RECENTS TRENDS AND DEVELOPMENT IN THE SYNTHESIS

OF QUINOLINE DERIVATIVES: REVIEW

ABSTRACT:
Quinoline is a class of natural mixtures of the aromatic
heterocyclic series described by a bicyclic heterocyclic system consists
of six member benzene ring fused with pyridine, reported as an
important building block in the field of medicinal chemistry. Among
heterocyclic compounds, quinoline is a privileged scaffold that appears
as an important construction motif for the development of new drugs.
synthetic routes have been developed for the synthesis of quinoline and
its derivatives due to its wide range of biological and pharmacological
activities. This article covers the synthesis as well as biological activities
of quinoline derivatives such as antimalarial, antibacterial, antifungal,
antiprotozoal, anthelmintic, local anaesthetic, anticancer, antiglaucoma,
antipsychotic, antiasthmatic and miscellaneous activities.
KEYWORDS: quinoline, quinoline derivatives, synthesis, biological
activity

1. INTRODUCTION:
Quinoline is a class of natural mixtures of the aromatic
heterocyclic series described by a two-fold ring structure made out of
benzene and a pyridine ring melded at two nearby carbon atoms, as
shown in figure.

N
quinoline

Quinoline or1-aza-naphthalene or benzo[b]pyridine is a nitrogen

containing heterocyclic aromatic compound, acting as a weak tertiary

1
base and has the ability to form salts with acids and
undergoing electrophilic substitution reactions as well as reactions
similar to those of pyridine and benzene . It shows both electrophilic and
nucleophilic replacement responses. Quinoline is a planner hetero-
aromatic compound in which 10π electrons move throughout the
structure and having a molecular formula of C9H7N. Quinoline is a
bicyclic heterocyclic system consists of six member benzene ring fused
with pyridine, reported as an important building block in the field
of medicinal chemistry.
Quinoline or1-aza-naphthalene or benzo[b]pyridine is a nitrogen
containing heterocyclic aromatic compound, acting as a weak tertiary
base and has the capability to form salts with acids and
undergoing electrophilic substitution reactions as well as reactions
similar to those of pyridine and benzene . It shows both electrophilic and
nucleophilic replacement responses. Quinoline is a planner hetero-
aromatic compound in which 10π electrons move throughout the
structure and having a molecular formula of C9H7N. Quinoline is a
bicyclic heterocyclic system consists of six member benzene ring fused
with pyridine, reported as an important building block in the field
of medicinal chemistry.
Quinoline and its derivatives1 have both natural and synthetic
origins. In addition, quinolines have groups according to their biological
action and structural modificationsas well as biological activity. With
Cinchona alkaloids and other naturally occurring pharmacologically
active chemicals, it is one of the most privileged N-containing motifs
known to date and tends to occur in a variety of natural products,
exhibiting a wide range of biological activity.
There are several classical synthetic routes available for
synthesizing the quinoline structural modification. Synthetic routes
2
which are widely used include Skraup reaction, Friedlander reaction,
Conrad-Limpach-Knorr reaction, Doebner-miller reaction, Skraup-
Doebner-Von Miller reaction, Conrad–Limpach reaction, and Combes
reaction, which majorly utilizes aniline as one of the common reactants.
However, there are several other reactions which need
special substituted anilines or other substituted reactants to yield
quinoline.
Quinoline core happens in a few regular mixtures (Cinchona Alkaloids)
and pharmacologically dynamic substances showing a wide scope of
organic action. Quinoline has been found to have antimalarial (Quinine,
quinidine, chloroquine, mefloquine, amodiaquine etc), antibacterial
(fluoroquinolone such as ciprofloxacin, sparfloxacin), antifungal,
antiprotozoal (Clioquinol), anthelmintic (oxamniquine), local anaesthetic
(dibucaine), anticancer (camptothecin, irinotecan, topotecan),
antiglaucoma (cartiolol), antipsychotic (Aripiprazole, brexpiprazole),
cardiotonic (vesnarinone) and antiasthmatic (montelukast).

CH3 C2H5

N Cl
HN C2H5

I N
Cl N
OH

chloroquine Clioquinol
OH
O NH C2H5
N

C2H5
CH3
O2N NH N
CH3 N O CH3

Oxamniquine Dibucaine

3
 CH3
H3 C
H3C NH

O HO
N

N O

O
H3 C

OH O NH O

Camptothecin cartiolol
Cl

Cl

N
N
O NH O

Aripiprazole

O
H3 C N

H3 C N
O

NH O

vesnarinone
O

OH HO CH3
S
H3 C

Cl N

Montelukast

4
[Link] OF QUINOLINE:
2
1. QUINOLINE SYNTHESIS NAME REACTION :

1.1. Skraup synthesis:

In this method, aniline, glycerol, sulfuric acid and mild oxidizing

agent are heated together to form quinoline
O
H
+ H2SO4

NH2 PhNO2
CH2 FeSO4 N

prop-2-enal quinoline
aniline

O
OH
H2SO4 H
OH
OH
CH2

O O OH OH
H
+
NH2 CH2 -H2O
NH NH NH NH N
1,2-dihydroquinoline quinoline

A mixture of glycerol, aniline,sulfuric acid, nitrobenzene and

ferrous III sulfate are heated together .The mixture was stirred at 110°C
for appropriate reaction time. The progress of the reaction was
monitored by thin layer chromatography. After complete reaction, the
mixture was quenched by the addition of saturated aq NaHCO 3 solution
and the reaction mixture was filtered and washed with ethanol.
The reaction is exothermic and tends to become very
[Link](II)sulfate is added to make the reaction less
[Link], or an alternative oxidant (iodine or chloraniline

5
are often recommended), is required to convert the product, 1,2-
dihydroquinoline into quinoline.

1.2. Friedlander synthesis:

In this method, o-amino bezaldehyde or o-aminoacetophenone
condenses with an aldehyde or ketone in alcoholic sodium hydroxide,it
yield quinoline

O H3C
-2H2O
+
NH2 O N
O-amino benzaldehyde Acetaldehyde Quinoline

O-amino bezaldehyde and acetaldehyde were thoroughly mixed in

ethanol, then sodium hydroxide catalyst was added, and the solution was
refluxed for appropriate time. The extent of the reaction was monitored
by TLC.

1.3. Conrad-Limpach-Knorr synthesis:

In this reaction, formation of α-hydroxyquinolines from β-
ketoesters and arylamines above 100°C. The intermediate anilide
undergoes cyclization by dehydration with concentrated sulfuric acid.

CH3 O CH3
CH3
O PhNO2
+ [Link] 3
CH3

NH2 EtOOC NH O N OH
O NH O
3-oxo-N-phenyl
aniline 4-methylquinolin-2(1H)-one 4-methylquinolin-2-ol
ethyl aceto acetate butanamide

6
 A mixture of aniline and ethyl aceto acetate in nitro benzene in a 3-
litre 3 necked flask, .Heat the mixture and add the solution of anhydrous
aluminium chloride in nitro benzene over the period of 45 minutes.
Replace the dropping funnel by a thermometer raise the temperature of
the solution to 1300c and maintain these temperature, with strring,for
3hours, Cool the reaction mixed to room temperature and add diluted
hydrochloric acid with strring in order to decompose the excess of
aluminium chloride.

1.4. Doebner-miller synthesis:

In this method,an aniline and two moles of acetaldehyde are heated
in the presence of HCl to form schiff’s [Link] molecules oh this
schiff’s base condense to form a quinoline.

HN

H
+ H
HCl
CH3 + CH3 2
NH2 O O N CH3 NH CH3

-C6H5NH2

N CH3 NH CH3

1.5. Skraup-Doebner-Von Miller synthesis:

In this way, an aniline with α,β-unsaturated carbonyl compounds to
form quinolines.

7
 HCl

NH2 + -
NH3 Cl

aniline

+
+ - N CH3
NH3 Cl
CH3
crotonaldehyde 2-methylquinoline

Aniline and 6M hydrochloric acid placed in a round bottomed flask

fitted with a reflex [Link] the flask in an ice bath, add slowly
followed by crontonaldehyde in toluene, the contents of the flask to
ensure through mixing and reflex for 2 hr.

1.6. Conrad–Limpach synthesis:

In this system, condensation of anilines with β-ketoesters to form
4-hydroxyquinolines via a Schiff base . The overall reaction type is a
combination of both an addition reaction as well as a rearrangement
reaction.
3 O OH
O R
2 3 2
O R R R
2 O
R
1
+ R 1 -R3OH 1
NH N R R
2
N
O

1.7. Pfitzinger synthesis:

In this technique,isatin in the presence of base,is convertes into
isotonic acid which is condensation with a ketone to give quinoline 4-
carboxylic acid.

8
 OH
O
O O

H C C2H5OH
O +3 KOH,H 2O
NH N
R
aryl subsitituted
quinoline 4-carboxylic R
isatin acetophenones
acid
COOH
O

H2 O O
O
NH NH2
isatin

Isatin with corresponding aryl substituted acetophenones,

potassium hydroxide in ethanol, mixture was refluxed for 24 hr,
acidified with 2 M aqueous hydrochloric acid, recrystallized from
ethanol to get compounds.

1.8. Combes synthesis:

In this process, condensation of 1,3dicarbonyl compounds with
arylamine give a β-amino enone which undergoes cyclization with loss
of water to give quinoline.

CH3 CH3
O
H2SO 4
+
O
NH2 N CH3
CH3
O O
H3C H3C

9
2. SYNTHESIS OF QUINOLINE DERIVATIVES WITHOUT
CATALYST:
2.1. Synthesis of ethyl 7-chloro-6-fluro 4-hydroxyquinoline-3-
carboxylate3:
3-chloro-4-fluro aniline with diethylethoxymethylene malonate
(EMME) give the corresponding open chain compound and which was
cyclised in di-phenyl ether at 2500C to give exclusively ethyl 7-chloro-4-
hydroxy-quinoline 3-carboxylate in good yield.

F COOEt H3 C EtOOC COOEt

0
+ EtOOC 120-130 C
H
Cl NH2 H3 C
H5 C2 O 0 NH
Ph O
250 C 2
diethyl ethoxy methylene
3-chloro-4-fluoroaniline malonate OH

F COOEt

Cl N

ethyl 7-chloro-6-fluoro-4-hydroxyquinoline-3-carboxylate

2.2. Synthesis of diethyl ({[2(trifluoromethyl) phenyl] amino}

methylene) malonate4:
A suspension of 2-(trifluoromethyl) aniline and diethyl
ethoxymethylene malonate is heated to1100C for 4 hr. The reaction
mixture was cooled to room temperature, the solid thus formed was
taken in pet ether and stirred for15 min and filtered to get compound

10
 COOEt EtOOC COOEt
0
+ EtOOC 120-130 C
H
F3 C NH2 F3 C 0 NH
H 5C2O Ph O
250 C 2
3-(trifluoromethyl)aniline diethyl ethoxy methylene
malonate OH

COOEt

F3 C N

ethyl 4-hydroxy-7-(trifluoromethyl)quinoline-3-carboxylate

2.3. Synthesis of quinoline-3-carbaldehyde5:

Synthesis of Acetanilide:
Aniline, acetic anhydride, zinc powder, and acetic acid were
added. The mixture was boiled under reflux using water condenser for a
[Link], it was cooled to room temperature and poured into crushed
ice water. The solid product was collected by suction filtration.

Synthesis of quinoline-3-carbaldehyde:
N, N-dimethylformamide was added to a 100mL round-bottom
flask guarded with drying tube; it was cooled to 0°C using ice bath.
Then, thionylchloride was added drop wise to it from dropping funnel
guarded by drying tube while being stirred by magnetic stirrer. This
addition was done for 30 minutes. After 5 minutes, the dropper funnel
was replaced by air condenser with guarding tube at its end, and the
mixture was heated for 22 hours at 85–90°C. Then it was cooled to room
temperature, poured into a beaker containing crushed ice water, and
stirred for 20 minutes. The solid product was collected by suction
filtration and washed with cold water.

11
 O O CH3
CH3COOH

NH O
NH2
+H3C O CH3 reflux 1hr
acetic anhydride N-phenylacetamide
aniline
DMF 0
85-90 C
SOCl2
O
H3C H
-
N + Cl
H
H3C SO2Cl

N Cl
2-chloroquinoline-3-carbaldehyde

H3C H3C H
Cl -
N + Cl
N + O S
H3C SO2Cl
H3C O Cl
N,N-dimethylformamide thinoylchloride

CH3 H3C H CH3 SO2Cl CH2

- -
+ N + Cl
+ CH3
Cl
NH O H3C N O N NH Cl
SO2Cl

H CH3 H3C H
-
N + Cl
H3C SO2Cl

H3C H
- - H SO2Cl
Cl ClSO2 N + Cl
N(CH3)2
CH3
CH3 H3C SO2Cl CH3
N N
N
CH3 CH3
CH3 N Cl
N Cl N Cl

-SO2Cl
-NH(CH3)

-HCl

+ CH3 H2O
N O
CH3
N Cl N
quinoline-3-carbaldehyde

12
2.4. Synthesis of quinoline-2, 4-dicarboxylic acids6:
Isatin and sodium pyruvate in water at 1100C was reported with
excellent yields.
COOH
O
O 0
NaOH/H 2O 110 C
O + H3C
COONa HCl N COOH
NH

isatin sodium pyruvate quinoline-2,4-dicarboxylic acid

3. SYNTHESIS OF QUINOLINE DERIVATIVES WITH

CATALYST:
3.1. Synthesis of polysubstituted Quinoline Derivative7:
NbCl5 (0.1mmol) in glycerol was added to a mixture of
cyclohexane 1,3-dione compounds and [Link]
mixture was stirred at 1100C for appropriate reaction time. The progress
of the reaction was monitored by thin layer chromatography. After
complete reaction, the mixture was quenched by the addition of
saturated aq NaHCO3 solution and the reaction mixture was filtered and
washed with ethanol.

O
O

O
+
NH2 N
O
(2-aminophenyl)
(phenyl)methanone cyclohexane-1,3-dione poly subsitituted quinoline

13
3.2. Synthesis of 2,4-Diphenyl-2-methyl-1,2-dihydroquinoline
derivative8:
Aniline condensation with two moles of acetophenone followed by
cyclization with the help of a zeolite catalyst at 1100C for 6 hr.

H3 C H3 C Toluene
CH3
+ + 0 2
110 C / 6hr
NH2 O O N

aniline acetophenone acetophenone

C6 H5
HN

NH NH
CH3 CH3

2-methyl-2,3-diphenyl-1,2-dihydroquinoline

3.3. Synthesis of 2-methyl 3, 4-di substituted quinoline derivatives9:

2-amino aryl/alkyl ketones and carbonyl compounds in the
presence of Montmorrilonite K-10, zeolite, nano-crystalline sulfated
zirconia (nano-crystalline SZ) in high yields.

R R
1
R
R1
O Catalyst

+ O CH3 EtOH,reflux
NH2 N CH3

14
3.4. Synthesis of 2-phenylquinoline derivative10:
2-aminobenzyl alcohol reacts with acetophenone in toluene or
polyethylene glycol (PEG-2000) by employing a palladium catalyst along
with KOH to isolate the corresponding quinoline derivative.

OH H3 C
Pd,KOH
+
NH2 O toluene,100c,20h N

2-phenylquinoline

3.5. Synthesis of 2, 3, 4-Trisubstituted quinolones11:

2,3,4-Trisubstituted quinolones, have been synthesized by
Friedlander annulations of 2-amino substituted aromatic ketones and
reactive methylene group containing carbonyl compounds in the
presence of ethyl ammonium nitrate (EAN)

CH3
R

O CH3 CH3
EAN
+ O
0
NH2 CH3 45 C N CH
3

1-(2-aminophenyl) 2,3,4-trisubstituted
butan-2-one quinolones
2-subsitituted methan-1-one

4. SYNTHESIS OF QUINOLINE BY MICROWAVE

IRRADIATION:

15
4.1. MICROWAVE IRRADIATION WITH SOLVENT:
4.1.1. Synthesis of 2-phenylquinolines12:
2-aminobenzyl alcohol and acetophenone with a catalytic amount
of sodium hydroxide and stoichiometric amount of T3P-DMSO as
oxidant and presented excellent yields.
The low reaction temperature and the use of an environmentally
friendly oxidant, non-toxic and safe to handle, stand as the main
advantages of this technique, but the high cost.

OH T3P/DMSO

NH2
+ H3C N
Propanephosphonic acidanhydride
NaOH/5 mins
0
O C2H5OH /60 C 10 mins

(2-aminophenyl)methanol 1-phenylethan-1-one 2-phenylquinoline

4.1.2. Synthesis of 3-Usnsubstituted 4-hydroxyquinolin-2(1H)-one

derivatives13:

Substituted aromatic amine and malonic acid under microwave

irradiation in dimethylformamide, without employing any solvent and
using polyphosphoric acid(PPA).

OH OH
O
MW
+
[Link] OR
NH2 HO
NH O
O 2.15 min,500W OR
R
[Link]

16
4.1.3. Synthesis of 6-substituted -3-(1-ethoxyethyl)-2-methyl-4-
phenylquinoline derivatives14:
O-aminoaryl substituted and ketones or β-diketones in the presence
of metal dodecyl sulfates or Lewis acid-surfactant catalysts
(LASC)/zirconium tetrakisdodecyl sulfate Zr(DS)4 /metal dodecyl
sulfates. Zr(DS)4.

CH3
R
O O
CH3 Cat(%5 aq) R
+ OEt

NH2 H3C OEt H2O/EtOH(2/1),reflux

N CH3

6-substituted
-3-(1-ethoxyethyl)-2-methyl-4-
phenylquinoline

4.2. MICROWAVE IRRADIATION WITHOUT SOLVENT:

4.2.1. Synthesis of 2, 3,-disubstituted quinolines derivatives 15:
O-aminobenzaldehyde and enolisable ketones under acid catalysis,
reporting yields above 50% in 6 to 12 minutes reaction time.
R R
O acid catalysis
+ 1 1
R N R
NH2
O

ortho amino benzaldehyde enolisable ketones 2,3-disubsitituted quinolines

4.2.2. Synthesis of 2,3,-disubstituted quinolines derivatives 16:

O-nitrobenzaldehyde and enolisable ketones under the use of
SnCl2 as an efficient oxidant toward the synthesis of 2,3-disubstituted

17
quinolines and reporting great yields in 2 to 3 minutes reaction
time(MV1050v).
R R
O SnCl
+ 1
2

1
R N R
NO2
O

2-nitrobenzaldehyde enolisable ketones 2,3-disubsitituted quinolines

4.2.3. Synthesis of 2,3,-disubstituted quinoline derivatives17 :

Aniline, aldehydes and acetylene derivatives catalysed by either
rare-earth metal catalysts (YCl3) or triflates(OTf)3. Both catalysts
originated excellent yields in 8 minutes reaction time (MV720v, 1800C).
2
H
YCl3 R

+ R
1 + HC
2
R
O Yttrium (III) chloride
NH2 0 R1
8 mins/ 180 C N
aniline
(OTf) 3 Triflates
8 mins/ 720W

2
R

1
N R

2, 3-disubsitituted quinolines

4.2.4. Synthesis of 2-phenylquinoline-4-carboxylic acid18:

Aniline, benzaldehyde and pyruvic acid and reporting great yields
in 60 sec reaction time at 1000C.

18
 COOH

COOH 0
+ + O
60 sec/100 C
O
NH2 CH3 N

aniline benzaldehyde 2-oxopropanoic acid 2-phenylquinoline-4-carboxylic acid

4.2.5. Synthesis of 3methyl Quinoline derivatives19:

Aniline derivatives and acetaldehyde under microwave irradiation
without any solvent. In this method they tried different bronsted acids
but found hydrochloric acid appeared to be the best catalyst(Al 2O3) for
this reaction, showing the highest yield. Moreover the yield of the
product was not affected by the nature of substituent in this reaction.

H
HCl(aq)Al 2O3
+ O
NH2 MW,7min
CH3
R N CH3
R

aniline acetaldehyde 3-methyl quinoline derivative

H H O
O
CH3
+ O
CH3 HO CH3
acetaldehydeacetaldehyde 3-hydroxybutanal

4.2.6. Synthesis of 2,4 diphenyl Quinoline derivatives20:

Aromatic amines, aromatic aldehydes and phenylacetylene in the
presence of catalytic amounts of potassium dodeca tungsto cobaltate

19
trihydrate (K5CoW12O40·3H2O) for the one-pot three-component
synthesis under microwave irradiation.

NH2 CHO
CH
+ + K5CoW 12O403H2O
MW
N

R1 R2 R1

R2

2,4-diphenyl quinoline
aniline paraldehyde phenylacetylene
derivative

4.2.7. Synthesis of steroidal quinoline derivatives21:

In this method steroidal quinoline derivatives were synthesized from a
one-pot reaction of steroidal β-bromovinyl aldehydes and arylamines in
high yield using microwave irradiation without the use of a catalyst and
in a solvent-free condition.

steroidal steroidal

Br Br
+
NH2 MW(600 watt),10min
O N

steroidal beta bromovinyl

aniline steroidal bromo quinoline
aldehyde

4.2.8. Synthesis of 2,3,4 tri alkylquinoline derivatives22:

A one-pot reaction of anilines with alkyl vinyl ketones on the
surface of a silica gel inseminated with indium(III) chloride under
microwave irradiation without any solvent.

20
 R3
R2
R2
R3 R1 InCl3/SiO2

NH2 MW
O R
N 1
R
R

alkyl vinyl ketones

aniline 2,3,4 tri alkyl quinoline

4.2.9. Synthesis of 2,4 di phenylquinoline derivatives23:

Anilines, aldehydes and terminal aryl alkynes. The reaction was

catalyzed by montmorillonite K-10, a strong and environmentally benign
solid acid. The multicomponent approach yields products with nearly
90% atom economy in excellent yields in a matter of minutes. The use
of microwave activation reduces the reaction time significantly.
R2

NH2 CHO
CH
+ + K-10,MW

R N
R1 R2 R1
R

aryl aldehyde aryl alkene 2,4 diphenyl quinoline

4.2.10. Synthesis of 4-methyl-2-phenylquinoline24:

Amino acetophenone and phenylacetylene in the presence of
Zn(OTf)2 as an effective catalyst under microwave irradiatio

21
 CH3
CH3

O 1mol%Zn(OTf) 2

HC
+ 450W
NH2
N

amino acetophenone phenylacetylene 4-methyl-2-phenylquinoline

4.2.11. Synthesis of carbonitrile quinoline derivatives25:

Benzaldehyde, methyl cyanoacetate and aromatic amine with
nanostructured TiO2 photocatalysts under solvent-free conditions under
microwave irradiation.

R1 CN
R1 CN
+ + TiO2 Nano Powder

NH2 O
30-60 sec/No Solvent
H3C O N OH

carbonitrile quinoline
methyl cyanoacetate benzaldehyde derivative

4.2.12. Synthesis of ethyl 6,7-dimethoxy-2-alkyl/arylquinoline-3-

carboxylate derivatives26:
A three-component one-pot reaction between 3,4-
dimethoxyaniline, aldehydes and ethyl-3,3-diethoxypropionate to a
quinoline derivative by using montmorillonite K-10 (Mont K-10) as a
green catalyst by utilizing the oxygen of air and water. Montmorillonite
K-10 (Mont K-10) was found to be more effective compared to other
Lewis acids as the expected product was isolated in good yield.

22
 OEt

H3CO CO2Et H3CO CO2Et

EtO
+ + R Mont K-10
H
O 0
H3CO NH2 H 2O,90 C,air H3CO N CH3

ethyl 6,7-dimethoxy-2-alkyl/aryl
3,4-dimethoxyaniline quinoline-3-carboxylate

4.2.13. Synthesis of 6,7-di substituted-2-phenylquinoline

derivatives27:
Aniline derivatives and cinnamaldehyde to a quinoline derivative
by using montmorillonite K-10(Mont K-10) clay-catalyzed. The
mechanism follows a domino process involving cyclization followed by
dehydration and then after oxidation delivers quinolines. The reaction
was carried out under solvent-free conditions and with the assistance of
microwave irradiation.
H
R1 O Mont K-10 R

MW,90C
1
R2 NH2 R N

4.2.14. Synthesis of polysubstituted quinoline derivatives28:

(2-amino-5-chlorophenyl)(phenyl)methanone and cyclohexanone
to a polysubstituted quinoline derivative by using propylphosphonic
anhydride (T3P) in short reaction times and in excellent yields. Here T3P
is used as a mild water scavenger catalyst in this coupling reaction..

23
 Cl
O
T3 P Cl
+
NH2 O
(2-amino-5-chlorophenyl) cyclohexanone N
(phenyl)methanone

4.2.15. Synthesis of quinoline derivatives29:

Enolisable ketone with molecular iodine as a catalyst in ethanol,
combining iodine and silica gel under solvent-free conditions, a
Friedlander heteroannulation method by using nano ZnO as a mild, non-
volatile, non-corrosive and efficient catalyst which provides
regiospecific synthesis under solvent-free conditions and using ionic
liquid [Hbim][BF4] under ultrasound at room temperature. These
methods avoid the use of hazardous acids or bases and harsh reaction
conditions.
R1
R1
O
O R3
SiO2/I2
+ R2
R3
heat/60c
NH2
N R2
R R

4.2.16. Synthesis of 2-(2-methylpropyl)quinoline and 2-methyl-3-

(propan-2-yl)quinoline derivatives30:
Carbonyl compound with isatin in NCW form the substituted
quinoline derivative (70–71) via in situ decarboxylation. Hot
pressurizing NCW to make it more ionized makes it a very good
dehydrating media suited for isatin opening, condensation and
cyclodehydration with carbonyls.

24
 O CH3
CH3 CH3 NCW
CH3
O + CH3 250c
+ CH3
O
NH N CH3
N CH3
2-(2-methylpropyl)quinoline 2-methyl-3-(propan-2-yl)quinoline

4.2.17. Synthesis of ethyl 6, 7-dimethoxy-2-alkyl/aryl quinoline-3-

carboxylate derivatives31:
Substituted o-amino acetophenone derivative and ethyl 3-
oxobutanoate by using NaHSO4·SiO2 as a heterogeneous and reusable
catalyst
1
R1 R CH3
1
R O O R
NaHSO 4.SiO2 OEt
O
+ H3C OEt 70c
NH2 N CH3

ethyl 3-oxobutanoate 3-(1-ethoxyethyl)-2-methyl 4,6-di

substituted quinoline

4.2.18. Synthesis of 2,3,6-tri substituted-4-aryl quinoline

derivatives32:
2-amino aryl ketones and carbonyl compounds in the presence of
silica nano-particles as catalysts under microwave irradiation give high
yields of quinoline derivatives. Silica nano-particles gave best results
compare to CaO, MgO, Al2O3 and SiO2.
Ph
Ph
R 1
R 1
O R R
SiO2
+
NH2 2 Nano Particles
O R 2
N R
2,3,6-tri substituted-4-aryl
quinoline

25
5. REACTION OF QUINOLINE:

5.1. Synthesis of Quinolinyl Triazole derivatives33:

Quinoline hydrazide and aryl-substituted isothiocyanate, was
refluxed in methanol to form Quinolinyl Carbothioamide. It reacts with
5 % NaOH (aqueous) at 70°C to form quinolinyl triazole.
Cl Cl Cl

Ar
NaOH
+ N
N S N N
O O O

Ar
O NH O NH N N
NH2 NH NH NH
Ar
S
S

SYNTHESIS, ANTIOXIDANT AND ANTICANCER ACTIVITY

OF NEW QUINOLINE-[1, 2, 4]-TRIAZOLE HYBRIDS

5.2. Synthesis of 8-alkoxyquinolin-5-amine derivatives34:

A mixture of 8-alkoxyquinolin-5-amine, formyl hydrazine,glacial
acetic acid, and triethyl orthoformate to form of 8-alkoxy-5-(4H-1,2,4-
triazol-4-yl)quinolines.
N N
NH2 N

HC(C2H5)3
HCONHNH 2

OR OR

26
5.3. Synthesis of quinoline-chalcone derivatives35:
Substitution reaction between compounds chalcone derivatives
with commercially available 4-chloro-2-methylquinoline gave target
compounds quinoline-Chalcone derivatives in the presence of HCl in
EtOH at 80 0C.
O

Cl O HN R

+
N CH3 H2N R N CH3
4-chloro-2-methylquinoline

5.4. Synthesis of quinoli-ylidene I bearing thiosemicarbazone

derivatives36:
4-hydroxy-3-nitroquinolin-2(1H)-one reacted with
thiosemicarbazide derivatives at 82°C to form 2-(4-hydroxy-3-
nitroquinolin-2(1H)-ylidene) hydrazine-1-carboxamide.

OH OH
NO2 1
NO2
O R
+ N
2
1
NH O H2N NH R N R
NH
4-hydroxy-3-nitroquinolin-2(1H)-one
HN N 2
R

O
(2Z)-2-(4-hydroxy-
3-nitroquinolin-2(1H)-ylidene)
hydrazine-1-carboxamide
5.4. Synthesis of 8-amino substituted quinoline derivatives37:
A mixture of 8-hydroxy quinoline,1,2-dichloro ethane and
anhydrous potassium carbonate in dry acetone to form 8-(2
chloroethanoxy) [Link] react with amine,anhydrous sodium
27
carbonate and sodium iodide in dry acetone to form 8-(2-amino-
ethanoxy)quinoline.

+ Cl

N Cl

OH N

O
Cl
quinolin-8-ol 1,2-dichloroethane 8-(2-chloroethoxy)quinoline
1
R
HN
2
R

N
1
O R
N
2
R

6. Medical application of quinoline derivatives:

Quinoline and its combined heterocyclic subsidiaries tried with
assorted pharmacological action establish a significant class of mixtures
for new medication

6.1. Antimicrobial activities:

1-oxo-3-phenoxy/hetrylamino-1H-pyrimido[1,2-a]quinoline-2,5-
dicarbonitrile derivatives tested for their antimicrobial activity38 using
disc diffusion technique against S. aureus, [Link], the standard
antibiotics showed zones of inhibition penicillin and ampicillin against
bacterial strains.

28
 CN

N N

O O

CN phenyl/Hetryl amino

6.2. Anticancer activity:

1-(7-Hydroxy-4-methyl-2-oxoquinolin-1(2H)-yl)urea/thiourea
derivatives as potential anticancer activity39 against breast cancer cells
(MCF–7), bone marrow cancer cells (K–562) and cervicalcancer cells
(HeLa) by MTT assay.
X

HN NH2

HO N O

CH3

6.3. Anti-inflammatory and analgesic

2-(4-substituted phenyl)-3-[(quinolin-2-yl) amino]-1,3-thiazolidin-
4-one derivatives are being developed as anti-inflammatory and
analgesic activity40.
3
S R
O
2
N R

NH 1
R

N
2-(4-substituted phenyl)-3-[(quinolin-2-yl)amino]-1,3-thiazolidin-4-one

29
6.4. Antituberculosis activity
Quinoline derivatives carrying active pharmacophores has been
synthesized and evaluated for their in vitro antituberculosis activity41
against Mycobacterium tuberculosis H37Rv (MTB), Mycobacterium
smegmatis (MC2), and Mycobacterium fortuitum following the broth
micro dilution assay method, when compared with first line drugs are
isoniazid (INH) and rifampicin (RIF) .

H3 C NH O
N 1
N R
CH3 NH

R N

6.5Anticonvulsant and Antihypertensive activities

A series of 8-substituted quinolines derivatives are tested against
seizures induced and antihypertensive activities42.

N
1
O R
N
2
R

30
CONCLUSION:

Quinoline derivatives are good medical applications. Synthesis of different

quinoline derivatives with increase in there number of
effectiveness against diseases. These are quinoline synthesis eg. From
include Skraup reaction, Friedlander reaction, Conrad-Limpach-Knorr
reaction, Doebner-miller reaction, Skraup-Doebner-Von Miller reaction,
Conrad–Limpach reaction, Combes reaction, etc. Quinoline and its
derivatives are known for their wide spectrum of pharmacological activities,
a number of synthetic methods have been developed from time to time for
their synthesis by conventional, homogeneous, and heterogeneous without
catalyzed methods, with catalyzed methods, microwave-assisted, solvent-
free conditions and many more. These quinoline derivatives very useful to
the researcher working in this field, and it would help them to develop new
synthetic methods for the potent quinoline derivatives with good or
enhanced biological activities for the future.

31
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39