INTRODUCTION

Chalcones, also known as 1,3-diaryl-2-propene-1-one, are α,β-unsaturated ketones

containing the reactive ketoethylenic group (–CO–CH=CH–). Benzalacetophenone or
benzylidene acetophenone are other names for these compounds. In chalcones, an aliphatic
three-carbon chain structurally connects two aromatic rings. The term "chalcone" is derived
from the Greek word "chalcos," meaning "bronze," which describes the characteristic color of
most natural chalcones. Chalcones are abundant in nature and can be found in fruits, tea, the
roots of Uvaria siamensis, Stevia lucida, and Pongamia pinnata (L.) Pierre, as well as in
various foodstuffs. The term "chalcone" was coined by Kostanecki and Tambor. These
compounds are colored due to the presence of a chromophore (–CO–CH=CH–), and the
intensity of the color depends on the presence of additional auxochromes. Alternative names
for chalcones include phenyl styryl ketones, β-phenyl acetophenone, γ-oxo-diphenyl-α-
propylene, and α-phenyl benzoethylene. They are non-chiral, small molecules with molecular
weights typically ranging between 300 and 600 g/mol and exhibit high lipophilicity. Due to
the delocalization of electron density in the (C=C–C=O) system, compounds containing an
α,β-unsaturated carbonyl system, such as chalcones, possess two electrophilic reactive
centers. This enables them to undergo reactions either through nucleophilic attack on the
carbonyl group (1,2-addition) or at the β-carbon via 1,4-conjugate addition, leading to the
formation of bioactive molecules. These reactions are particularly useful in the synthesis of
biologically active five- and six-membered heterocycles. Chalcones, characterized by their
α,β-unsaturated ketone structure (Fig. 1), have attracted significant attention in medicinal
chemistry due to their diverse pharmacological properties.

Chalcones exhibit potent antioxidant activity,1 which plays a crucial role in combating
oxidative stress-related diseases such as cancer, cardiovascular disorders, and
neurodegenerative diseases. Their ability to scavenge free radicals and inhibit oxidative
damage makes them promising candidates for therapeutic applications. In addition, many
chalcones possess anti-inflammatory properties,2 which help alleviate inflammation
associated with conditions such as arthritis, asthma, and inflammatory bowel diseases. By

1
modulating inflammatory pathways, chalcones show potential for the development of novel
anti-inflammatory agents. Furthermore, chalcones have demonstrated significant
antimicrobial activity3 against a broad spectrum of pathogens, including bacteria, fungi, and
viruses. This antimicrobial efficacy highlights their importance in the development of new
antibiotics, antifungal agents, and antiviral drugs, particularly in the context of increasing
antimicrobial resistance. Some naturally occurring chalcones are also available as marketed
drugs.

Xanthohumol- Anticancer Licochalcone A – Anti microbial

Xanthoangelol- Anti-obesity Cardamonin- Anti-HIV protease

Butein - Antioxidant Isoliquiritigenin - Anti-inflammatory

2
METHODS OF SYNTHESIS OF CHALCONES

1. Claisen-Schmidt condensation

The reaction of 2,4-dihydroxyacetophenone with furan-2-carbaldehyde in the

presence of a base led to α,β-unsaturated ketones (chalcones). Claisen-Schmidt
condensation is the most dominating method employing diversity of catalysts such as
LiOH, H2O, K2CO3, NaOCH3, KOH, NaOH, AlCl3, Ba(OH)2, HCl, Boric acid, CsOH-
γAl2O3, Cesium salts of 12-Tungstophosphoric acid.4

2. Aldol Condensation

Aldehydes/ ketones containing α-hydrogen atoms undergo reversible self-addition in

the presence of base to give β-hydroxy aldehydes which on dehydration resulted in α,β-
unsaturated carbonyl compounds.5

3. Julia-Kocienski Olefination

A series of chalcones is synthesized by the condensation of a new Julia coupling

reagent, 2-(ethanesulfonyl)-1-phenylethan-1-one and aromatic aldehydes in the presences
of a base such as DBU.6

3
4. Meyer-Schuster Rearrangement

Through a formal 1,3-hydroxyl shift and tautomerization in a Meyer–Schuster

rearrangement, propargyl alcohols are transformed into chalcone. For the production of
chalcones, scientific researchers have discovered an effective gold-catalyzed process.7

5. Stille coupling reactions

. Pd was used as a catalyst for the selective formation of Z sulfenyl chalcones

was reported by using Stille cross-coupling with the Z-α-sulfenyl-β-chloroenones.8

6. Heck reaction

Chalcones have been synthesized by vinylation of aryl halide (such as phenyl

halide) with styrene under carbon monoxide in the presence of palladium catalyst
which undergoes carbonylative coupling.9

4
7. Suzuki Coupling reaction

The synthesis of chalcones by employing carbon-carbon bond formation was

stimulated by palladium wherein coupling between cinnamoyl chloride and
phenylboronic acid gives chalcones.10

8. Friedel-Craft acylation reaction

Chalcone can be made from 3,5-dihydroxy-2,4-dimethylbenzaldehyde and

cinnamoyl chloride using a strong Lewis acid catalyst, such as aluminium
trichloride.11

9. One-Pot synthesis of Chalcones

By skipping intermediary purification and increasing yields, one-pot synthesis

is a technique for increasing reaction efficiency and conserving time. Using CrO3 as
an oxidizing agent, chalcone can be produced from alcohol and ketone in a single
pot.12

5
10. Cross-coupling between terminal alkynes and aldehydes

A cross coupling reaction between terminal alkynes and aryl aldehydes was
also reported to be involved in the synthesis of chalcones and their derivatives.
Moreover, it was reported that the coupling between terminal alkyne and aldehyde
could be accomplished using a Lewis acid (SnCl2) or copper salts (CuSO4).13

11. Decarboxylative cross-coupling reaction

Decarboxylative cross-coupling reactions between α-keto acids and alkenes

using a silver-catalyzed decarboxylation process resulted in chalcones.14

12. Microwave-Assisted Synthesis

Microwave-assisted organic synthesis (MAOS) is a valuable technique in

green chemistry, known for significantly reducing reaction times while enhancing
product yields. Equimolar amounts of the corresponding aldehydes and 2-acetyl
heterocyclic derivatives were combined and dissolved in the least amount of alcohol.
Aqueous potassium hydroxide solution was gradually added and combined. A 70–
80% yield was achieved after the reaction mixture was microwave-irradiated for two
to five minutes at a power of 180 watts.15

6
13. Ultrasound-Assisted Synthesis

Adole et al, reported the first synthesis method for obtaining - 2(E)-3-(2,3-
dihydro-1-benzofuran-5-yl)-1-phenylprop-2-en-1-one under ultrasound irradiation,
when acetophenones and 2,3-dihydrobenzofuran-5-carbaldehyde reacted in ethanol
with sodium hydroxide presence and under ultrasound radiation at room
temperature.16

14. Enzyme-Catalyzed Synthesis

Acylase from Aspergillus melleusalso showed activity in the synthesis of

E-chalcone. This acylase also catalyzed the reaction between acetophenone and
p-nitrobenzaldehyde, together with the recombinant D-aminoacylase.17

15. Heteroaromatic Hybrid Chalcone Synthesis

The heteroaromatic units incorporated into the chalcone framework include

both single-ring systems (such as furan, pyrrole, thiazole, thiophene, pyridine, and
pyrimidine) and fused-ring systems (including indole, benzimidazole, benzothiazole,
benzofuran, pyrazolopyridine, and quinoline).18

7
16. Chalcone synthesis by ionic liquids

Ionic liquids are quite distinct from molten salts, which melt at greater
temperatures. The first ionic liquid is Chloroaluminate, was invented in 1948. The
reactants aldehydes and ketones were mixed with aqueous media. Then 1-ethyl-3
methylimidazolium (EMIM) hydrogen sulphate (HSO4) ionic liquid was mixed into
reaction media as a catalyst and reflux. After completion of the reaction, the product
was formed.19

17. Synthesis of chalcone by Nano catalyst

Equimolar concentration of benzaldehyde and acetophenone were mixed

together. Then added the nano catalysts like MCM-41-SO3H, CuNPs/C, copper ferrite
(CuFe2O4) in this solution mixture. Then Stirred this solution continuously until the
yellow colour precipitate was formed. Thus, the crude chalcone was prepared. Then
the crude chalcone was purified by column chromatography or recrystallization
process.20

8
 PRESENT WORK

The synthetic intermediates- chalcones were prepared by the reaction of one mole of
ketone with one mole of aldehyde in the presence of base to (2E)-3-(1H-indol-2-yl)-1-(1H-
indol-3-yl)prop-2-en-1-one. The acyl anion generated from ketone in the presence of base
attacks carbonyl carbon of aldehyde resulted in the formation of β-hydroxyketone (Scheme
I). Adopting the similar methodology the compounds, (2E)-1-(7-hydroxy-1-benzofuran-2-yl)-
3-(1H-pyrrol-2-yl)prop-2-en-1-one from 2-acyl-7-hydroxy-benzofuran and pyrrole-2-
carboxaldehyde and (2E)-1-(1H-indol-3-yl)-3-(4-methoxyphenyl)prop-2-en-1-one from 3-
acyl-indole and 4-methoxybenzaldehyde were prepared. This on heating eliminates water to
afford α,β-unsaturated ketone (Scheme I). The reaction was repeated under Ultrasonication at
a frequency of 35 KHz for 20-35 min to afford the desired compounds in high yield when
compared with Conventional method of stirring.

REACTION-I

MECHANISM:

SCHEME I

9
REACTION-II

REACTION-III

Identification of the compounds by spectral parameters

The IR spectra of these compounds 3, 6 and 9 displayed absorption bands in the regions
1612-1720 cm-1 and 1523-1622 cm-1 due to C=O and C=C stretching frequencies.

The 1H NMR spectrum of 3 exhibited a doublet in the downfield region at δ 6.45 ppm
which is due to Hβ. The signal of Hα displayed another doublet at 6.15 ppm. The J value
(J≈16.0 Hz) indicated that the olefin protons are in trans geometry. The aromatic protons
displayed multiplet in the region δ 6.81-7.80 ppm.

The13C NMR spectrum of 3 showed signals at δ 189.8 ppm (C=O), 140.9 ppm (C-HB),
127.4 ppm (C-HA), CH carbons of 2-indole and 3-indole appeared at 101.2 ppm and 138.5
ppm respectively and the remaining signals were due to aromatic carbon atoms.

10
Hβ Hα
Hα

11
 EXPERIMENTAL

Conventional method

An equimolar mixture of indole-3-carboxaldehyde (0.005 M, 0.7258 g), 3-acyl-indole

(0.005 M, 0.7959 g) and 95% ethanol (15 mL) were taken in a 100 mL conical flask equipped
over a magnetic stirrer. To this aqueous NaOH (0.015 M, 0.6 g, 10 mL) was added and stirred
for 3-4 hrs. After completion of the reaction (monitored by TLC), the contents were poured
into ice water (3 mL) . The solid separated was filtered and dried. It is recrystallized from
ethanol to get analytically pure compound.

Ultrasonication method

In a 100 mL conical flask equimolar ratio of indole-3-carboxaldehyde (0.005 M,

0.7258g), 3-acyl-indole (0.005 M, 0.7959 g) and 95% ethanol (15 mL) were taken. To this
aqueous NaOH (0.015 M, 0.6g, 10 mL) was added and equipped in ultrasonic bath at a
frequency of 35 KHz. After completion of the reaction (monitored by TLC), the contents
were poured into ice water . The solid separated was filtered and dried. It is recrystallized
from ethanol to get a pure compound.

The same procedure was used to synthesize (2E)-1-(7-hydroxy-1-benzofuran-2-yl)-3-

(1H-pyrrol-2-yl)prop-2-en-1-one and (2E)-1-(1H-indol-3-yl)-3-(4-methoxyphenyl)prop-2-en-
1-one and the results were mentioned in Table I.

TABLE I

Ultrasonication
Melting Conventional method
Compound name method
point
Yield Time Yield Time
(C)
(%) (hrs) (%) (min)

(2E)-3-(1H-indol-2-yl)-1-(1H-
126 -128 65 2 82 35
indol-3-yl)prop-2-en-1-one

(2E)-1-(7-hydroxy-1-benzofuran-
2-yl)-3-(1H-pyrrol-2-yl)prop-2- 180-182 68 1 1/2 79 20
en-1-one

(2E)-1-(1H-indol-3-yl)-3-(4-
152-154 67 1 85 22
methoxyphenyl)prop-2-en-1-one

12
 REFERENCES

1. Bale A T, Salar U, Khan K M, Chigurupati S, Fasina T, Ali F, Ali M, Nanda S S,

Taha M, Perveen S, Lett. Drug Des. Discov. 18, 249–257 (2021).
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(2019).
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130 (2023).
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and Maguire A R, Tetrahedron 88, 132091 (2021). b. Seo S, Gao M, Paffenholz E,
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Omega 7, 27769-27786 (2022).
10. Ramar T, Subbaiah M A, and Ilangovan A, J. Org. Chem. 87, 4508–4523 (2022).
11. Zhuang C, Zhang W, Sheng C, Zhang W, Xing C, and Miao Z, Chem. Rev. 117, 7762-
7810 (2017).
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C H, and Neves B J, Molecules 22, 1210 (2017).
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Org. Lett. 24, 8435–8440 (2022).
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1611–1615 (2021).
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17. Mitrev Y N, Mehandzhiyski A Y, Batovska D I, Liese A, Galunsky B J, Serb. Chem.
Soc. 81, 1231-1237 (2016).
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Org. Chem., 52, 2132-2146 (2020).

13
 INTRODUCTION

Pyrazole, characterized by a five-membered heterocyclic ring containing two adjacent

nitrogen atoms, serves as an important core structure. Pyrazoles are considered privileged
scaffolds due to their versatility in various sectors of the chemical industry, particularly in
medicine and agriculture. Previous reviews have extensively highlighted the significance of
pyrazoles and their diverse biological activities, including antituberculosis, antimicrobial,
antifungal, anti-inflammatory, anticancer, and antidiabetic effects.1 Pyrazoles have gained
considerable attention owing to their wide range of applications. A large number of
derivatives of this small heterocyclic system have been reported in both clinical and
preclinical studies for the potential treatment of various diseases. The number of drugs
containing a pyrazole nucleus has increased significantly over the past decade. Furthermore,
the pyrazole moiety plays a crucial role in numerous organic ligands and acts as an important
coordinating unit. Recent studies have revealed interesting applications of the pyrazole
framework in organic synthesis, where it can function both as a directing group and as a
transforming group.2 Pyrazole is a fundamental structural unit present in many small
molecules that exhibit a broad spectrum of agricultural and pharmaceutical activities.
Specifically, pyrazole derivatives have been identified as inhibitors of protein glycation and
display a wide range of biological properties, including anti-inflammatory, antibacterial,
antifungal, anticancer, antidiabetic, antioxidant, antidepressant, antituberculosis, and antiviral
activities.3-4

Crizotinib (Anti-cancer) Celecoxib (Anti-Inflammatory)

Diphenamisole (Analgesic) Betazole Lonazolac (Anti-inflammatory)

14
 Pyrazoline and its derivatives are commonly found in various pharmaceuticals with
significant and diverse activities, including non-nucleoside HIV reverse transcriptase
inhibitors5 neurotensin receptors with analgesic properties, antagonists, and non-steroidal
mineralocorticoids,6 anticancer,7 antitumor,8 antioxidant,9 antimicrobial,10 antitubercular,11
antimalarial,12 anti-amoebic,13 antibacterial,14 antifungal,15 antidiabetic,16 anti-inflammatory
ones,17 antiviral18 and cytotoxic.19

15
METHODS OF SYNTHESIS OF PYRAZOLINES

1. Synthesis of pyrazolines from chalcones and Hydrazine

The synthetic pathway to pyrazoline derivatives was reported via

20
[3+2]cyclocondensation reaction of α,β-unsaturated ketones and hydrazine. Chalcones
are reacted with phenylhydrazine in the presence of a mixture of acetic acid-sodium
acetate aqueous solution at room temperature.21

The synthesis of pyrazolines from chalcones and hydrazine involves the cyclization of c-
halcones with hydrazine hydrate, leading to the formation of pyrazole derivatives.22

2. Synthesis of pyrazoline from Chalcone and Diazomethane

The 1,3-dipolar cycloaddition reaction between diazo compounds and dipolarophiles

is one of the earliest and most well-studied methods for the synthesis of 2 pyrazolines. In
the majority of these protocols, chalcone derivatives or other α,β-unsaturated ketones and
diazoalkanes were used.23 The condensation of diazomethane with chalcone derivative
results in good yield of pyrazoline which on oxidation leads to the formation of
pyrazole.24

16
 The region and stereoselectivity of 1,3-dipolar cycloaddition between diazo-
propane(diazoalkane) and chalcone derivative typically proceeds under mild conditions
and is compatible with standard organic solvents leads to the formation of pyrazole ring
via a concerted cycloaddition mechanism.25

3. From Nitrile imines

Nitrile imines are highly reactive and versatile dipoles and conventionally
generated in situ from unstable hydrazonyl halides under basic conditions. The nitrile
imines were demonstrated for 1,3-dipolar cycloaddition with various dipolarophiles,
including alkene and alkyne groups. With its green nature, ease of operation, and air and
moisture tolerance, this method find wide applications in organic synthesis.26 The
protocol comprises (3+2)-cycloaddition of the in situ generated trifluoroacetonitrile
imines with enones leading to trans-configured 5-acyl-pyrazolines in a fully regio- and
diastereoselective manner. Initially formed cycloadducts were aromatized by treatment
with manganese dioxide. Depending on the solvent used, the oxidation step either led to
fully substituted pyrazoles (DMSO) or proceeded via a deacylative pathway to afford
1,3,4-trisubstituted derivatives (hexane) with excellent selectivity.27

17
 PRESENT WORK

The desired five membered heterocycles- pyrazolines are prepared by the reaction of
chalcones with hydrazine hydrate in alcohol. Thus the compound 3,3'-(4,5-dihydro-1H-
pyrazole-3,5-diyl)bis-(1H-indole) was obtained by the treatment of (E)-1,3-bis(1H-indol-3-
yl)prop-2-en-1-one with hydrazine hydrate in the presence of glacial acetic acid in methanol
(Scheme II). The reaction was also repeated under ultrasonication at a frequency of 35 KHz,
the reaction proceeded at faster rate when compared with conventional method. Adopting
similar methodology, 3-(5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)-1H-indole was
prepared by the cyclocondensation of chalcone- (E)-3-(4-methoxyphenyl)-1-(1H-indol-3-yl)
prop-2-en-1-one with hydrazine hydrate.

REACTION-I

MECHANISM

SCHEME II

18
REACTION-II

Identification of the compounds by spectral parameters

The IR spectrum of 3 displayed absorption bands at 1595 cm-1 (C=N) and 3202
cm-1 (NH).

The 1H NMR spectrum of 3 exhibited AMX splitting pattern for methine and
methylene protons which indicates that the two methylene protons are in different chemical
environment. Thus three double doublets observed at δ 4.59, 4.07 and 3.72 ppm are assigned
to HA, HM and HX, respectively. The Coupling constant is found to be JAM = 15.8 Hz, JAX =
6.4 Hz and JMX = 13.6 Hz, which confirms that HA & HM are cis, HA & HX are trans and HM
& HX are geminal. A broad singlet is observed at δ 6.45 ppm is attributed to NH, which
disappeared on deuteration. Besides these, a multiplet displayed in the region δ 7.212-7.406
ppm is due to aromatic protons.

In the 13C NMR spectrum of 3, the signals observed at δ 151.8, 44.9 and 49.4 ppm are
assigned to C-3, C-4 and C-5 of pyrazoline respectively. Besides 123.1 ppm, 127.2 ppm were
assigned for CH carbon of 2-indole and 3-indole rings respectively. In addition to this, the
signals observed at 111.2, 119.9, 121.8, 121.9, 126.5, 127.3, 137.1, 132.0 ppm were assigned
to aromatic carbons.

19
20
 EXPERIMENTAL

PROCEDURE FOR THE PREPARATION OF PYRAZOLINES FROM

CHALCONES

Conventional Method

In a 100mL flat-bottomed flask, chalcone (E)-1,3-bis(1H-indol-3-yl)prop-2-en-1-one (1

mmol, 0.386 g/mol), hydrazine hydrate (1 mmol,0.05 g/mol) and methanol (5 mL) were taken
and equipped over a magnetic stirrer. The contents were stirred at 50 0C for 4-5 hrs. After
completion of the reaction (monitored by TLC) the reaction mixture was poured into ice
water. The solid (3,3'-(4,5-dihydro-1H-pyrazole-3,5-diyl)bis-(1H-indole) separated was
filtered and dried. It was recrystallized from ethanol to get a pure compound. Adopting
similar methodology 3-(5-(4-methoxyphe-nyl)-4,5-dihydro-1H-pyrazol-3-yl)-1H-indole was
also prepared and the results are presented in Table I.

Ultrasonication Method

Chalcone (E)-1,3-bis(1H-indol-3-yl)prop-2-en-1-one (1 mmol, 0.386 g/mol), hydrazine

hydrate (1 mmol, 0.05 g/mol) and methanol (5 mL) were taken in a 100 mL flat-bottomed
flask and equipped over an ultrasonic bath. The reaction mixture was sonicated at a frequency
of 35 KHz at 40 0C for 45-50 min. The progress of the reaction was monitored by TLC. After
completion of the reaction the contents were poured into ice water. The solid (3,3'-(4,5-
dihydro-1H-pyrazole-3,5-diyl)bis-(1H-indole)) was separated was filtered and dried. It was
recrystallized from ethanol to get pure compound. Adopting similar methodology 3-(5-(4-
methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)-1H-indole was also prepared and the results
are presented in Table I.

TABLE I
Compound Melting point Conventional Method Ultrasonication Method
name (oC)
Yield (%) Time Yield (%) Time
(hrs) (min)
3,3'-(4,5-dihydro-
1H-pyrazole-3,5- 242-244
62 1 1/2 81 21
diyl)bis -(1H-indole)

3-(5-(4-methoxyphe-
nyl)-4,5-dihydro-1H-
pyrazol-3-yl)-1H- 198-200 64 2 79 32
indole

21
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23
 INTRODUCTION

Isoxazoles are five-membered heterocyclic rings containing adjacent oxygen and

nitrogen atoms and constitute an important class in heterocyclic chemistry. The molecular
formula of isoxazole is C3H3NO. The study of heterocyclic compounds has attracted
significant attention due to their remarkable pharmacological potential, leading to extensive
research in recent years. The isoxazole ring is an important pharmacophore characterized by
the presence of adjacent nitrogen and oxygen atoms. It plays a crucial role in both naturally
occurring and synthetic biologically active compounds, including Cycloserine, Acivicin and
Muscimol, which were originally isolated from microorganisms, higher plants and marine
sponges.

Biological Importance of Isoxazole

Substituted isoxazoles are important structural motifs found in many drugs and drug
candidates. One of the fundamental objectives of organic and medicinal chemistry is the
design and synthesis of molecules with potential therapeutic value for human use. The wide
range of biological activities and pharmaceutical applications of isoxazole derivatives has
contributed to their growing importance, as the isoxazole ring is a key component in many
bioactive molecules. Isoxazole derivatives exhibit a broad spectrum of therapeutic activities,
including antifungal, antiviral, antihistaminic, antimicrobial, antioxidant, anticancer, and anti-
inflammatory effects. Beyond their medicinal significance, these compounds are also widely
used in agricultural and industrial applications as insecticides, herbicides, fungicides, and
anticorrosive agents. Several isoxazole-based drugs have successfully reached the market,
including Valdecoxib (anti-inflammatory),1 Leflunomide (anti-rheumatic),2
Sulfamethoxazole (antibacterial),3 Tivozanib (anticancer),4 Drazoxolon (antifungal),5
Danazol (anti-gonadotropin),6 Zonisamide (antiepileptic),7 Isoxaben (herbicidal),8
Risperidone (antipsychotic)9 and Pleconaril (antiviral).10

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METHODS OF SYNTHESIS OF ISOXAZOLINES

1. Nitrile oxide based reaction

The [2+3] cycloaddition reaction between alkynyl dimethyl silyl ethers and aryl or
alkyl nitrile oxide gives is oxazolyl silanols.11

2. Hydroxylamine based reaction

A convenient route for the substituted Isoxazoline is achieved by refluxing

[Link] with chalcone in presence of ethanol.12

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 PRESENT WORK

The desired five membered heterocycles- Isoxazolines are prepared by the reaction of
chalcones with hydroxylamine hydrochloride in alcohol. Thus, the compound 3,5-(1H-indol-
3-yl)-4,5-dihydroisoxazole is obtained by the treatment of chalcone-(E)-1,3-di(1H-indol-3-yl)
prop-2-en-1-one with hydroxylamine hydrochloride in the presence of NaOH in methanol
(Scheme III). The reaction was also repeated under ultrasonication at a frequency of 35 KHz,
the reaction proceeded at faster rate when compared with conventional method. By adopting
the same method, the compound 3-(1H-indol-3-yl)-5-(4-methoxyphenyl)-4,5-
dihydroisoxazole was synthesized.

REACTION-I

MECHANISM:

SCHEME III

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REACTION-II

Identification of the compounds by spectral parameters

The IR spectrum of 3 displayed absorption bands at 1568 and 3147 cm-1 correspond to
C=N and NH stretches, respectively.

The 1H NMR spectrum of 3 showed AMX splitting pattern for methine and methylene
protons of isoxazoline ring. The double doublets observed at 4.33, 3.95 and 2.93 ppm are
assigned to HA, HM and HX. The Coupling constant is found to be JAM = 11.5 Hz, JAX = 5.5 Hz
and JMX = 10.75 Hz, which confirms that HA & HM are cis, HA & HX are trans and HM & HX
are geminal. A multiplet observed in the region 7.25-7.36 ppm is due to aromatic protons.

In the 13C NMR spectrum of 3, the signals observed at δ 156.1, 42.5 and 75.2 ppm are
assigned to C-3, C-4 and C-5 of isoxazoline. The signals corresponding to aromatic carbons
appeared at expected region.

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 EXPERIMENTAL

PROCEDURE FOR THE PREPARATION OF ISOXAZOLINE FROM CHALCONE

Conventional Method

In a 100 ml flat-bottomed flask, chalcone-(E)-1,3-di(1H-indol-3-yl) prop-2-en-1-one

(0.3863 g/mol), hydroxylamine hydrochloride (1 mmol, 2.143 g/mol) and methanol (5 mL)
were taken and equipped over a magnetic stirrer. The contents were stirred at 50 °C for 4-5
hrs. After completion of the reaction (monitored by TLC) the reaction mixture was poured
into ice water. The solid (3,5-(1H-indol-3-yl)-4,5-dihydroisoxazole) separated was filtered
and dried. It was recrystallized from ethanol to get a pure compound. Adopting similar
methodology 3-(1H-indol-3-yl)-5-(4-methoxyphenyl)-4,5-dihydroisoxazole was also
prepared and the results are presented in Table I.

Ultrasonication Method

Chalcone-(E)-1,3-di(1H-indol-3-yl) prop-2-en-1-one (1 mmol, 0.3863/0.2773 g/mol),

hydroxylamine hydrochloride (1 mmol, 2.143 g/mol) and methanol (5 mL) were taken in a
100 ml flat-bottomed flask and equipped over an ultrasonic bath. The reaction mixture was
sonicated at a frequency of 35 KHz. at 40 C for 45-50 min. The progress of the reaction was
monitored by TLC. After completion of the reaction the contents were poured into ice water.
The solid (3,5-(1H-indol-3-yl)-4,5-dihydroisoxazole) separated was filtered and dried. It was
recrystallized from ethanol to get a pure compound. Adopting similar methodology 3-(1H-
indol-3-yl)-5-(4-methoxyphenyl)-4,5-dihydroisoxazole was also prepared and the results are
presented in Table I.

TABLE I

Compound Melting Conventional method Ultrasonication method

name point Yield Time (hrs) Yield Time (min)
(0C) (%) (%)

3,5-(1H-indol-3-yl)-4,5-
dihydroisoxazole 214-216 68 2 1/2 79 23

3-(1H-indol-3-yl)-5-(4-
metho- xyphenyl)-4,5- 196-198 62 3 85 31
dihydroisoxazole

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 REFERENCES

1. Pandhurnekar C P, Pandhurnekar H C, Mungole A J, Butoliya S and Yadao B G, J.

Heterocycl. Chem., 60, 537-5659 (2023).
2. Sonu K, Kamal Y T , Girendra Kumar G, Arun Kumar M , Baby Rabiya Parveen B
R , Arvind K, Mhaveer S, Harpreet S, Heliyon, 10, e40300 (2024).
3. Afzal S, Richie R B, Kishor P, Srinath N, Venkata K, Shahanaaz S, Molecules, 25,
1047 (2020).
4. Afzal S, Kishore P, Venkata K, MDPI Proc., 41, 2020.
5. Shijun S , Zunyun J, Hongyi C, Xinyu W, Pei-Xue G, Weihua Z, Ming-Zhi
Z, Honglin Z, Qing X, Yingguang Z., J. Agric. Food Chem., 73, 29160-29170 (2025).
6. Wang J Y, Zhang Y, & Ding J, Journal of Clinical Medicine Research, 17, 299-308
(2025).
7. Saini R, Baliyan V, Sharma S, & Darbari S, Inter. J. Adva. Innov. Res., 11, (2024).
8. Kailashpati T, Prashant K, Najam A S, Virendra R S, Pest. Res. J., 37, 1-8 (2025).
9. Purushothama S C, Chandrashekaraiah S, Inter. J. Pharma. Scie. Drug Res. (2025).
10. Zoi-Bo Y, Pei L, Yin Ju H, Molecules, 24, 3766 (2024).
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(2023).

31
 SUMMARY

The present work deals with the synthesis of pyrazolines and isoxazolines from the
corresponding chalcones. The synthetic intermediates chalcones were prepared by the
Claisen-Schmidt condensation between araldehydes and ketones in the presence of base
(Scheme I).

SCHEME I

SCHEME II

The desired five membered heterocycles- pyrazolines were prepared by the reaction of
chalcones with hydrazine hydrate in the presence of glacial acetic acid in alcohol.

SCHEME III

The five membered heterocycles- isoxazolines are prepared by the reaction of

chalcones with hydroxylamine hydrochloride in the presence of NaOH in methanol.

The structures of all synthesized compounds were established by IR, 1H -NMR and
13
C NMR spectra.

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