'-(4-bromophenyl)-5'-(piperazin-1-
ylmethyl) spiro[indoline-3,2'-pyrrolidin]-2-one
CHARACTERISATION OF 4’-
SUBSTITUTED SPIRANES
 3'-benzoyl-4'-phenyl-5'-(piperazin-1-ylmethyl)
spiro[indoline-3,2'-pyrrolidin]-2-one

FT-IR spectrum
FT-IR absorption bands (cm-1) of compounds
of
4’-sustituted spiranes

Carbonyl C=O
Compounds -NH
Due to benzoyl Due to indolone

group group

18 3408.44 1716.83 1674.28

19 3406.41 1715.03 1670.18

20 3409.48 1711.80 1671.20

21 3400.44 1712.03 1679.22

H NMR spectrum of 3'-benzoyl-4'-phenyl-5'-(piperazin-1-ylmethyl)
1

spiro[indoline-3,2'-pyrrolidin]-2-one
1
H chemical shifts (ppm) of compounds 4’-substituted spiranes

C-8,C-12
Compounds H-3 H-4 H-5 H-6 Aromatic protons
N-H Others
C-9,C-11

18 5.02 4.49 4.15 1.25 2.21- 2.60 0.88, 6.47, 7.95 - 6.75-7.46

19 5.03 4.47 4.10 1.28 2.25- 2.76 0.97, 6.67, 7.93 1.95 (CH3) 6.68-7.46

20 5.08 4.48 4.11 1.27 1.85 -2.37 0.89, 6.47, 7.95 4.14 (OCH3) 6.75-7.46

21 5.18 4.64 4.32 1.57 2.19- 2.87 1.43, 6.59, 8.10 - 6.75-7.45
1
H-NMR spectrum of 3'-benzoyl-4'-(p-tolyl)-5'-(piperazin-1-
ylmethyl)
spiro[indoline-3,2'-pyrrolidin]-2-one
1
H NMR spectrum of 3'-benzoyl-4'-(4-methoxyphenyl)- 5'-(piperazin-1-ylmethyl)
spiro[indoline-3,2'-pyrrolidin]-2-one
1
H- NMR spectrum of 3'-benzoyl-4'-(4-bromophenyl)-5'-(piperazin-1-ylmethyl)
spiro[indoline-3,2'-pyrrolidin]-2-one
 C NMR spectrum of 3'-benzoyl-4'-phenyl- 5'- (piperazin-1-ylmethyl)
13

spiro[indoline-3,2'-pyrrolidin]-2-one
13
C chemical shifts of 4’-substituted spiranes (δ ppm)

Compounds 18 19 20 21

C-2 66.9 67.8 66.8 67.8

C-3 62.3 62.0 62.3 62.0

C-4 60.4 60.5 60.4 60.5

C-5 61.0 61.1 61.1 61.1

C-6 29.7 29.6 29.6 29.5

C-9 & C-11 59.1 59.2 59.2 59.2

C-8 & C-12 50.9 50.8 50.8 50.7

C=O, Benzoyl 197.2 197.1 197.2 196.1

C=O, Indolone 182.1 182.3 182.4 181.3

21.4 54.3
Others -
-
(CH3) (OCH3)

Aromatic and ipso 109.5- 108.7-

108.6-144.1 109.5-144.1
carbons 144.2 144.2
 C NMR spectrum of 3'-benzoyl-4'-(p-tolyl)- 5'-(piperazin-1-ylmeth
13

spiro[indoline-3,2'-pyrrolidin]-2-one
13
C NMR spectrum of 3'-benzoyl-4'-(4-methoxyphenyl)-5'-(piperazin-1-ylmethyl
)spiro[indoline-3,2'-pyrrolidin]-2-one
13
C NMR spectrum of 3'-benzoyl-4'-(4-bromophenyl)-5'-(piperazin-1-
ylmethyl) spiro[indoline-3,2'-pyrrolidin]-2-one
Molecular Docking Studies
 Docking studies were performed to gain insight into the
protein inhibitor interactions inside the enzyme binding sites.
 Molecular docking studies of all the compounds were
performed with Argus lab and the visualization is carried out
using discovery studio 4.5.
 A comparative and automated docking study with newly
synthesized lead compounds was performed to determine the
best in silico conformation.
3D and 2D view of binding interaction
D and 2D view of binding interaction of standard drug 1RV1
 CONCLUSION

In a view of microwave assisted synthesis was carried out to synthesise the

following new compounds.
 3’-benzoyl-4’-phenyl-5’-(piperazine-1-ylmethyl) spiro[indoline-3,2’-
pyrrolidine]-2-one.
 3’-benzoyl-4’-(p-tolyl)-5’-(piperazine-1-ylmethyl)spiro[indoline-3,2’-
pyrrolidine]-2-one.
 3’-benzoyl-4’-(4-methoxyphenyl)-5’-(piperazine-1-ylmethyl)
spiro[indoline-3,2’-pyrrolidine]-2-one.
 3’-benzoyl-4’-(4-bromophenyl)-5’-(piperazine-1-ylmethyl)
spiro[indoline-3,2’-pyrrolidine]-2-one.
 In the IR spectrum of the representative compound the
-NH group of indolone, pyrrole and piperazine moiety exhibits
a broad absorption peak at higher frequency i.e. 3408.44 cm-1 is
due to the presence of adjacent carbonyl group and piperazine
ring.

 A strong absorption band at 1716.83 cm-1 is due to benzoyl

carbonyl stretching and a shoulder band at 1674.28 cm-1 is due
to indolone carbonyl stretching.

 The aromatic and aliphatic C-H stretching absorption

bands are observed in the region of 2810-3084 cm-1.
 The 1H-NMR spectrum, the indolone, pyrrole and
piperazine -NH proton signals are observed at 7.95,
6.47 and 0.88 ppm respectively.
 A doublet appears at 5.02 ppm is assigned to H-3
proton of the pyrrolidine moiety. A triplet appears at
4.49 ppm is assigned to H-4 proton and a multiplet
appears at 4.15 ppm is assigned to H-5 proton signal.
H-6 proton signal appears at 1.25 ppm.
 The signals appears in the region of 2.21-2.60 ppm
with eight proton integral are assigned for piperazine
ring protons.
 C-NMR spectrum of 18 exhibits the presence of
13

two carbonyl carbons, one due to benzoyl and

another due to indolone moiety at 197.2 and 182.1
respectively and the signals of aromatic carbons
are observed in the region of 144.1-108.6 ppm. .
The spiro carbon (C-2) of the pyrrolidine ring
appears in the most downfield region at 66.9 ppm
among all the carbons of this ring. The peak
observed at 62.3 is regarded as due to C-3 because
of an adjacent carbonyl group of benzoyl moiety
Molecular Docking studies were performed to gain insight
into the protein inhibitor interactions inside the enzyme
binding sites .
Docking of synthesized ligands with 1RV1 exhibit amino
acids present in the active pocket of the receptor. Docked
2D and 3D images of with standard drug molecules,
provides the ligand pose energy, van der waals interaction,
conventional hydrogen bond, pi-pi interaction, alkyl and
pi-alkyl interaction of all the docked compound.
The best ligand pose energy of compound 21 is -14.86
kcal/mol whereas the standard drug molecule is -11.64
kcal/mol.