part - i studies on compounds consisting quinoline and 2...

Part - I

Studies on Compounds Consisting

Quinoline and 2-Pyridone

Heterocycles

PART 1 STUDIES ON QUINOLINE & 2-PYRIDONE

7

SYNTHESIS, CHARACTERIZATION AND ANTIMICROBIAL SCREENING OF SOME BIO-ACTIVE HETEROCYCLIC COMPOUNDS

Introduction to quinoline

Quinoline is a hygroscopic, unpleasant-smelling, colorless, oily liquid. It occurs in

coal tar and bone oil, and is made from phenyl amine and nitrobenzene. Quinoline

is a basic compound, forming salts with mineral acids and forming quaternary

ammonium compounds with haloalkanes. It was first isolated by Runge in 1834,

from coal tar bases and subsequently Gerhardt in 1842 obtained it from the

alkaline pyrolysis of cinchonine, an alkaloid related to quinoline; from which the

name quinoline is derived. The word quinine in turn, derives from quina a Spanish

version of a local South American name for the bark of quinine-containing

Cinchona species. It is used for making medicines and dyes. Quinolines and their

derivatives are receiving increasing importance due to their wide range of

biological and pharmacological activities.

Quinoline ring structure is obtained by o-condensation of benzene ring with

pyridine. It is also called l-azanaphthalene or benzo[b]pyridine. In quinoline, the

nitrogen atom is one atom away from the position at which the rings are fused.

In an isomer, isoquinoline, the nitrogen atom is positioned two atoms away from

the fused ring. The numbering in quinoline commences from the nitrogen atom

which is assigned position-1 (Figure-1). 1

Molecular structure and general properties of quinoline2

Quinoline and isoquinoline are related to pyridine exactly as is benzene related to

naphthalene i.e. in the aromatic system, both the molecules contain 10 π electrons.

The presence of electron donating groups at 2- and 4-positions of quinoline

increases the basicity. The pyridine ring in quinoline is electron deficient.

Therefore, nucleophilic attack takes place at the 2- and 4-positions. The π electron


Page 28


densities have been calculated for quinoline by the molecular orbital method and

show electron deficiency at these two positions. The electrophilic attack preferably

takes place at 5 and 8-positions. Quinoline is a base since, as for pyridine, the lone

pair of electrons on the nitrogen atom is not utilized in its internal resonance.

Quinoline is an aromatic compound with resonance energy of 47.3 kcal/mol. The

valence bond description of quinoline shows two of the neutral contributors, (1)

and (3), to the resonance hybrid as quinonoid in character, whereas in (2) either the

carbocycle or the heterocycle must exist in the form of a 1,3-diene. The presence of

the pyridine nucleus is reflected by the inclusion of doubly charged canonical

forms.

N N N

NN

1

2

345

8

6

7N

1 2 3 4

NN

5678

Figure-2: Resonance in quinoline However, the representations (6) to (8) involve disruption of both monocyclic π

systems simultaneously. It follows that these are of higher energy, and they

contribute very much less to the overall description of the molecule than do the

alternatives (4) and (5) that affect only the pyridine system. The bond lengths of

quinolines, which are irregular, support the resonance description; thus, the

1,2-, 5,6- and 7,8-linkages are shorter than that of the carbon-carbon bond in

benzene (more double bond character). There is also a dipole of 2.9 D directed

towards the nitrogen atom.

Quinoline derivatives are also used for the preparation of nano- and meso-

structures having enhanced electronic and photonic properties.3 Quinolines and


Page 29


their derivatives are very important compounds because of their wide occurrence

in natural products4 and biologically active compounds.5 The quinoline nucleus

can also be frequently recognized in the structure of numerous naturally occurring

alkaloids having interesting pharmacological activity. A large variety of quinolines

have displayed interesting physiological activities and found attractive

applications as pharmaceuticals and agrochemicals, as well as being general

synthetic building blocks.4b

Figure-3: Quinoline alkaloids having pharmacological activity

Often the type and degree of substitution of the quinoline ring has a profound

effect on the biological activity of a given substrate. In addition to the synthetic

building blocks, variously substituted quinolines and their derivatives have

been employed in heterocyclic chemistry.4b Some derivatives containing

quinoline ring system have been shown to possess useful pharmacological

activities, such as Dibucaine hydrochloride is an anaesthetic, Pamaquine is an

antimalarial agent, Apomorphine is antiperkinosine and Oxamniquine is

schistosomicidal.


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Figure-4: Clinically used synthetic quinolines

Synthesis of quinoline22

Recently, more and more new simple and elegant syntheses of substituted

quinolines have been described.6-19 Many synthetic methods such as Skraup,

Doebner–von Miller, Friedlander, Combes reactions have been developed for the

preparation of quinolines,20,26 but due to their great importance, the development

of novel synthetic approaches remains an active research area.21

(I) Quinolines from arylamine and 1,3-dicarbonyl compounds

Anilines react with 1,3-dicarbonyl compounds to give intermediates, which can be

cyclized with acid to give substituted quinolines.

1. The Conard-Limpach-Knorr synthesis

Conard-Limpach-Knorr synthesis uses β-keto esters and leads to quinolones.23

Anilines and β-keto esters (9) can react at low temperature to give a kinetic

product, β-aminoacrylate (10), cyclization of which gives 4-quinolone (11). At

higher temperature, β-keto ester anilides (12) are formed and cyclization of these

afford 2-quinolones (13). β-Aminoacrylates (10), for cyclization to 4-quinolones, are

also available via the addition of anilines to acetyllinic esters.24


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NH

O

R1

OR3

NH2

+

OR3

O

R1O

rt 250 C

NH

O

R1

NH

O

O

R1

250 C

NH

O

R1

140 C

R2R2 R2

R2R2

-R3OH

-R3OH

10 11

12 13

R, R1, R2, R3 = Different alkyl substituents

9

R R

RR

R

50 %

2. The Combes synthesis

Condensation of a 1,3-dicarbonyl compound (14) with an aryl amine gives a high

yield of β-amino-enone (15), which can then be cyclized with con. acid.25

Mechanistically, cyclization step can be viewed as an electrophilic substituition by

the ortho protonated amino-enone, as showed, followed by loss of water to give

aromatic quinoline (16).

(II) Quinolines from aryl amine and α,β-unsaturated carbonyl compounds

Arylamines react with an α,β-unsaturated carbonyl compound in the presence of

an oxidizing agent to give quinolines. When glycerol is used as an in situ source of

acrolein, quinolines carrying no substituents on the heterocyclic ring are produced.

1. The Skraup synthesis26

In this extraordinary reaction, quinoline is produced when aniline, concentrated

sulphuric acid, glycerol and mild oxidizing agent are heated together.27 The

reaction has been shown to proceed by the dehydration of glycerol (17) to acrolein


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(18) to which aniline then adds in a conjugate fashion. Acid-catalyzed cyclization

produces 1,2- dihydro quinoline (19) finally dehydrogenated to quinoline (20) by

the oxidizing agent. The corresponding nitrobenzene or arsenic acid have been

used classically, though with the inclusion of a little sodium iodide, the sulfuric

acid can serve as oxidant.28 The Skraup synthesis is the best for ring synthesis of

quinolines unsubstituted on the hetero-ring.29

Orientation of ring closure in Skraup syntheses

In principle, meta-substituted arylamines could give rise to both 5- and

7-substituted quinolines. In practice, electron-donating substituents direct ring

closure para, thus producing 7-substituted quinolines; meta-halo-arylamines

produce mainly the 7-halo isomer. Arylamines with a strong electron-withdrawing

meta substituent give rise mainly to 5-substituted quinoline.

(III) Quinolines from ortho-acylarylamines and carbonyl compounds

1. The Friedlander synthesis20e

Amongst various methodologies reported for the preparation of quinolines,

Friedlander annulation is one of the simplest and most straightforward protocols.

Friedlander synthesis involves condensation followed by cyclodehydration

between an aromatic 2-aminoaldehyde or ketone with an α-methylene

functionality. Friedlander reaction can occur under base,5c,5d,20d,30a Bronsted

acids,20d,30a,31 Lewis acid,11,32 inorganic salt33 or ionic liquid-catalyzed34 conditions.

Generally, better product yields were achieved for the acid-catalyzed Friedlander


Page 33


reaction.30a The orientation of condensation depends on the orientation of enolate

or enol formation.30a

In Friedlander synthesis, ortho-acylarylamines35 (21) condense with a ketone or

aldehyde (which must contain α-methylene group) by base or acid catalysis to

yield quinolines. The use of oxime ether, as synthon for the α-methylene ketone,

has been shown to be advantageous.36

Recently, Yao and co-workers reported an easy and efficient synthesis of

3-nitroquinoline derivatives (23) from o-aminobenzaldehyde and β-nitrostyrenes

(22) in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) and silica gel.37 This

one-pot reaction represents an interesting variation in the Friedlander type

quinoline synthesis.

2. The Pfitzinger synthesis

In 1886 Pfitzinger reported a formal extention of the known Friedlander protocol

for the synthesis of quinolic acid which is known as Pfitzinger synthesis (also

known as the Pfitzinger-Borsche reaction). o-Aminoaraldehydes are sometimes


Page 34


difficult to access. In this modification, isatins (24), which are easy to synthesise,

are hydrolysed to o-aminoarylglyoxalates (25), which react with ketones affording

quinoline-4-carboxylic acids (26).38

(IV) Doebner reaction39

The Doebner reaction is the one pot chemical reaction of aniline with an aldehyde

and pyruvic acid to form quinoline-4-carboxylic acids (27).

(V) Vilsmeier-Haack synthesis40

The classical Vilsmeier-Haack reaction is one of the most useful general synthetic

methods employed for the formylation of various electron rich aromatic, aliphatic

and heteroaromatic substrates.41 However, the scope of the reaction is not

restricted to aromatic

formylation and use of

the vilsmeier-Haack

reagent provides a facile

entry into a large

number of heterocyclic

systems.42 In 1978, the group of Meth-Cohn demonstrated a practically simple

procedure in which acetanilide (28) was efficiently converted into 2-chloro-3-

quinolinecarboxaldehyde (29) in 68% yield.43 This type of quinoline synthesis was

termed as “Vilsmeier Approach” by Meth-Cohn.44

Rajjana et al.45 have demonstrated that acetanilides, particularly deactivated ones

(R = -Br, -Cl, -NO2), undergo rapid cyclization in micellar medium to afford

2-chloro-3-quinolinecarboxaldehyde. Cyclization in the presence of cetyl trimethyl

ammonium bromide (CTAB) under Vilsmeier-Haack conditions afforded 2-chloro-

NHCOCH3

75°C, 4-16.5 hrsN

CHO

ClRR

DMF-POCl3

28 29R = H, 2-CH3, 4-CH3, 4-OCH3, 4-OC2H5, 4-Cl


Page 35


3-quinolinecarboxaldehyde in good yield in 45-90 min. Rajjana et al.46 also

demonstrated dramatic enhancements when ultrasonically irradiated Meth-Cohn

quinoline syntheses were performed; again deactivated acetanilides were found

to undergo efficient cyclization in good yield. Gupta et al.47 reported that the

Vilsmeier-Haack cyclization of acetanilides using supported reagent and

microwave irradiation in solvent free condition is rapid and efficient. Reaction

yields are good, although only a few activated derivatives have been

investigated.

Trifluoromethyl quinolines are the subject of considerable growing interest

because of its medicinal importance, particularly as antimalarial agents

(e.g., mefloquine). Recently, several authors have been reported the regioselective

synthesis of 3-trifluoromethylquinolines from simple anilines. 48-50 When heated in

the presence of phosphoryl chloride, 2-anilinovinyl perfluoroalkyl ketones (30)

afforded 2-(perfluoroalkyl)quinolines (32). 1, 3-Diaminoallyl cations, vinologous

formidinium salts, (31) were postulated to act as the turntables in this

condensation.48


Page 36


Synthesis of substituted quinoline N-oxides via cyclization of alkylidene

o-nitroarylacetonitriles:

Substituted quinoline N-oxides (34) are prepared via base induced cyclization of

alkylidene derivates of o-nitroarylacetonitriles (33) which are readily available via

the vicarious nucleophilic substitution cyanomethylation of nitroarenes followed

by Knoevenagel condensation.51

A novel metal free approach for the synthesis of substituted quinolines (36) was

reported using HCl (cat)-DMSO system.52,15 A catalytic amount of HCl in DMSO


Page 37


activates aldehydes, which react with benzylideneanilines (35) to form substituted

quinolines (36).

Another useful aniline

derivative substituted at the

2-position to construct a

quinoline system is

o-(trifleoromethyl)aniline.

Strekowski et al. developed a

facile route to synthesize

substituted aminoquinolines

(38) via anionic cyclization of

ketimines (37) derived from

o-(trifluoromethyl) aniline in

which each fluorine of the CF3

group is successfully displaced by a series of internal nucleophilic process using

strong bases (RNHLi). 2-Substituted 4-fluoroquinolines (39) were also obtained by

the reaction of o-(trifluoromethyl)aniline with lithium enolates derived from

methyl ketones. 53-55

o-Aminobenzonitrile is a versatile synthon for the construction of nitrogen

heterocycles. The amino group of

this compound is readily

substituted with a number of

electrophiles to form intermediate

products that are cyclized under

CN

N Ar

CH3 LDA,

N

NH2

Ar

Ar = Aryl, heteroaryl

40 41

Et2O

O

R1+ N

R3

R25 mol %HCl,air, DMSO

N

R1, R2, R3 = Different substituents

R3

R1

R2

35 36

15-82 %


Page 38


the conditions of general acid/base catalysis. This approach has been used in the

preparation of several substituted quinolines.56,53 Schiff’s bases (40), obtained from

o-aminobenzonitrile and (hetero)arylmethylketones were lithiated with lithium

diisopropylamide (LDA) at the methyl group that induced intramolecular

cyclization of initial imines to give the 2-(hetero)aryl-4-aminoquinolines (41) in

high yield.56 This two-step method is experimentally simple and efficient.

Mitsuhiro A et al.57

synthesized the requisite

diene, N-allyl-N-protected-

o-aminostyrene (42), from

anthranilic acid derivatives,

which were subjected to treat with Ru-benzylidene catalyst in CH2Cl2 (0.01 M) to

give substituted 1,2-dihydroquinolines (43) using ene–ene metathesis and

ene–enol ether metathesis. Versatile substituted quinoline derivatives were readily

prepared in excellent yield from anthranilic acid derivatives using this method.

Perumal et al. react a variety of anilines and aldehydes with enamine (44) in the

presence of 5 mol% cerium(IV) ammonium nitrate (CAN) to form a series of

tetrahydroquinolines (45). The reactions were performed at room temperature

with very short reaction time and in good yields. In addition, the resulting

tetrahydroquinolines could be oxidized to the corresponding substituted

quinolines using CAN in high yield.58

Narender P et al.59 developed facile and simple synthetic method for

multisubstituted quinolines from the Baylis–Hillman adducts in excellent yields

under mild conditions in quicker timings. The BH adducts obtained from the

N

Ts

Ru

PCy3

ClPCy3

Cl

PhCH3

N

CH3

Ts

CH2Cl2

42 43


Page 39


reaction between substituted 2-chloronicotinaldehydes (46a-f) and acyclic alkenes

(47a–h)60 were efficiently acetylated61 by treatment with either AcCl/pyridine or

Ac2O/Et3N, cat. 4-(N,N-dimethylamino)pyridine (DMAP) to give the

corresponding BH acetates (48a–h) in 80–92% yield which on treatment with

ethyl cyanoacetate gives substituted 8-cyano quinolines (49a-c) via successive

SN2’–SNAr elimination–decarboxylation and auto-oxidation reactions, respectively.

Biological profile of quinoline

Quinolines and their derivatives are important constituents of pharmacologically

active synthetic compounds, as these systems have been associated with a wide

spectrum of biological activities62-65 such as antibacterial,66 antifungal,67

anti-inflammatory,68,69 anticancer,70 DNA binding capability,71 antitumor,72,73

anti-HIV,74,75 antiplatelet,76 antidepressant,77 antiulcer,78 antiallergic,79

antiproliferative,80 antiparasitic,81 antimalarial,82 antihypertensive83 and act as


Page 40


DNA-intercalating carrier,84 cardiac stimulant85 and tyrokinase PDGF-RTK

inhibiting agents.5c

Ronald C B et al.86 synthesized a series of

4-(3-aryloxyaryl)quinolines with alcohol

substituents on the terminal aryl ring as

potential liver X receptor (LXR) agonists.

The most potent compound was 2-(3-{3-

[3-benzyl-8-(trifluoromethyl) quinolin-4-

yl]phenoxy}-phenyl)propan-2-ol (50)

which had an IC50 = 3.3 nM for LXRb binding and EC50 = 12 nM (122% efficacy

relative to T0901317) in an adenosine-binding cassette transporters (ABCA1)

mRNA induction assay in J774 mouse cells.

A novel and exceedingly potent series of

phosphodiesterase 4 (PDE4) inhibitors has

been identified. This series has been

optimized by Michael D W87 to afford

GSK256066 (51), a compound with

picomolar activity in vitro and properties

suitable for inhaled dosing. More detailed

investigations of the in vitro and in vivo activities of GSK256066 (51), including its

duration of action and therapeutic index, have been carried out and a clinical

evaluation of this compound in asthma and chronic obstructive pulmonary disease

(COPD) is underway.

A series of quinoline derivatives have been synthesized

and evaluated by Marcus V N et al.88 for their in vitro

antitubercular activity against mycobacterium

tuberculosis H37Rv strain using the Alamar Blue

susceptibility test and the activity expressed as the

minimum inhibitory concentration (MIC) in µg/mL. Compounds (52a) and (52b)

exhibited a significant activity at 6.25 and 3.12 µg/mL, respectively, when

NCl

HN NH2n

52a; n = 852b; n = 10

52a,b


Page 41


compared with first line drugs such as ethambutol and could be a good starting

point to develop new lead compounds in the fight against multidrug resistant

tuberculosis.

Shikui Z et al.89 synthesized a novel series of 2-cyclopropyl-4-thiophenyl

quinoline-based mevalonolactones from the substituted anilines by several

reactions. Among them, (4R,6S)-6-[(E)-2-(2-cyclopropyl-6-fluoro-4-(4-fluorothio-

phenyl)-quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (53a),

(4R,6S)-6-[(E)-2-(2-cyclopropyl-6-fluoro-4-(3-methoxy-thiophenyl)-quinoline-3-yl)-

ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-

pyran-2-one (53b) and (4R,6S)-6-[(E)-2-(2-

cyclopropyl-6-fluoro-4,7-di(3-methoxythio

phenyl)-quinoline-3-yl)-ethenyl]-3,4,5,6-

tetrahydro-4-hydroxy-2H-pyran-2-one (53c)

showed potent hydroxymethylglutaryl-

Coenzyme A (HMG-CoA) reductase

inhibitory activity comparable with

pitavastatin.

PF-2545920 (54) is a drug developed by Pfizer for the treatment of schizophrenia.

It acts as a phosphodiesterase inhibitor selective for the PDE10A subtype. Older

PDE10A inhibitors such as papaverine

have been shown to produce

antipsychotic effects in animal models,90

and more potent and selective PDE10A

inhibitors are a current area of research

for novel antipsychotic drugs, which act

through a different pathway to

conventional dopamine or 5HT2A antagonist drugs and may have a more

favourable side effects profile.91 PF-2545920 (54) is currently one of the furthest

advanced PDE10A inhibitors in development and has progressed through to Phase

II clinical trials in human beings.92

N

O

NN

CH3

N54 (PF-2545920)


Page 42


The ErbB family has been

the target of drug

discovery efforts and has

resulted in the

development of EKB-569

(55), an irreversible-

binding inhibitor of EGFR,

currently in clinical trials

for EGFR-dependent

tumors.93 This compound

is predicted to covalently

modify a cysteine residue

(cysteine-773) within the

ATP binding site of the kinase.94 HKI-272 (56) is a potent, low molecular weight,

orally active, irreversible pan-erbB receptor tyrosine kinase inhibitor recently in a

clinical trial. It inhibits the growth of tumor cells that express erbB-1 (epidermal

growth factor receptor, EGFR) and erbB-2 (HER-2) in culture and xenografts.

HKI-272 (56) also inhibits the growth of cultured cells that contain sensitizing and

resistance-associated EGFR mutations.

The NK3 receptor, which have now been

implicated in a range of conditions, including

nociception, inflammation, cough and

schizophrenia.95 Jason M E et al. synthesized a

novel series of orally active non-peptide NK3R

antagonists, which are able to occupy receptors

within the CNS based on N',2-diphenyl

quinoline-4-carbohydrazide core, out of which compound (57) has good

selectivity and promising psychokinesis (PK) activities.96

A new series of substituted quinoline-2(1H)-one and 1,2,4-triazolo[4,3-a]-quinoline

derivatives were designed and synthesized by Zhe-Shan Q et al.97 to meet the

N

CN

HN

O

Cl

N

EtO

HN

ON

H3C

CH3

N

CN

HN

F

ClHN

O

(H3C)2N

O

H3C 55 (EKB 569)

56 (HKI-272)


Page 43


structural requirements essential for anticonvulsant

activities. The triazole, but not the triazolone, modified

series showed stronger anticonvulsant effects. Among

them, compound (58), 5-(m-fluorophenyl)-4,5–

dihydro-1,2,4-triazolo[4,3-a]quinoline, showed the

strongest anticonvulsant effect with ED50 of 27.4 mg/kg and 22.0 mg/kg in the

(maximal electroshock) anti-MES and subcutaneous pentylenetetrazol (anti-scPTZ)

test, respectively.

Diarylquinoline TMC207 (exR207910) (59), which was developed at Johnson &

Johnson Pharmaceutical Research & Development, possesses a new mechanism of

action based on the interaction

with the enzyme adenosine

triphosphate (ATP) synthase,

which is the energy source for

the bacterium. Currently, this

drug is in clinical trials and is

very promising against MDR-TB.98

A series of quinoline-3-carbothioamides and their

analogues were prepared via four synthetic

routes and evaluated for their antinephritic and

immunomodulating activities by Tojo T et al.99

The optimal compound (60) strongly inhibited

the T-cell independent antibody production in mice immunized with

trinitrophenyl-lipopolysaccharide (TNP-LPS) and was highly effective in two

nephritis models, namely chronic graft-versus-host disease and autoimmune

MRL/l mice.

Brief introduction to 2-pyridone

2-Pyridone is an organic colourless solid compound, used in peptide synthesis.

2-Pyridone is a multiple bioactive small molecule and an important

pharmacophore that can form hydrogen bonded structures related to the


Page 44


base-pairing mechanism found in DNA and RNA.100,101 The most prominent

feature of 2-pyridone is the amide group; a nitrogen with a hydrogen bound to it

and a keto group next to it. In peptides, amino acids are linked by this pattern, a

feature responsible for some remarkable physical and chemical properties. In this

and similar molecules, the hydrogen bound to the nitrogen is suitable to form

strong hydrogen bonds to other nitrogen and oxygen containing species.102

In view of the classical aromatic properties of 2-pyridones, significant participation

of resonance structures such as (64) and (65) have been invoked by a number of

authors.103,104 2-Pyridones are in tautomeric equilibrium with isomers bearing

hydroxyl group at second position. It is because it retains aromaticity within the

nitrogen atom donating its lone pair electrons to the aromatic sextet. The two

forms are interchanged via the intramolecular proton transfer between the amine

hydrogen and the carbonyl oxygen of the molecule. The pyridone forms are

favoured in ionic solvents and also in the solid state. 2-Pyridones are weak acids

having pKa≈11. Deprotonation in a basic medium produces ambident anions,

which can be attacked by electrophiles O, N and C.

2-Pyridone in nature

The 2(1H)-pyridone ring system and the corresponding dihydro and tetrahydro

derivatives are found abundantly in a wide variety of naturally occurring alkaloids

and novel synthetic biologically active molecules.105 A new pyridone alkaloid,

militarinone A, has a pronounced neurotrophic effect.106 Lyconadin A, a Lycopodium

alkaloid with a unique pentacyclic skeleton that contains a 2-pyridone moiety was

demonstrated to possess modest anticancer activity.107 Harzianopyridone is

representative of the atpenin class of penta-substituted pyridine based natural


Page 45


product that was reported to be potent inhibitor of SQR. Harzianopyridone is

generally represented in the literature as the 4-hydroxy-2-pyridone tautomer.108

Substituted 2-pyridones represent useful scaffolds for drug discovery and are also

versatile synthetic building blocks. 2-Pyridones constitute important core units in a

large number of pharmaceuticals, agrochemicals, and functional materials.

N O

OH

OOH

HOOH

Militarinone A

N

HNH

H

H

H3CH

O

HNH

MeO

MeO

O

OH O

HarzianopyridoneLyconadin A

Figure-7: 2-Pyridone in naturally occuring compounds

NH

N

O

H2N

Amrinone(Phosphodiester (PDE) III inhibitor)

N O

OH

Ciclopirox(Antifungal)

NH

O

CNN

N

Olprinone(Cardiotonic agent)

NH

NH

OO

O

O

Diazaquinomycin A(Antitumor antibiotic)

Figure-8: Structures of biologically active 2-pyridone-containing compounds

Pyridinone L-696, 229; R = HPyridinone L-697, 695; R = Cl

(HIV-1 Inhibitors)

N

O

HN

HNO

R

R


Page 46


The development of their efficient synthesis is, therefore an important target in

current organic synthesis.109 A few selected examples include phosphodiester

inhibitor110 Amrinone, antifungal agent Ciclopirox,111 an anticancer antibiotic

Diazaquinomycin A,112 a cardiotonic agent113 Olprinone, L-696,229 and

L-697,661114,115 were identified as specific HIV-1 inhibitors used in clinic.

Methods for the preparation of 2-oxopyridine

Krivokolysko S G et al.116 have used Meldrum’s acid to synthesize sulfur

containing partially hydrogenated pyridones.117-119 They have prepared

non-hydrogenated pyridones by the reaction of di(methylthio)methylene-

substituted Meldrum’s acid (66) with cyanothioacetamide by boiling in ethanol

in the presence of sodium ethoxide. The synthesized sodium pyridine-2-thiolate

(67) was converted into the corresponding sulphide (68) by alkylation with

methyl iodide.

O

O

O SMe

SMe

OMeMe

66

NCCH2CSNH2

EtONa, EtOHNH

NH

O

CN

SNa

SMe

O

SMeCN

SMe+

MeI

67 68

Ashraf H A et al.120 have developed an efficient and facile synthesis of

4,6-diaryl-2-oxo-1,2-dihydropyridine-3-carbonitriles (69) via three-component

cyclocondensation from aromatic aldehydes, aromatic ketones, and ethyl

cyanoacetate in the presence of ammonium acetate and ethanol under reflux.

CHO

R1

R2

+O

O

NC NH

O

CN

R1

R2

R1, R2 = Different substituents

O

CH3

CH3COONH4

69

Ethanol


Page 47


Ring transformation that uses electron-deficient heterocyclic compounds is one of

the powerful method for synthesizing polyfunctionalized compounds that are not

easily prepared by an alternative procedure.121 3-Methyl-5-nitropyrimidin-4(3H)-

one (70) serves as an excellent substrate for this reaction, which proceeds

three components ring transformation with ketones in the presence of ammonium

acetate to afford 6-substituted 3-nitropyridin- 2(1H)-ones (71).122-125

Condensation of ethyl benzylidenecyanoacetate with thiocarbamoylacetamide in

the presence of an equimolar amount of piperidine yielded a new method for the

synthesis of 6-alkylthiosubstituted 3,4-dihydropyridin-2(1H)-ones (72), which was

reported by Krauze A et al.126

Bogdanowicz-Szwed K et al.127 have used another way of leading to the

construction of the pyridine skeleton. The reaction of malononitrile with


Page 48


3-morpholino-3-(2-thienyl)acrylic acid anilides (73) was carried out in acetonitrile

solution in the presence of a catalytic amount of triethylamine resulting in good

yields of 2-oxopyridine-5-carbonitriles (74).

A new method for the convergent and rapid assembly of substituted 2-pyridones

(75) was developed by Tanaka K et al.128 through the formation of N-alkenyl

alkynylamides (amide-linked 1,5-enynes) by N-acylation of imines with alkynoyl

chlorides and the subsequent cationic Au(I)/PPh3-catalyzed cycloisomerization.

R1

O

OH

ChlorinationR1

Cl

O

(Et)3N

R3R4

O

R3R4

NR2

R2 NH2 +

N

R1

R4

R3 O

R2

AuCl(PPh3)/ AgBF4(CH2Cl)2, rt

75R1, R2, R3, R4 = Different substituents

Dehydration

R1

N

O

R3R4

R2

N-Substituted 4,6-dimethyl-3-cyano-2-pyridones (76) have been prepared by

Mijin D et al.129 from acetylacetone, N-substituted cyanoacetamides, and

piperidine as a catalyst under microwave irradiation without solvent. The rapid

and simple method produced pure products in high yields.


Page 49


Teruyuki K et al.130 synthesized polysubstituted 2-pyridones (77) by controlling

the ratio of alkynes and isocyanate in the presence of Rhodium (I) as a catalyst.

Primary β-enamino phosphonates (78) can be obtained by the action of metallated

diethyl methyl phosphonate on nitriles. The enamines (78) can then undergo a

reaction with ethyl propiolate to give adduct, which can then rearrange either

thermally or with sodium hydride to give pyridones (79).131

Edmont V S et al.132 developed simple and easy microwave assisted procedure to

direct replacement of the hydroxy group in 4-hydroxy-6-methyl-2-pyrone (80)

with benzylamine or 2-phenylethylamine without any solvent. 4-Hydroxy-6-

methyl-2-pyrone (80) reacted with benzylamine or 2-phenylethylamine under

microwave irradiation at 850 W to give the corresponding N,N'-disubstituted

4-amino-6-methyl-2-pyridones (81). The main advantages of this procedure are


Page 50


dramatically shortened reaction times, higher amine utilization and considerably

improved yield.

Antonio J D et al.133 synthesized bis(pyridyl)methanes by reaction of compound

(80) with aqueous ammonium hydroxide to produce the corresponding pyridone

(82). Treatment of (82) under basic conditions in the presence of several aldehydes

resulted in the condensed pyridones (83) in variable yields.

The enamine (85) of cycloalkanones react smoothly with 4-trimethylsiloxy-1,3-

oxazine-6-ones (prepared in situ) by the action of trimethylsilylketene on acyclic

isocyanates (84) to give bicyclic 2-pyridones (86).134

α,β-Unsaturated acid chlorides (88) can react with enaminonitriles (87) in the

presence of triethylamine to produce polysubstituted 3,4-dihydro-2(1H)-pyridones


Page 51


in presence of (89) regiospecifically under mild conditions.135

The variation which makes use of cyanoacetamide as the nitrogen containing

component leads to 3-cyano-2-pyridones (90, 91a). Providing the two carbonyl

groups are sufficiently different in reactivity, only one of the two possible isomeric

pyridone is formed via reaction of the more electrophillic carbonyl group with the

central carbon of the cyanoacetamide.136,137 Using 2-amino-1-nitroethanone instead

of cyanoacetamide produces 3-nitro-2-pyridones (91b).138

Maxime D C et al.139 synthesized new bicyclic 2-pyridones of pharmaceutical

interest in a two step procedure: reduction of the nitro group in diethyl

2-[(1,2-dimethyl-5-nitro-1H-imidazol-4-yl)methylene]malonate with the help of

weak reducing agent titanium (III) chloride in a H2O-acetone mixture at room

temperature. The resulting intermediate was then heated in ethanolic sodium

ethoxide solution to give the bicyclic pyridone ethyl 2,3-dimethyl-5-oxo-4,5-

dihydro-3H-imidazo[4,5-b]pyridine-6-carboxylate (92) by cyclization.


Page 52


Kenichiro I et al.140 described the Pd-catalyzed one-pot rearrangement of

2-allyloxypyridine (93). The catalyst/base combination of Pd[P(t-Bu)3]2/Ag2CO3

was found to be optimal for this one-pot rearrangement. The initial rearrangement

of 2- allyloxypyridine (93) to N-allyl-2-pyridone (94) was found to be catalyzed by

both Pd(0) and Pd(II) complexes with different mechanisms. Moreover, one-pot

rearrangement/arylation of (93) with aryl iodide took place under the influence of

Pd[P(t-Bu)3]2/Ag2CO3 catalytic system to afford synthetically useful N-substituted

2-pyridones in good to excellent yields.

N O5 % Pd[P(t-Bu)3]2

Xylene, 80 CN O N O

Ar

ArI

Ag2CO3

93 94

Ar = Different aromatic substituents

A new LiI-promoted O- to N-alkyl migration has been developed by

Erica L L et al.141 for the conversion of o-alkyloxy pyridines (95) to the

corresponding N-alkyl-2-pyridones

(96) in good to excellent yields. This

method serves as an efficient means

for the preparation of N-alkyl-2-

pyridones and allows for the

incorporation of a wide range of

substituted benzyl groups in high yields with complete consumption of the

residual O-alkylated material. Despite some limitations, this transformation

provides an excellent means for the preparation of N-alkyl-2-pyridones (96).

R = Different aromatic substituents

N O

95

R

LiI (0.5 eq)

100οCN O

R96


Page 53


Young K K et al.142 developed new and facile synthesis of 5-carboxy-2-pyridone

(100) from readily available coumalic acid (97) via dimethyl 4-(methoxymethylene)

-2-pentenedioate (98) and dienamino ester intermediates (99). Reaction of coumalic

acid (97) with acetyl chloride in refluxing methanol afforded intermediate (98)

which on reaction with various amines to gave dienamino esters (99), which could

be isolated or cyclized directly to produce the corresponding 5-carbomethoxy-2-

pyridones (100) in high yield. 5-Carboxy-2-pyridone has been used as a key

intermediate for the synthesis of recently developed insecticide Imidacloprid

acting on the nicotinergic acetylcholine receptor.143

O

OH

O

O

CH3COCl

RNH2THF/DMF

RHN

H

DBUXylene/DMF

MeOH

N

R

O

MeOOC

R = H, N-Bu, -C6H5, -CH2C6H5, 2-pyridyl, 2-thiazolyl

97 98a major

99100

H

MeOO

OMe

H

H

OOMe

H

MeOO

OMe

H

CO2Me

OOMe

98b minor

+

H

OMe

OOMe

OH

Chien-Hong C et al.144 disclose the reaction of 2-pyridyl acetate (101) with

benzyne, generated in situ from isoamyl nitrite and anthranilic acid, that proceeds

smoothly to give 1-(2-acetylphenyl)-2-pyridones (102) in 58% yield. The present

reaction may be viewed as a 1,4-addition of 2-pyridyl acetate to the carbon-carbon

triple bond of benzyne leading to disubstituted benzene derivatives. The reaction

involves formation of a new C-N and C-C bonds with the cleavage of a C-O bond.

In addition, there are very few examples of addition to benzyne that resulted in

the formation of disubstituted product.145 The reaction displays an unprecedented


Page 54


1,4-addition of 2-pyridyl carboxylate to benzyne at 1,2-positions. This new

addition reaction offers a simple and mild method for the introduction of an amide

and a carbonyl to an aromatic ring at ortho positions.

Biological importance of 2-pyridone

Heterocycles incorporating a 2(1H)-pyridone framework constitute an extensively

studied class of compounds owing to their diverse biological activities ranging

from anti-HIV, antibacterial and antifungal to free radical scavengers. Pyridin-

2(1H)-ones are known to possess a wide range of biological activities such as

analgesic, antimalarial, anti-inflammatory, anti-HIV, phytotoxic, antitumoral and

antiviral properties.146-154

Edward E K et al.155 designed a novel class of phenylacetic acid isomers

possessing N-difluoromethyl-1,2-dihydropyrid-2-one pharmacophore attached to

its C-2, C-3 or C-4 position for evaluation as anti-inflammatory agents. A number

of compounds exhibited a combination of potent in vitro cyclooxygenase-2

(COX-2) and 5-lipoxygenase (5-LOX) inhibitory activities. 2-(1-Difluoromethyl-2-

oxo-1,2-dihydropyridin-4-yl)phenylacetic acid (103) exerted the most potent

anti-inflammatory activity among this group of compounds.

Makoto A et al.156 synthesized a series of 2-pyridone containing imidazoline

derivatives and evaluated as Neuropeptide Y (NPY) receptor subtype Y5

antagonists. Compound (104) was found to have potent Y5 antagonistic activity

and negligible susceptibility to human P-glycoprotein (P-gp). In addition, this

compound showed statistically significant inhibition of food intake in the agonist

induced food intake model and no adverse cardiovascular effects in anesthetized


Page 55


N

NH CH3

N

NO

F2HC

104

F

F

HOOC

N CHF2

O103

dogs. Based on these biological profiles, compound (104) was selected as a clinical

development candidate for the treatment of obesity and CNS-related dysfunctions.

Maria T C et al.157 synthesized

bis(pyridyl)methanes and these

newly synthesized compounds were

evaluated in vitro as antitumor

agents against 60 human tumor cell

lines. Some derivatives exhibit tumor

growth inhibition activity. In

particular, derivative 1-[bis(3-

(ethoxycarbonyl)-4-hydroxy-2-morpholino-1,6-dihydro-6-oxopyridin-5-yl)methyl]-

2,6- dichlorobenzene (105), the most active of the series, possesses significant activity

on all cell lines at concentrations ranging from 1×10–6 to 1×10–5 M.

Collins I et al.158 have developed a novel series of 3,6-bis(heteroaryl)-5-aryl-1-

methyl-2-pyridones (106) with high affinity for the benzodiazepine (BZ) binding

site of human γ-aminobutyric acid (GABAA) receptor ion channels, low binding

selectivity for 2- and/or 3- over 1-containing GABAA receptor subtypes and

high binding selectivity over 5 subtypes. Kim K S et al.159 have discovered some

conformationally constrained 2-pyridone (107) analogue as a potent Met kinase

inhibitor. Many of these analogues showed potent antiproliferative activities

against the Met dependent GTL-16 gastric carcinoma cell line. It possesses a

favourable pharmacokinetic profile in mice and demonstrates significant in vivo

antitumor activity in the GTL-16 human gastric carcinoma xenograft model.

NH

NH

OO

EtOOC COOEt

OH

Cl

OH

105

NN

Cl

OO


Page 56


Ammar Y A et al.160 have synthesized a new series of polysubstituted 1-aryl-2-oxo-

1,2-dihydropyridine-3-carbonitriles (108) as novel Pirfenidone analogues, which

have shown very high antifibrotic activity. Rollas S et al.161 have reported 6-amino-

4-aryl-2-oxo-1-(1-pyrid-3-yl)-1,2-dihydropyridine-3,5-dicarbonitrile series (109),

which exhibited a high percentage of tumor growth inhibition at concentrations of

10-5 to 10-7 M in cancer cell lines.162

Nehal A H et al.163 synthesized some new heterocyclic compounds containing

pyridone scaffold by the cyano condensation reaction of 2-acetyl-5,6,7,8-

tetrahydronaphthalene with the appropriate aromatic aldehydes and ethyl

cyanoacetate in one pot reaction and investigated their role in the modulation of

various inflammatory mediators. Novel compound (110) was recognised as a

promising multi-potent anti-inflammatory agent which is found to induce the


Page 57


macrophage growth, macrophages binding affinity to

bacterial lipopolysaccharide (LPS), and phagocytic

activity, and it inhibited LPS-stimulated nitric oxide

(NO), tumor necrosis factor-α (TNF-α), prostaglandin

E-2 (PGE-2), 5-lipoxyganase (5-LO), and

cycloxygenase-2 (COX-2).

Matsui T et al.164 have carried out synthesis and

pharmacological evaluation of a series of 1,2-dihydro-l-[(5-methyl-l-imidazo1-4-yl)

methyl]-2-oxopyridine as 5-HT3 antagonists. Among all the synthesized

compounds, (111) showed the most potent activity in the inhibition of Bezold-

Jarisch reflex in rats. Compounds (112) and (113) were orally active in the

protection against cisplatin-induced emesis in dogs or ferrets.

N

N

NNH

OH

O CH3

N

NNH

O CH3

N

NNH

O CH3

Cl

H2N

111 112

113

Swaminathan R N et al.165 discovered an orally bio-available and highly efficacious

compound based on the 7-amino-naphthyridone scaffold. Benchmark compound

(114) potently inhibited p38 in vitro, was functionally active, and displayed

excellent pharmacokinetic profiles in two

animal species. Compound (114) reduced

inflammation in animal disease models at

EC50 doses as low as 0.2 mpk. Follow-up

studies and identification of appropriate

drug candidates in this area are underway.

NH

CN

O

H3C CH3

110


Page 58


Michael E J et al.166 have synthesized and identified certain 2-pyridone derivatives

as novel, small-molecule inhibitors of bacterial enoyl-ACP reductase (ENR) from

B. Anthracis. Compound (115a) showed good ENR-inhibitory activity as well as

reasonable antibacterial activity, thus providing a lead compound for further

development. Compounds (115b) and (117) showed nearly a twofold

improvement in ENR inhibitory activity over compound 2. Compound (116), a

‘reversed’ pyridone, is also an encouraging lead for the development of a new

class of ENR inhibitors.

Ke Li et al.167 designed and synthesized four novel 5-substituted pyridine-

2(1H)-one derivatives (118a,b and 119a,b) using addition–elimination reactions,

all four compounds (most notably compound 118a) were found to be highly

efficient against hepatitis B virus (HBV) in cultured HepG2 2.2.15 cell, making

them promising drug candidates for potential bioactive molecule against

hepatitis B.


Page 59


Jinyou Xu et al.168 discovered a novel series of potent and selective dipeptidyl

peptidase-4 (DPP-4) inhibitors. The optimized compound (120b) exhibited good

pharmacokinetic profiles in three

preclinical species. In vitro and in vivo

metabolism studies revealed that

N-demethylation occurred in compound

(120a), leading to the formation of the

initial lead compound (120a), which had

unacceptable hERG binding. Replacement of the N-methyl pyridone with a less

metabolically labile group and improving the potency of (120b) will be the focus of

future work in this series. Consequently, inhibition of DPP-4 is rapidly emerging

as a novel therapeutic approach to the treatment of type 2 diabetes.169

We have synthesized the following heterocyclic compounds on the basis of the

literature survey and pharmacological importance of the quinoline and 2-pyridone

derivatives. This part is divided into following six sections.

Section 1 : 6-Amino-1-((2-chloroquinolin-3-yl)methyleneamino)-4-(aryl)-2-oxo

-1,2-dihydropyridine-3,5-dicarbonitriles.

Section 2 : 6-Amino-1-((2-chloro-8-methylquinolin-3-yl)methyleneamino)-4-

(aryl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitriles.

Section 3 : 6-Amino-1-((2-chloro-6-methylquinolin-3-yl)methyleneamino)-4-


Section 4 : 6-Amino-1-((2-chloro-6-methoxyquinolin-3-l)methyleneamino)-4-


Section 5 : 6-Amino-1-((2-chloro-6-ethoxyquinolin-3-yl)methyleneamino)-4-


Section 6 : 6-Amino-1-((2,6-dichloroquinolin-3-yl)methyleneamino)-4-(aryl)-

2-oxo-1,2-dihydropyridine-3,5-dicarbonitriles.

N

CH3

N

NH3+

O

FTFA-

R

O120a; R = H120b; R = -CH3

120a,b

EXPERIMENTAL

Page 60


EXPERIMENTAL PROCEDURE

Synthesis of 2-chloro-alkylquinoline-3-carbaldehydes

Dimethylformamide (19.2 ml, 0.250 mole) was charged in a three-necked round

bottom flask equipped with a thermometer, a drying tube and mechanical stirrer

and cooled to 0°C. To it, phosphorous oxychloride (64.4 ml, 0.70 mole) was added

drop wise with stirring at 0-10°C. To the solution, corresponding aryl amine (Ia-f)

(0.10 mole) was added and the mixture was refluxed for 3 hrs at 75°C. The reaction

mass was then cooled to room temperature and poured onto crushed ice. Solid

separated was filtered, washed with water and recrystallized from ethyl acetate to

give light yellow compound. Physical data of compounds (IIa-f) are recorded in

following Table-A.

The progress of the reaction and the purity of compounds were checked on TLC

[Aluminium sheet silica gel 60 F245 (E. Merck)] plates using ethylacetate:n-hexane

(2:8) as an irrigator and the plates were developed in an iodine chamber.

v TABLE A

Sr. No. -R1 -R2 Molecular Formula

Yield (%)

M.P. (°C)

Elemental Analysis % Carbon %Hydrogen % Nitrogen Req Obs Req Obs Req Obs

IIa -H -H C10H6ClNO 60 148 62.68 62.57 3.16 3.03 7.31 7.14

IIb -CH3 -H C11H8ClNO 61 159 64.25 64.11 3.92 3.65 6.81 7.62

IIc -H -CH3 C11H8ClNO 59 154 64.25 64.12 3.92 3.66 6.81 6.65

IId -H -OCH3 C11H8ClNO2 62 160 59.61 59.46 3.64 3.32 6.32 6.24

IIe -H -OC2H5 C12H10ClNO2 63 162 61.16 61.01 4.28 4.11 5.94 5.75 IIf -H -Cl C10H5Cl2NO 58 167 53.13 53.00 2.23 2.10 6.20 6.10

SECTION 1 EXPERIMENTAL

Page 61


SYNTHESIS OF 6-AMINO-1-((2-CHLOROQUINOLIN-3-YL)METHYLENE-

AMINO)-4-(ARYL)-2-OXO-1,2-DIHYDROPYRIDINE-3,5-DICARBONITRILES

N

CHO

Cl

Reflux,1 hr

N Cl

N

HN

O

CN+

Reflux,3-4 hrs

N

NN

NC

CNR

H2N

CN

CN

OCl

IIa

III

R = Different substituents

R

Methanol,H2NHNCOCH2CN

IV

Ethanol,Piperidine


Page 62


PHYSICAL CONSTANTS OF 6-AMINO-1-((2-CHLOROQUINOLIN-3-YL)

METHYLENEAMINO)-4-(ARYL)-2-OXO-1,2-DIHYDROPYRIDINE-3,5-

DICARBONITRILES

v TABLE-1

Sr. No. -R Molecular Formula

Yield (%)

M. P. (°C)

Elemental Analysis % Carbon %Hydrogen % Nitrogen

Req Obs Req Obs Req Obs JH1-1 -H C23H13ClN6O 58 243 65.02 64.87 3.08 2.89 19.78 19.66

JH1-2 -4-CH3 C24H15ClN6O 57 249 65.68 65.45 3.45 3.22 19.15 19.00

JH1-3 -4-OCH3 C24H15ClN6O2 59 255 63.37 63.21 3.32 3.15 18.48 18.33

JH1-4 -3,4,5-(OCH3)3 C26H19ClN6O4 60 259 60.65 60.51 3.72 3.55 16.32 16.21

JH1-5 -3-OH C23H13ClN6O2 60 262 62.66 62.40 2.97 2.84 19.06 18.90

JH1-6 -4-OH C23H13ClN6O2 59 245 62.66 62.42 2.97 2.82 19.06 18.91

JH1-7 -3-NO2 C23H12ClN7O3 61 240 58.80 58.69 2.57 2.43 20.87 20.75

JH1-8 -4-NO2 C23H12ClN7O3 58 257 58.80 58.67 2.57 2.42 20.87 20.72

JH1-9 -4-F C23H12ClFN6O 62 251 62.38 62.21 2.73 2.64 18.98 18.77

JH1-10 -2-Cl C23H12Cl2N6O 60 247 60.15 60.04 2.63 2.45 18.30 18.20


Page 63



Synthesis of N'-((2-chloroquinolin-3-yl)methylene)-2-cyanoacetohydrazide (III)

To a solution of compound (IIa) in 1,4-dioxan, 2-cyanoacetohydrazide was added

portion-wise with stirring. The resulting mixture was refluxed for one hr and

cooled down to room temperature. The separated solid was filtered and

recrystallized from the mixture of chloroform and methanol. Yield: 90%; m.p.:

210°C; Elemental anal. obs.C, 57.08%; H, 3.20%; N, 20.47%.Calcd. for C13H9ClN4O:

C, 57.26%; H, 3.33%; N, 20.55%.

The progress of the reaction and the purity of the compound was checked on TLC

[Aluminium sheet silica gel 60 F245 (E. Merck)] plates using ethyl acetate:n-hexane


Synthesis of 6-amino-1-((2-chloroquinolin-3-yl)methyleneamino)-4-(4-methoxy-

phenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (JH1-3) (IV)

A mixture containing compound (III) (0.01 mole), 2-(4-methoxybenzylidene)

malononitrile (0.01 mole) and 2 drops of piperidine in ethanol (99.9%) (50 mL) was

refluxed for 2-3 hrs. The mixture was then cooled down to room temperature and

the crystals formed were filtered, air dried and recrystallized from aqueous DMF.

Yield: 59%; m.p.: 255°C; Elemental anal. obs. C, 63.21%; H, 3.15%; N, 18.33%.

Calcd. for C24H15ClN6O2: C,63.37%; H, 3.32%; N, 18.48%.




All other compounds of this series were prepared by using the same method and

their physical data are recorded in Table-1.


Page 64


SYNTHESIS OF 6-AMINO-1-((2-CHLORO-8-METHYLQUINOLIN-3-YL)


DICARBONITRILES

N

CHO

Cl

NH2NHCOCH2CN Reflux,1 hr

N Cl

N

HN

O

CN+

Reflux,3-4 hrs

N

NN

NC

CNR

H2N

CN

CN

OCl

R

IIb

III

IVR = Different substituents

CH3

CH3

CH3

Ethanol,Piperidine


Page 65


PHYSICAL CONSTANTS OF 6-AMINO-1-((2-CHLORO-8-

METHYLQUINOLIN-3-YL)METHYLENEAMINO)-4-(ARYL)-2-OXO-1,2-

DIHYDROPYRIDINE-3,5-DICARBONITRILES

v TABLE-2


Yield (%)

M.P. (°C)



JH2-2 -4-CH3 C25H17ClN6O 57 240 66.30 66.22 3.78 3.50 18.56 18.32

JH2-3 -4-OCH3 C25H17ClN6O2 58 246 64.04 63.89 3.65 3.30 17.92 17.66

JH2-4 -3,4,5-(OCH3)3 C27H21ClN6O4 60 248 61.31 61.28 4.00 3.77 15.89 15.55

JH2-5 -3-OH C24H15ClN6O2 61 255 63.37 63.21 3.32 3.02 18.48 18.15

JH2-6 -4-OH C24H15ClN6O2 60 257 63.37 63.20 3.32 3.24 18.48 18.33

JH2-7 -3-NO2 C24H14ClN7O3 55 250 59.57 59.39 2.92 2.87 20.26 20.03

JH2-8 -4-NO2 C24H14ClN7O3 59 259 59.57 59.35 2.92 2.88 20.26 20.04

JH2-9 -4-F C24H14ClFN6O 60 233 63.10 63.00 3.09 2.89 18.40 18.05

JH2-10 -2-Cl C24H14Cl2N6O 61 230 60.90 60.55 2.98 2.67 17.76 17.45


Page 66



Synthesis of N'-((2-chloro-8-methylquinolin-3-yl)methylene)-2-cyanoacetohy-

drazide (III)

To a solution of compound (IIb) in 1,4-dioxan,2-cyanoacetohydrazide was added




200°C; Elemental anal. obs. C, 58.57%; H, 3.68%; N, 19.44%. Calcd. for

C14H11ClN4O: C, 58.65%; H, 3.87%; N, 19.54%.




Synthesis of 6-amino-1-((2-chloro-8-methylquinolin-3-yl)methyleneamino)-4-

(4-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (JH2-3) (IV)

A mixture containing compound (III) (0.01mole), 2-(4-methoxybenzylidene)

malononitrile (0.01 mole) and 2 drops of piperidine in absolute ethanol (50 mL)

was refluxed for 2-3 hrs. The mixture was then cooled down to room temperature

and the crystals formed were filtered, air dried and recrystallized from aqueous

DMF. Yield: 72%; m.p.: 246°C; Elemental anal. obs. C, 63.95%; H, 3.55%; N, 17.73%.

Calcd. for C25H17ClN6O2: C, 64.04%; H, 3.65%; N, 17.92%.







Page 67


SYNTHESIS OF 6-AMINO-1-((2-CHLORO-6-METHYLQUINOLIN-3-YL)


DICARBONITRILES


Page 68



METHYLQUINOLIN-3-YL)METHYLENEAMINO)-4-(ARYL)-2-OXO-1,2-


v TABLE-3


Yield (%)

M. P. (°C)



JH3-2 -4-CH3 C25H17ClN6O 60 229 66.30 66.14 3.78 3.65 18.56 18.43

JH3-3 -4-OCH3 C25H17ClN6O2 59 235 64.04 63.89 3.65 3.57 17.92 17.88

JH3-4 -3,4,5-(OCH3)3 C27H21ClN6O4 58 238 61.31 61.28 4.00 3.87 15.89 15.72

JH3-5 -3-OH C24H15ClN6O2 55 246 63.37 63.25 3.32 3.22 18.48 18.33

JH3-6 -4-OH C24H15ClN6O2 56 248 63.37 63.23 3.32 3.25 18.48 18.32

JH3-7 -3-NO2 C24H14ClN7O3 60 251 59.57 59.40 2.92 2.79 20.26 20.11

JH3-8 -4-NO2 C24H14ClN7O3 57 253 59.57 59.41 2.92 2.80 20.26 20.13

JH3-9 -4-F C24H14ClFN6O 61 249 63.10 62.99 3.09 2.90 18.40 18.23

JH3-10 -2-Cl C24H14Cl2N6O 63 243 60.90 60.78 2.98 2.87 17.76 17.62


Page 69



Synthesis of N'-((2-chloro-6-methylquinolin-3-yl)methylene)-2-cyanoacetohydr-

azide (III)

To a solution of compound (IIc) in 1,4-dioxan,2-cyanoacetohydrazide was added





C14H11ClN4O: C, 58.65%; H, 3.87%; N, 19.54%.




Synthesis of 6-amino-1-((2-chloro-6-methylquinolin-3-yl)methyleneamino)-4-














Page 70


SYNTHESIS OF 6-AMINO-1-((2-CHLORO-6-METHOXYQUINOLIN-3-YL)


DICARBONITRILES


Page 71



METHOXYQUINOLIN-3-YL)METHYLENEAMINO)-4-(ARYL)-2-OXO-1,2-


v TABLE-4


Yield (%)

M. P. (°C)

Elemental Analysis % Carbon % Hydrogen % Nitrogen

Req Obs Req Obs Req Obs JH4-1 -H C24H15ClN6O2 61 256 63.37 63.28 3.32 3.20 18.48 18.30

JH4-2 -4-CH3 C25H17ClN6O2 62 251 64.04 67.88 3.65 3.45 17.92 17.67

JH4-3 -4-OCH3 C25H17ClN6O3 59 260 61.92 61.50 3.53 3.33 17.33 17.23

JH4-4 -3,4,5-(OCH3)3 C27H21ClN6O5 57 248 59.51 59.10 3.88 3.55 15.42 15.25

JH4-5 -3-OH C24H15ClN6O3 60 240 61.22 61.00 3.21 3.07 17.85 17.69

JH4-6 -4-OH C24H15ClN6O3 58 260 61.22 61.04 3.21 3.08 17.85 17.70

JH4-7 -3-NO2 C24H14ClN7O4 60 256 57.67 57.40 2.82 2.76 19.61 19.44

JH4-8 -4-NO2 C24H14ClN7O4 62 266 57.67 57.44 2.82 2.77 19.61 19.45

JH4-9 -4-F C24H14ClFN6O2 55 264 60.96 60.50 2.98 2.78 17.77 17.55

JH4-10 -2-Cl C24H14Cl2N6O2 57 258 58.91 58.70 2.88 2.70 17.18 17.00


Page 72



Synthesis of N'-((2-chloro-6-methoxyquinolin-3-yl)methylene)-2-cyanoacetohyd-

razide (III)

To a solution of compound (IId) in 1,4-dioxan, 2-cyanoacetohydrazide was added





C14H11ClN4O2: C, 55.55%; H, 3.66%; N, 18.51%.




Synthesis of 6-amino-1-((2-chloro-6-methoxyquinolin-3-yl)methyleneamino)-4-

(4-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (JH4-3)(IV)





DMF. Yield: 59%; m.p.: 260°C; Elemental anal. Obs. C, 61.50%; H, 3.33%; N,

17.23%. Calcd. for C25H17ClN6O3: C, 61.92%; H, 3.53%; N, 17.33%.







Page 73


SYNTHESIS OF 6-AMINO-1-((2-CHLORO-6-ETHOXYQUINOLIN-3-YL)


DICARBONITRILES


Page 74



ETHOXYQUINOLIN-3-YL)METHYLENEAMINO)-4-(ARYL)-2-OXO-1,2-


v TABLE-5


Yield (%)

M.P. (°C)


Req Obs Req Obs Req Obs JH5-1 -H C25H17ClN6O2 59 243 64.04 63.86 3.65 3.55 17.92 17.78

JH5-2 -4-CH3 C26H19ClN6O2 58 250 64.66 64.44 3.97 3.65 17.40 17.21

JH5-3 -4-OCH3 C26H19ClN6O3 60 248 62.59 62.41 3.84 3.67 16.84 16.56

JH5-4 -3,4,5-(OCH3)3 C28H23ClN6O5 61 240 60.16 59.98 4.15 4.02 4.15 3.97

JH5-5 -3-OH C25H17ClN6O3 58 241 61.92 61.67 3.53 3.34 17.33 17.22

JH5-6 -4-OH C25H17ClN6O3 59 247 61.92 61.70 3.53 3.40 17.33 17.22

JH5-7 -3-NO2 C25H16ClN7O4 59 258 58.43 58.01 3.14 2.97 19.08 18.87

JH5-8 -4-NO2 C25H16ClN7O4 62 256 58.43 58.21 3.14 2.99 19.08 18.88

JH5-9 -4-F C25H16ClFN6O2 58 245 61.67 61.45 3.31 3.03 17.26 17.00

JH5-10 -2-Cl C25H16Cl2N6O2 60 239 59.66 59.33 3.20 3.00 16.70 16.50


Page 75



Synthesis of N'-((2-chloro-6-ethoxyquinolin-3-yl)methylene)-2-cyanoacetohyd-

razide (III)

To a solution of compound (IIe) in 1,4-dioxan, 2-cyanoacetohydrazide was added





C15H13ClN4O2: C, 56.88%; H, 4.14%; N, 17.69%.




Synthesis of 6-amino-1-((2-chloro-6-ethoxyquinolin-3-yl)methyleneamino)-4-



malononitrile(0.01 mole) and 2 drops of piperidine in absolute ethanol (50 mL) was

refluxed for 2-3 hrs. The mixture was then cooled down to room temperature and

the crystals formed were filtered, air dried and recrystallized from aqueous DMF.

Yield: 60%; m.p.: 248°C; Elemental anal. obs. C, 62.41%; H, 3.67%; N, 16.56%.








Page 76


SYNTHESIS OF 6-AMINO-1-((2,6-DICHLOROQUINOLIN-3-

YL)METHYLENEAMINO)-4-(ARYL)-2-OXO-1,2-DIHYDROPYRIDINE-3,5-

DICARBONITRILES


Page 77


PHYSICAL CONSTANTS OF 6-AMINO-1-((2,6-DICHLOROQUINOLIN-3-

YL)METHYLENEAMINO)-4-(ARYL)-2-OXO-1,2-DIHYDROPYRIDINE-3,5-

DICARBONITRILES

v TABLE-6


Yield (%)

M.P. (°C)


Req Obs Req Obs Req Obs JH6-1 -H C23H12Cl2N6O 62 224 60.15 60.00 2.63 2.55 18.30 18.04

JH6-2 -4-CH3 C24H14Cl2N6O 61 222 60.90 60.59 2.98 2.77 17.76 17.55

JH6-3 -4-OCH3 C24H14Cl2N6O2 63 229 58.91 58.71 2.88 2.76 17.18 16.90

JH6-4 -3,4,5-(OCH3)3 C26H18Cl2N6O4 58 243 56.84 56.75 3.30 3.00 15.30 15.10

JH6-5 -3-OH C23H12Cl2N6O2 57 247 58.12 58.00 2.54 2.45 17.68 17.45

JH6-6 -4-OH C23H12Cl2N6O2 59 252 58.12 57.98 2.54 2.33 17.68 17.55

JH6-7 -3-NO2 C23H11Cl2N7O3 62 249 54.78 54.56 2.20 2.01 19.44 19.22

JH6-8 -4-NO2 C23H11Cl2N7O3 60 255 54.78 54.57 2.20 2.00 19.44 19.23

JH6-9 -4-F C23H11Cl2FN6O 60 221 57.88 57.66 2.32 2.12 17.61 17.50

JH6-10 -2-Cl C23H11Cl3N6O 59 227 55.95 55.76 2.25 2.11 17.02 16.77


Page 78



Synthesis of 2-cyano-N'-((2,6-dichloroquinolin-3-yl)methylene)acetohydrazide

(III)

To a solution of compound (IIf) in 1,4-dioxan, 2-cyanoacetohydrazide was added





C13H8Cl2N4O: C, 50.84%; H, 2.63%; N, 18.24%.




Synthesis of 6-amino-1-((2,6-dichloroquinolin-3-yl)methyleneamino)-4-







Calcd. for C24H14Cl2N6O2: C, 58.91%; H, 2.88%; N, 17.18%.






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part - i studies on compounds consisting quinoline and 2...

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