Preamble - INFLIBNETshodhganga.inflibnet.ac.in/bitstream/10603/39776/5/05_chapter1.pdfSardar Patel...

Chapter-1

Sardar Patel University 1

Preamble

Organic synthesis has a long history that can be traced back to ancient times.

However, it was not recognized as such, because it was practiced randomly and

historically. In 1825 on one hand, the beginning of the nineteenth century was the

dawn of chemistry where Professor Wöhler [1] was the first who succeeded in

synthesizing an organic compound (Urea) in laboratory from ammonium cyanate.

This synthesis was followed by other milestones such as synthesis of acetic acid,

glucose, camphor, quinine etc. On the other hand, twentieth century was devoted to

the development of various processes for the organic syntheses that can bring about

increase in molecular complexity from the simple building blocks. These processes

were referred to as “Named Organic Reactions.”

The main focus of the organic synthesis lies not only in its capacity to prepare

enormous organic substances but more significantly in its capacity to create new

entities which have beneficial impact on the health and welfare of human civilization.

The important applications of these compounds in everyday life are pharmaceuticals

that can cure or prevent diseases, for population control and agricultural growth,

textiles and dyes, paints, polymers, cosmetics, detergents and high technological

materials used in automobile, aerospace, electronics and computers. Consequently the

science of organic synthesis is driven by the continuous discovery of novel and

complex molecules that fascinate and challenge to the organic chemists to synthesize

more efficient and economic ways. Therefore zeal towards higher level of

achievements in organic synthesis both in terms of methodology and in terms of

complexity of targets remains unabated. In this context, in the last century more

expedient and economical processes reported in literature are:

• Microwave assisted synthesis of various organic compounds.

• Solid phase synthesis of peptides and different organic reactions (oxidation,

reduction, nitration, sulphonation, etc.) using phase transfer catalyst.

• Total organic synthesis of natural products.

• Multicomponents reactions such as Diels-Alder reaction, Enamine reaction,

Mannich reaction, Biginelli reaction, etc.

• Asymmetric synthesis of chiral drugs

• Catalysis, Transition metal complexes in organic synthesis.

Chapter-1


As a result, in the 21st century these are the frontiers of enormous potential

providing wonderful opportunities for the synthesis of various complex moieties like

natural products, amino acids, hormones, nucleic acids, chiral drugs, etc. as well as

challenge for a sustainable environment calls for the use of clean procedures

(ecofriendly) which can avoid the use of harmful solvents. In addition to this, the

impact of science of organic synthesis on biology and medicine in particular, merits

special mention in this century. Eventually with its share of glorious moments, the

science of organic synthesis determine and direct the path of discovery of new

synthetic strategies and methods and new chemical entities for both academically

oriented organic chemists and industry for their potential to lead to practical and

profitable applications with sustainable technology.

In this context, five membered nitrogen containing heterocyclic ring system is

one of simple strategy reported for preparing variety of various organic compounds of

high medicinal and biological value. Its importance in organic synthesis is clearly

evident in the reviews of Blick, Karbe, Nobles, Reichert, and others [2-9]. Besides

this, the chemistry of quinoline and imidazoles have also been reviewed in a

considerable number of publications and patents deals with the heterocyclic system

based useful as chemotherapeutic agents as well as reactive intermediates for the

synthesis of various organic compounds. Hence, we have planned to undertake the

work on “Synthesis, characterization and material applications of imidazoles”.

Therefore it would be reasonable at this juncture to describe imidazoles derivatives in

brief.

Chapter-1


1.1 INTRODUCTION OF QUINOLINE

Quinoline (1-azanaphthalene or benzo[b]pyridine) is a stable base and an

important class of heterocyclic compound known for long time. Quinoline was first

isolated in an impure state in 1834 by Runge from coal-tar distillate [10]. Gerhardt

obtained quinoline, probably contaminated by lepidine by distillation of cinchonine

and quinine with caustic alkali, and named it quinoleine. This name was subsequently

changed to quinoline by Berzelius. Many valuable synthetic dyes and medicines have

been produced from various quinoline derivatives. Since the preparation of quinoline

must proceed from available materials, the different methods have been described

below.

1.1.1 Synthesis of Quinolines

(1) Skraup’s synthesis

Skraup’s synthesis is one of the most common methods for the preparation of

quinoline compounds. Quinoline is produced when aniline, concentrated sulfuric acid,

glycerol and a mild oxidizing agent are heated together. It is acid catalyzed reaction

[11,12].

NH 2

+

O

H Glycerol

con . H SO2 4

PhNO 2 , 1300

C

N

HO

H

NH

H O2

N

[O]

(2) Combes synthesis

Condensation of a 1,3-diketone and aryl amine produces a high yield of a β-

amino-enone, which can then be cyclized in the presence of concentrated acid to give

quinoline [13,14].

NH2

RO

O

+

R

R R

RN

O

R

H

R RR

con . acid

R

N

R

Chapter-1


(3) Conrad-Limpach-Knorr synthesis

Reaction of anilines with β-ketoester gives quinolones [15].

NH 2

+O

OEt

O CH 3

N

OEtO

CH 3H

N

O

OH

250 C0

250 C0

50 %

70 %

N

O

CH 3

N O

CH 3

H

H

At room temperature, product is kinetically and thermodynamically controlled

at 140 0C.

(4) Pfitzinger synthesis

Isatin is hydrolysed to o-amino keto acid which condenses with ketones or

acids that have a reactive methylene group.

N

O

O

H3CNaOH

H O2

NH2

O

COONa

H3C

+

O

R

R

H O2

N

H3C

COOH

R

R

(5) Friedlander synthesis

It comprises condensation of o-aminobenazaldehyde [16,17] and compound

having active methylene group, adjacent to an aldehyde, ketone, or acid group.

NH2

O

H

O

+

R

R N

R

R

Piperidine

Other method for the synthesis of quinoline and its various derivatives has

been reported in literature [18-21].

1.1.2 Synthesis of 2- Chloro-3-Formyl Quinoline :

In the broad field of quinoline, 2-chloro-3-formyl quinoline possesses a

prominent position in the intermediate category as it can be utilized for the synthesis

Chapter-1


of many heterocyclic compounds. There has been much more interest towards the use

of Vilsmeier-Haack reagent in organic synthesis of several nitrogen and oxygen

heterocycles. It has proved to be a mild and efficient method for the formylation of

reactive aromatic and hetero aromatic and carbonyl compounds. The utility of this

reagent also explores the powerful route for the synthesis of substituted 2-chloro-3-

formyl quinoline. Meth-Cohn Otto and co-workers have shown that treatment of

acetanilide with the Vilsmeier-Haack reagent with POCl3 as solvent allows the

preparation of 2-chloro-3-formyl quinoline(i) [22-27].

N

CH3

OH

+ DMF + POCl3

N

CHO

Cl

[102]

Mechanism

N

CH 3

OH

DMF + POCl 3

N

CH 3

OH N

CH 3

Cl

Vilsmeirer Haack

reagent

N

C

N

CH N

CH3

CH3

H3C CH3

Cl

+

Cyclization

N

CHO

Cl

POCl3

Kidwai Mazahir and Jindal Shelly have described [28] the method for the

preparation of substituted 2-chloro-3-formyl quinoline(ii) starting from

acetoacetanilide.

N

H3C O

OH

DMF + POCl 3

N Cl

CHO

CH 3

[103]

(i)

(ii)

Chapter-1


Pawar P. A., Bajare P. B. and co-workers [29] have also reported synthesis of

2-chloro-3-formyl-4-methyl quinoline(iii) from acetophenone oxime under the

Vilsmeier cyclization conditions.

DMF + POCl 3

N Cl

CHO

CH3

[104]

CH3

NOH

Synthesis of 4-chloro-3-quinolinecarboxaldehyde(iv) [30] can also be

prepared from o-aminoacetophenone using Vilsmeier reagent.

CH3

O

NH2

DMF + POCl

3 - 6 hrs , 90oC

3

N

Cl

CHO

[105]

1.1.3 Reactions of 2-chloro-3- formyl quinoline :

The substituted 2-chloro-3-formyl quinolines are the unique intermediates as

they can be utilized for various functional group interconversions. It undergoes

various electrophilic and nucleophilic substitution reactions. Some examples are

shown below.

N

CHO

Cl

R

R

R

1

2

Pyridyl Lithium

HNO 3

N

CHO

Cl

NR

R

1

2

N

CHO

Cl

NO 2

R

R

R

1

2

R

(iii)

(iv)

Chapter-1


The presence of electron rich nitrogen at 1-position and electron withdrawing

formyl group at 3-position activates the chlorine towards various displacement

reactions. Some examples of the displacement reaction at 2-position are cited below.

Formyl group of the 2-chloro-3-formyl quinoline also undergoes various addition and

condensation reactions to give different compounds. Formyl group at 3-position is

highly reactive towards hydrazine hydrate, phenyl hydrazine and hydroxylamine.

N

CHO

Cl

R

N Cl

CH NNH

R

N Cl

CH NNHPh

R

N Cl

CH NOH

R

2

NH NH . H O2

2

2

2

2

PhNHNH

NH OH . HCl

It also reacts with the compounds containing active methylene group. Some

important reactions at formyl group of 2-chloro-3-formyl quinoline are illustrated

here.

N

CHO

Cl

R

N Cl

COOEt

CN

R

N Cl

CH 3

NO 2

R

CN

H2C

COOEt

NO 2

H2C

CH 3

EtOH , piperidine

MeOH

Chapter-1


It also undergoes oxidation, reduction and Grignard reactions.

N

CHO

Cl

R

N Cl

OH

O

R

N Cl

OH

R

N Cl

CH3

R

OH

KMnO

NaOH

NaBH

CH MgBr

4

4

3

For the replacement of chlorine by sulphur, sodium sulphide in DMF was

found to be an efficient reagent which also provides scope for further reaction. The

corresponding ortho-nucleophilic substitution achieved by refluxing quinolines in

aqueous acetic acid affords the 2(H) quinolone and further reaction of quinolones with

electrophile favours N-alkylation. Reaction with sodium azide in PTSA and EtOH

affording tetrazoloquinolines.

N

CHO

Cl

R

N

CHO

S

N

CHO

O

N

CHO

N3

R

R

R

H

H

NaN3

PTSA , EtOH

AcOH

Na2S

DMF

CHO

N

R

HN NH

NH

N

N N

N

CHO

R

Chapter-1


3-Phenyl-2H-pyrano [2,3-b] quinolin-2-ones and 3-acetamido-2H-pyrano [2,3-b]

quinolin-2-ones have been prepared by Perkin type condensation of 3-formyl-2- quinolin-2-

ones with sodium salt of phenylacetic acid and acetylglycine, respectively.

N

CHO

OH

R1

R2

R3

N

CHO

OHH

R1

R2

R3

N O

Ph

O

R1

R2

R3

N O

NHCOCH 3

O

R1

R2

R3

Phenylacetate

Ac2O

Acetyl glycineEt 3N

R1 R2 R3

= H

= H ==

==

=

=

=

=

=

=

= OMe

= Me

= = Me=

H

R1R2 R3

H

R1R2

R3OMe

R1R2

R3Me

R1 R2R3H

R2

R3

==R1 R3 H Cl

= H=R1R2

[106] [107]

Among quinolines, 2-chloro-3-formyl quinolines are versatile intermediate for

various heterocyclic ring systems. When 2-chloro-3-formyl quinoline is condensed

with ethyl mercaptoacetate in ethanol, it generates a five membered thiophene ring(v).

N

CHO

Cl

HSCH COOEt2

NaOEt , EtOH

N S

COOEt

[108]

Kalluraya B. and other have prepared fused tetracyclic derivatives 3-

aryl/alkyl-9-substituted-1,2,4-triazolo[3,4-b] [1,3,4] quinoline [3,2-f] thiadiaze-

pines(vi) by reaction of 6-substituted-2-chloro-3-formyl quinolines and 3-substituted-

4-amino-5-mercapto-1,2,4-triazole [31].

N

CHO

Cl

R

N

N

N

R

HS

H2N

+EtOH , H 2SO4

N S

N

N

NN

RR

1

1

[109]

Where, R= H,CH3,OCH3, R1=methyl, n-propyl,

phenyl, p-chloro phenyl

(v)

(vi)

Chapter-1


Nandha Kumar R. and co-workers [32] have prepared 2,3-heteroannelated

quinoline derivatives like quino[3,2-f]benzoxazepines(vii) by reaction of substituted

2-chloro-3-formyl quinoline and 2-aminophenol in methanol.

N

CHO

Cl

R

R

R

H2N

HO

+

N

R

R

R

O

N

1

2

3

1

2

3

[110]

anhy . MeOH

Where, R1 = H, CH3, OCH3

R2 = H, CH3

R3 = H, OCH3

When 2-chloro-3-formyl quinoline is condensed with guanidine nitrate in

alcoholic sodium hydroxide to give 3-amino pyrimido [4, 5 -b] quinoline(viii).

N

CHO

Cl

R

R

R1

2

3

N

R

R

R

N

N

NH2

1

2

3

Guanidine nitrate

alc . NaOH

[112]

where , R1= R2 = R3 = H ; R3=CH3, R1=R2= H ; R1=OCH3, R

1=R3=H;

R1=CH3 , R2= H, R3=H ; R3= OCH3, R

1=R2= H

Some tricyclic condensed quinoline system can be obtained from 2-chloro-3-

formyl quinoline; for example, the preparation of thieno quinoline derivative(ix) is

described as under .

(vii)

(viii)

Chapter-1


N

CHO

Cl

NH OH . HCl NaOH

Ac O2

2

N Cl

CN

NaSH X H O2

N SH

ClCH COCH

DMF aq. KOH

2 3

N S

COCH 3

NH2

[113]

CN

Kombarov P.V. and his co-workers have reported synthesis of 3,4-dihydro-

2H-[1,3] thiazino [6,5-b] quinolines(x) based on 7,8-dimethyl 2-chloro-3-formyl

quinoline via the consecutive step conversion in to its Schiff’s base with a primary

amine, reduction to the corresponding amino methyl derivative, conversion to

thiourea with isothiocynates and heterocyclization by intramolecular substitution of

the chlorine atom [33].

N

CHO

Cl

CH3

H3C

NH2CH2CH2OMe1.

2.NaBH 4,MeOH

N Cl

CH3

H3C

NOMe

H

RNCS EtOH

N Cl

CH3

H3C

N

S

NH

RCH2CH2MeO

KOH / MeOH

N

CH3

H3C S

N

N

OMe

R[114]

R =Me, CH2 Ph, 4-Me-C6H4

Rajendran S. P. and his co-workers [34] have reported the synthesis of some fused

quinoline derivatives, thieno[2,3-b]quinoline(xi) from 3-(2-chloro-3-quinolyl)acrylic esters

which in turn were prepared from 2-chloro-3-formyl quinolines.

(ix)

(x)

Chapter-1


N O

COOEt

R3

R1

R2

POCl 3

N

COOEt

Cl

R3

R1

R2

H

Thiourea , Ab.EtOH

N

COOEt

S

R3

R1

R2

H

Br2 , Anhy. CHCl 3

Et 3N , Anhy. CHCl 3

R3

R1

R2 N S

[115]

R1= R2= R3= H ; R1=Me , R2= R3=H ; R2=Me , R1=R3= H ; R3=Me , R1=R2=H

2-Chloro-3-formyl quinoline on treatment with benzil in the presence of

ammonium acetate and acetic acid gives 2-amino-3-[(4’5’-diphenyl)-imidazol-2’-yl]

quinoline(xii) while with ethyl aminocrotonate gives 2-amino-3-[4’-(2’,6’-dimethyl-

3’,5’-dicarbethoxy-1’,4’-dihydropyridyl)] quinolines(xiii).

1

N

N

N

R

R

NH 2

Ph

Ph

N

R

R

NH 2

NH

CH3

EtOOC

COOEt

CH3

1[116] [117]

R= H, Me, OMe R= H, Me, OMe

R1=H, Me R1=H, Me

Parekh and co-workers [35] have reported the synthesis of some

5-oxoimidazolines derivatives by the reaction of 2-chloro-3-formyl-8-methyl

quinoline with hydrazine hydrate and then fusion with 4-aryl-2-phenyl-5-

oxazolinones(xiv).

N Cl

CH 3

N N

N

O

R

Ph

[118]

where R=unsubstituted phenyl,2-furyl,2-thienyl

(xi)

(xii) (xiii)

(xiv)

Chapter-1


Dubey P.K. et al [36] have prepared some novel 3-(2-chloro-3-quinolyl)-5-

phenyl[1,3]thiazolo [2,3-c] [1,2,4]triazloes(xv).

N Cl

RN

N

N

SR

1

2

[119]R1=H, Me

R2=H, Me, Br, Cl

Mogilaiah K. and co-workers [37] have synthesized a pyrazolo[3,4-

b]quinoline derivatives by reaction of 2-hydrazino-3-(4-methoxyphenyl)-1,8-

naphthyridine and substituted 2-chloro-3-formyl quinolines(xvi).

N N

NR

N N

H3CO

[120]

Where, R=H, 6-CH3, 7-CH3, 8-CH3, 8-OCH3, 6-Cl, 6-Br

Korodi Ferene and co-workers [38] have reported [1,2,4] triazolo[5’1’:2,3]

thiazino [6,5-b]quinoline derivatives(xvii) synthesized by reaction of 2-chloro-3-

formyl quinoline with 1,2,4-triazols.

N S

N N

N

R

R1

R2

R1

R2

R = OH, OEt, OAc, Cl, OCH 2 CH 2 OH, S CH 2 CH 2 OH, NH-[CH 2] 3-

=

= H, Me, Et

-6, -7, -8- Me, -6,-7,-8-OMe, -7, -8-Cl

[121]

(xv)

(xvi)

(xvii)

Chapter-1


1.1.4 Therapeutic interest of quinoline

A number of derivatives of quinoline serve as valuable therapeutic agents.

Some hundred years ago cinchona bark was introduced for the treatment of malaria,

and until very recently quinine has remained the standard remedy for this disease.

Several other synthetic antimalarial drugs are based on quinoline nucleus e.g.

chloroquine. Considerable interest has been created in the chemistry of quinoline due

to their versatile therapeutic activities like bactericidal, antihistaminic, antimalarial,

antidepressant, analgesic, anti-ulcer, antiviral, herbicidal, antitumor, anti-allergic,

anticonvulsant, anti-inflammatory etc. Some of the therapeutically active compounds

derived from 2-chloro-3-formyl quinoline derivatives are reviewed here [39-44].

Suresh T. and co-workers [45] have reported the synthesis of various 4-phenyl-3-

thiopyrimido[4, 5-b]quinoline derivatives which shows antibacterial and antifungal

activities(xviii).

N

CHO

Cl

R

R

R

1

2

3

N

R

R

R

N

N

S

1

2

3HN C NH 2

S

+Gla . AcOH

15h

[122]

R1 R2 R3= = = H

R1

R2R3

=CH 3 R2 R3= = H

= = H=CH 3 R1

R3

OR1

=

CH 3 =

OCH 3 R2= = H R1

R2 R3= = H

Gupta Rajiv et al [46] have reported anti-inflammatory, antibacterial and

antifungal activities of quinoline derivatives, 2-chloro-6/8-subtistuted-3-(3-alkyl/aryl-

5,6-dihydro-5-triazolo-[3,4-b][1,3,4]thiadiazol-6-yl)-quinolines(xix).

N

CHO

Cl

R

R

1

2

+

N

NN

R

NH2

SH

DMF

N Cl

R

R

N

N

SN

N

R

H

1

2

H

[123]

where R1= OMe, Me, H

R2= H

(xviii)

(xix)

Chapter-1


Pyranoquinoline alkaloids have gained considerable importance in recent

years due to their pharmacological activities like anticonvulsant, coronary

constricting, optically brightening and antifungal activities.

Quinoline ring fused with heterocyclic system is also found in natural as well

as in the synthetic compounds of biological interest. Dictemine and Skimmianine are

the example of such naturally occurring compounds, which are associated with

smooth muscle contracting properties. B.Kalluraya and co-workers have reported

antifungal and antibacterial activities of thiadiazepines derivatives of 2-chloro-3-

formyl quinoline.

It is a well known fact that the presence of azomethine linkage in the

compound is found to exhibit biological activity, particularly antifungal activity.

Rajendran S. P. and Karvembu R. have prepared schiff bases of type(xx), which

displayed an antifungal activity.

N

CHO

Cl

R

R

R

1

2

3

PyridineN

R

R

R

O O

NH 21

2

3

MeOHC H CHO6 5

C H 6 5

N

R

R

R

O

N

O

1

2

3

CH

[125]

R2

R3

R2R1= R3

R2R1= R3 = H = Me

= =

R1= R2

R1= R3

H

= H

= H

=

=

OMe

OMe

where

H2NCH2COOC 2H5.HCl

Parikh et al [47] have reported antifungal and antibacterial activities of some

schiff bases(xxia) and their 2-azetidinones derivatives(xxib) of 2-chloro-3-formyl

quinoline.

(xx)

Chapter-1


N Cl

N R

OCH 3

OCH 3

N Cl

OCH 3

OCH 3

N O

R

Cl

[126a] [126b]

R= C6H4

-C6H3

4-Me- C6H4, Ph, 4-Br- C6H4, 4-Cl- -C6H4, , 4-NO 2

C6H44-OMe- , 2,5-(OMe) 2 , 2,4-Me 2 - C6H3

Fathy N. M. and Aly A. S. have prepared azomethine derivatives of 2-chloro-

3-formyl quinoline of the type(xxii), which shows bactericidal and fungicidal activity.

N

CH

ClR

N R2

1

[127]

R1= Me, Cl

R2= NH 2, NHPh, NHCONH 2

H 2N-C6H4-tolyl , halo phenyl

A number of pyrazole derivatives are reported to possess diverse biological

activities like, analgesics, anti-inflammatory, antipyretic, sedative and hypoglycemic.

Bell, Malcom R. and co-workers have patented pyrazolo quinoline derivatives as

potent antiviral agents. Antimicrobial activity of some novel pyrazolo[3,4-b]quinoline

derivatives have been reported by El-Sayed O. A. and Aboul-Enein H.Y. A large

number of hydrazones are reported as antibacterial, antiviral and antitubercular

agents. Amir Mohd. and co-workers have reported synthesis and anti-inflammatory

activities of some new hydrazones of aryl alkanoic acid(xxiii).

N

RN

Cl

N

O

CH 3H

[128]

R= H, CH3 , OCH3 , Br

Antimicrobial activity of quinoline derivatives(xxiv, xxv) of type are reported

by Khunt et al.

(xxia) (xxib)

(xxii)

(xxiii)

Chapter-1


N Cl

N

O

R

N Cl

N

CN

NH 2

[129] [130]

H3COH3CO

2-furyl, 2-thienyl, (un) substituted phenyl

Selvi G. and Rajendran S. P. have reported [48] 2-[3-(2-choloro quinolinyl)]-

3-aryl-4-thiazolidinones(xxvi) as potential antibacterial agents.

N Cl

N

S

O

R1

R2

R3

R4

R5

R6

R7[133]

R1 = R2 = R5 = R6 = H; R3 = R4 = -CH=CH-CH=CH- ; R7= H

R1 = R2 = R5 = R6 = H; R3 = R4 = -CH=CH-CH=CH- ; R7= -OCH3

R1 = R2 = R5 = R6 = H; R3 = R4 = -CH=CH-CH=CH- ; R7= -CH3

Acrkman J. H. and co-workers have reported [49] pyrazolo[3,4-b]quinolines

(xxvii) as antiviral agents

N

H3CO

N

N

R1

R2

[134]

R1 = H ; R2 = NH2

(xxiv) (xxv)

(xxvi)

(xxvii)

Chapter-1


1.2 APPLICATIONS OF IMIDAZOLE DERIVATIVES

The emergence of powerful and elegant imidazoles has stimulated major

advances in chemotherapeutic agents of remarkable significance in medicine, biology

and pharmacy. As the work incorporated in the present thesis deals with synthesis of

imidazoles and their antimicrobial activity as well as reactive intermediates, it would

be worthwhile to discuss in brief about the history and developments of these

Mannich Bases as chemotherapeutic agents and reactive intermediates.

Chemotherapeutic Agents

Until 1960 considerable work had been reported on synthesis and

pharmacological activity of imidazoles derivatives for analgesic, antispasmodic,

anaesthetic and antimicrobial activity [50-57]. In this context W.I.Nobles has patented

imidazoles having antibacterial, anticonvulsant, analgesic and anti-inflammatory

activity [58]. Besides these Mannich Bases, there are many reports envisaged the

application of imidazole based on Mannich reaction to the compounds containing an

acidic hydrogen on a nitrogen atom to yield N-Mannich Bases of imidazole which

have been evaluated for their pharmacological action [59-71]. The chemical structure

of some of five membered nitrogen containing heterocycles having significant

biological activity are furnished in Table-1.1 and Table-1.2, respectively.

Chapter-1


Table-1.1 Chemical structures of Five memberd nitrogen containing

heterocycles and their biological activity

Substrate Amine C-Mannich Base Biological

activity Ref.

COCH3

N

CH3

NH(CH3)2

COCH2CH

2N(CH

3)2

N

CH3 Analgesic 45

NH

R = HNMe2

HNEt2

HNC5H10

NH

R2NH

2C N

HR

2NH

2C CH

2NR

2

+

Antimalarial agent

46

OH

H5C

6

C(CH3)3

HN(C2H

5)2

OH

H5C

6

C(CH3)3

CH2 N(C

2H

5)2

Antimalarial agent

47

N

OH

NH Cl

NH

N

OH

CH2

NH

N

Cl

Amebacibal agent

48

N

OH

Cl

HN(C2H

5)2 N

OH

Cl

(C2H

5)2HN H

2C

Anti amebic

agent 49

N

N N R2

R

R1

R1

NHR2''

R"2 = Me2 = Et2,

N

NR2

R1

N R2

CH2NR"

2

R

Hypotensive and

Antiaggregant agent

50

NN

CH3

OCH3

NHNH

N

N

CH3

OCH3

CH2

NN CH2

N

N

CH3

O

CH3

Antimicrobial agent

51

Chapter-1


Table-1.2 Chemical structures of Five memberd nitrogen containing

heterocycles and their biological activity

Substrate Amine N-Mannich Base biological

activity

Ref

NH

NH

CH

2

R= morpholine,

Piperidine

NN

CH

2

CH2R CH

2R

Tranquilizing effect

52

NH

N

R

R = H, CH3, C

2H

5, n-C

3H

7

CONHNH2

NH2

N

N

R

CH2 CONHNH

2HN

Anticonvulsive agent

53

NH

NH

S

MeO

R = Morpholine = Piperidine = Aniline = 4-Cl or Br Aniline N

N

S

MeO

CH2

CH2 R

R

Antiviral agents

54

N

N

CH2-CH

2

CH3

O

NHN

S

N O

N N CH3

R' = -N(C2H

5)2

N

N

CH2 CH

2

CH3

O

NN

S

CH2-R'

Antimicrobial agents

55

CONHN

NHCOCH3

Cl

NH

O

NH O

CONHN

NHCOCH3

Cl

NO

CH2 N O

Antifungal agent

56

NH

N

O SNH

O2N

C3H

7

ONH

ONNN

O SNH

O2N

C3H

7

CH2

Antifungal agent

56

NH

N

O SNH

Br

COCH3

NH2

NN

O SNH

Br

COCH3

CH2

HN

Antileishmanial agent

56

OMe

Cl

CONH2

SNH2

NH R

O

O

OMe

Cl

CONHCH2NH S NH R

O

O

Antibacterial agent

57

Chapter-1


Bryant [72] in 1965 reported the synthesis of nitrogen containing pyrrole

derived from various nitrogen containing five membered ring systems such as pyrrole,

pyrazole, benzimidazole and benzotriazole. He also studied the pharmacological

activity of a series of nitrogen compounds for example antimalarial, anaesthetics,

analgesic activity. Pyrrole condensed with formaldehyde and secondary amines

according to the following equation.

NH

HCHO R2NH

NH

NH

CH2NR

2NR2H

2C NR

2H

2C

+ + +

Pyrrole 20 Amine

Before the detection of chloroquine resistant falciperum malaria in the early

1960’s, chloroquine (I) and the Amodiaquine (II) were the best therapeutic and

suppressive drugs available for combating malarial infections. Both drugs had rapid

therapeutic action and few side effects and they were cheap to produce. Then

pyronaridine (III), a drug developed in China [73] during 1970, structurally similar to

Amodiaquine and is a potent blood Schizontocide. This has been shown to be highly

effective against P.falciperum and plasmodium vivax malaria. This has been

stimulated the interest in Mannich Base drugs for the treatment of Malaria.

NCl

NOMe

HN OH

CH2

CH2

N

N

Pyronaridine

NCl

NH CH(CH2)2NEt

2

Me

Chloroquine

NCl

NH OH

CH2NEt

2

Amodiaquine

I II III

Parmar Surendra et. al [74] have reported that hydrazine derivatives reported

to be potent inhibitors of the enzyme MAO and inhibitors of this enzymes have

exhibited pronounced anticonvulsant activity. Further Benzimidazole derivatives have

also been shown to possess CNS depressant activity. On the basis of these

observations they have carried out the synthesis of substituted benzimidazole

hydrazides by using Mannich Bases as reactive intermediate treated with hydrazine

Chapter-1


hydrate as shown in Scheme-1.1. They have prepared the aminomethylated

compounds of 2-alkyl benzimidazole by o-phenylenediamine, formalin and ethyl p-

amino benzoate. The corresponding hydrazides were prepared by the reaction of

esters with hydrazine hydrate. All of the benzimidazole hydrazides exhibited lower

anticonvulsant activity against pentylene tetrazol-induced inhibitory activity.

Scheme-1.1

N

N

R

CH2

NH COOEt

NH2

NH2

NH

N

R

N

N

R

CH2

NH CONHNH2

RCOOH

1. formalin2. ethyl p-aminobenzoate

Hydrazine

hydrate

o-phenylenediamine 2-alkylbenzimidazole

N-Mannich Base Substituted benzimidazole hydrazide

R = H, CH3, C2H5,

n-C3H7, iso-C3H7

A series of nitrogen containing Quinazolinone derivatives (Scheme-1.2) have

been synthesized from Quinazoline-4-one and various primary aromatic amines in the

presence of formaldehyde.

Scheme-1.2

N

N

O

CH2-NH

N

NH

O

HCHO NH2

X

X = H, 4-Me, 4-OMe, 4-Cl, 3-Cl, 2-OEt, 4-Ph, 2-,3-,4-COOH

+ +

Quinazoline-4-one Quinazoline-4-N-Mannich Base

x

Chapter-1


Varma R.S. and coworkers [75] have reported the synthesis of series of 5-

methoxy 1,3-disubstituted benzimidazoline-2-thione as potential biological active

agents. They have carried out the reaction of 5-methoxybenzimidazoline-2-thione

with formaldehyde and secondary as well as secondary and primary aromatic amino

compounds (Scheme-1.3). They have investigated the antiviral activity against

Sunnhemp rosette virus (SRV) and observed that majority of these compounds

inhibited the growth of SRV invitro and invivo.

Scheme-1.3

N

N

S

MeO

CH2

CH2

N

N

A

A

NH

NH

S

MeO

HCHO N A

A = morpholino, piperidino, anilino, 4-Cl anilino, OCH3 anilino,4-NO2 anilino, 4-COOH anilino,

+ +

5-methoxy Benzimidazoline-2-thione

5-methoxy Benzimidazoline-2-thione

Barbara et. al [76] have reported the comparative study of exvivo antimalarial

activity of twelve new quinoline di-Mannich Base compounds containing 7-

chloroquine or 7-trifluoromethyl quinoline moiety along with amodiquine,

chloroquine and pyronaridine antimalarials. Of these twelve Mannich Bases tested

against six culture of p.falciperum and of these eight Mannich Bases showed exvivo

and invitro antimalarial activity in serum greater then amodiquine, chloroquine and

pyronaridine and following four Mannich Bases DM-1, DM-2, DM-3 and DM-4

(Scheme-1.4) induced a very high level of activity.

Chapter-1


Scheme-1.4

N

NH

X

CH2NR

2

OH

CH2NR

2Y

A

: A,X= CF3, Y=H, NR

2=pyrrolidinyl

: A,X= CF3, Y=H, NR

2 = piperidinyl

: A,X =CF3, Y=H, NR

2=p-methylpiperazinyl

N

NH

X

CH2NR

2

CH2NR

2Y

z

OH

A,X=Cl, Y=H, NR2=piperidinyl

B

NCl

NOMe

HN OH

CH2

CH2

N

N

Pyronaridine

NCl

NH CH(CH2)2NEt

2

Me

Chloroquine

NCl

NH OH

CH2NEt

2

Amodiaquine

DM-1

DM-2

DM-3

DM-4 :

Burckhalter and coworkers [77] have described the application of N-

substituted heterocyclic intermediates in drug synthesis. On the basis of these

discoveries, Afaf H. El-masry and co-workers [78] have made efforts to incorporate a

benzimidazole into a triazole moiety by Mannich reaction of oxadiazole with different

secondary amines namely diethyl amine, morpholine or N-methyl piperazine and

paraformaldehyde to give Mannich Base compounds MO-1, MO-2 and MO-3

(Scheme-1.5). These compounds were tested against Gram +Ve bacteria, Gram –Ve

bacteria, yeast and fungi for antibacterial and antifungal activity.

Chapter-1


Scheme-1.5

N

N

CH2CH

2

CH3

NN

O SH

N

N

CH2CH

2

CH3 N

HN

O S

HCHO

N

N

CH2CH

2

CH3 NN

O S

CH2R

R = -N(C2H

5)2

R = N O

R = N N-CH3

20Amine

Oxadiazole

MO-1;

MO-2;

MO-3;

Perusal of literature has revealed that aminomethylated derivatives of

compounds belonging to aromatic and heterocyclic systems exhibit a broad spectrum

of pharmacological activity [79-82]. In this context a series of imidazo [1,2-a]

benzimidazole derivatives were prepared by V.A.Anisimove et al. and studied the

pharmacological activity viz. hypotensive effect, antiaggregant effect, membrane

stability effect, spasmolytic effect, neuroprotic effect and toxicity of these products.

For this purpose aminomethylation of imidazo-[1,2-a]-benzimidazoles (I) with

formaldehyde and various dialkyl amines under the mild condition of HCl yielded

water soluble dihydrochlorides (Scheme-1.6).

Scheme-1.6

N

NN

R

R'

N

NN

CH2NR''

2

R

R'

.

R'''

R'''1. CH2O, NHR''2

2. HCl

R'''

R'''

2 HCl

Imidazo[1,2-a] benzimidazole

Chapter-1


Recently, Joshi H.S. and coworkers [83] have described an efficient method

for the heterocyclic synthesis by the reaction of 3-phenoxy benzaldehyde with

secondary amines such as piperidine, morpholine, indole and N-methyl piperazine and

amides like acetamide, urea and thiourea (Scheme-1.7). They have also been tested

these Mannich Bases for their antituburcular and antimicrobial activity.

Scheme-1.7

O

HO

O

R OH

H

O

R NHCOCH3

H

O

R

H

N N

O

R

HHH O

O

R

H

N N

O

R

HH S

CH3CONH

2 NH2CONH

2NH

2CSNH

2

+ R-H

C C

Secondary Amine

3-Phenoxybenzaldehyde

R = Piperidine, Morpholine, Indole, N-methyl Piperazine

N- containing heterocycles of benztriazole [84] were synthesized by reacting

benztriazole with formaldehyde and various secondary amines (Scheme-1.8). These

synthesized heterocycles were evaluated for analgesic and anti-epileptic activity.

Among these synthesized compounds MT-1, MT-2, MT-3, MT-4 and MT-5 showed

significant analgesic activity.

Chapter-1


Scheme-1.8

NH

N

N

HCHO

N

N

N

CH2

R

NC

2H

5

C2H

5 NH

NCOCH3 NCOC

6H

5 NCH

2COONa

ClCl

+ + Sec. amine

Benztriazole

R = ; R =

R = ; R =

R = ;

MT-1: MT-2:

MT-3: MT-4:

MT-5:

Moreover, Senthilraja M. and Anand S. Thangadhurai [85] have synthesized

isatin based heterocycles (Scheme-1.9) by the reaction of schiff bases of isatin with

pyrimethamine. All these new derivatives have screen for antibacterial and antifungal

activity and have exhibited higher potency compared to standard drugs against all

bacterial as well as fungal organisms.

Scheme-1.9

NH

O

O

N

N

ClNH2

NH2

C2H

5

CH3COOH

NH

N

O

N

N

Cl

NH2

C2H

5

HCHO HNR

R'

N

N

O

CH2

N

N

Cl

NH2

C2H

5

NRR'

NN N

CH3

N C2H

5

C6H

5

C6H

5

+

NRR' = , ,

Isatin PyrimethamineSchiff Base of Isatin

N ,

Chapter-1


Varma R.S. [86] has recently delivered memorial lecture on aminomethylation

reaction of nitrogen and sulfur containing five membered heterocyclic compounds

(shown below) such as isatin, benzimidazoles, benzotriazole, benzimidazoline-2-

thione, benzthiazoline-2-thione, 1,3,4-oxadiazolinn-5-thione and 1,2,4-triazolin-5-

thiones with formaldehyde and amines. Secondary as well as primary amines bearing

different substituents have been employed successfully in aminomethylation reaction.

The resulting aminomethylated product have been tested for antibacterial, antifungal,

antiviral, anticancer, antileishmanial and antifilarial activity. A number of such

nitrogen containing ring systems have exhibited promising antifungal and

antileishmanial activities.

NH

O

O

N

NH N

H

NH

S

NH

O O

NH

O SN

N

NH

NH

S S

NH

N

S

NH

N

N S

Ph

Isatin BenzimidazoleBenzimidazoline-2-thione

Benzoxazoline-2 Benzoxazoline-2-thione Benzotriazole

Benzthiazoline-2-thione 1,3,4-Oxadiazolin-5-thione 4-phenyl-1,2,4-triazolin-5-thione

1.3 MISCELLANEOUS

The nitrogen containing ring systems had since been extended and is

increasingly used in preparative chemistry providing pool of information for synthetic

chemistry. Originally mannich reaction has been used to synthesize β-amino carbonyl

compounds from the three components; a ketone, an amine and aldehyde. Later,

Auwers and Wagner et.al [87,88] have reported the synthesis of amino methyl

phenols by the reaction of phenols, formaldehyde and secondary amines

Chapter-1


(Scheme-1.10). The phenols prepared were found to exhibit a partially cryptophenolic

character (insoluble in cold aqueous NaOH but dissolved on heating.)

Scheme-1.10

OH

(C5H

10N)

2CH

2

OH

CH2NC

5H

10

C5H

10NH+ ++

Phenol Piperidine

2-Substituted imidazoles, 2-substituted benzimidazoles and 3,5-substituted

pyrazoles can be prepared in good yields through the lithiation of N-(dialkyl amino

methyl) derivatives of imidazole, benzimidazole and pyrazole [89]. The lithiation

occurs smoothly at the 2-, 2- and 3- or 5- positions respectively upon treatment with

n-butyl lithium in THF followed by the reaction with elecrophiles like primary alkyl

halides, aldehyde, ketones, tertiary alcohols, isocynates and subsequent facile acid-

catalyzed hydrolysis of protecting groups on nitrogen atom (Scheme-1.11). Thus the

method for the functionalized heterocycles offers advantages over number of other

methods in which the protecting groups can be introduced and especially removed

very easily. A lithiation procedure is simple and a wide range of electrophiles can be

used where yields are generally high. The method appears to be quite general and

should be applicable to a variety of other analogous heterocyclic systems.

Chapter-1


Scheme-1.11

NHN

HCHO

NHMe2

. NN CH2N

CH3

CH3

NHN

E

NH

N HCHO

NH

N

N

CH2

N

NH

N

E

NH

N

HCHO

NH

NN

CH2

NNH

N

E

NH

N

E

HCl

1. n-BuLi, Et2O, -70 0C

2.electrophile

3. H3+O

1 2 3

1. n-BuLi, Et2O, -70 0C

2.electrophie

3. H3+O

4

5

6

1. n-BuLi, Et2O, -70 0C

2.electrophie

3. H3+O

7

8

9

2-substituted imidazole

2-substituted benzimidazole

3- or 5- substituted pyrazole

electrophile E = Ph2CO,PhNCO, CH3I

Imidazole

Benzimidazole

Pyrazole

Bradshaw and co-workers [90] have reported the 8-hydroxyquinoline ligand

synthesized by Mannich reaction of secondary macrocyclic (azacrown ether) diamines

with 8-hydroxy quinoline and its 2- and 7- substituted derivatives and formaldehyde

in benzene. The resulting mannich bases (AC-1 and AC-2) had a high affinity and

selectivity for mercury (Hg+) and had proven to be a chemo-sensor for mercury (Hg+).

Chapter-1


Mannich Base of Crown ethers of 8-hydroxy quinoline

N

X

OH

N

OH

X

N

O

O O

O

N

N

X

OH

N

OH

X

N

O

O O

O

N

Where, X = Cl, NO2, H

Where, X = Cl, H

7-substituted derivative

2-substituted derivative

AC-1

AC-2

With the increasing occurrence of nitrogen in drugs and natural products,

highly asymmetric variants of multicomponent reaction has been recently investigated

by Barry M. Trost and Terrell L. R. [91]. They have demonstrated the application of

dinuclear zinc catalyst in catalytic asymmetric type reaction. The reaction of

glyoxalate imines with different hydroxyl acetophenone derivatives by using standard

dinuclear catalyst gave a high yield of amino alcohol of good diastereo selectivity

(syn adduct) and excellent enantioselectivity (Scheme-1.12).

Scheme-1.12

Ar

OHO

N OMe

R

EtO2C

HN OMe

R

OH

Ar

O

CO2Et

+THF, -5 0C6-12 hrs

dinuclear zinc catalyst

HydroxyAcetophenone

Glyoxalate imine

amino alcohol adduct

Chapter-1


One of the challenges for organic chemist is to synthesize optically active

organic molecules from simple achiral starting materials using asymmetric catalysts.

In this context the highly valuable optically active compounds of α,β-diamino acids

are synthesized by the development of the first enantioselective lewis acid catalyzed

condensation reaction [93] of imino glycin alkyl esters with imines (Scheme-1.13).

The enantioselective Lewis acid catalyst are N-Tosyl-C-Phenyl imine. The

mechanism of the highly enantioselective reaction is discussed. A various

contributions of metal salts and the chiral copper (I) ligands are used as the catalysts,

the most effective catalyst are chiral copper (I) complexes having phosphino-

oxazoline (P,N) ligands as shown below.

Scheme-1.13

NPh

Ph

CO2Me

N

R1

N

Ph

Ph

R1

Ts

R1

NHTs

CO2MeEt3N

THF

+

R1 = Ph, p-MeOC6H4, o-BrC6H4, m-ClC6H4

phosphino oxazoline ligand

-200 C

N- Tosyl amine

O

N PAr2

Ar = Ph

P-N Ligand

2,4-Me-C6H3

2,4,6-Me-C6H2 (c)

Cu (a)

(b)

(+)

ClO4

(-)

Phosphino oxazoline ligand

[135]

Chapter-1


Sha Lou, B. M. Taoka and others [92] have proposed a chiral base mediated

direct addition of β-keto esters to acyl imines. They also have reported the

enantioselective addition of β-keto esters to acyl aryl imines catalyzed by cinchonine

and cinchonidine and these products are being further used in the synthesis of

enantioriched dihydro pyrimidones and α-amino alcohols (Scheme-1.14).

Scheme-1.14

O OR2

O

R3O N

H

O

Ph O OR2

O NH

O

OR3

Ph

R3 = t-Bu

R3 = Et

R3 = CH

3

R3 = allyl

N NH

O

O OR2

PhCH3

R1

R1

10 mol%catalyst

R1=CH3

R1=CH3

R2=allyl

R2=CH3

+1.Pd(PPh3)4

BnNCO

2. ACOH, EtOH mw, 1200C, 10 min

Bn

Dihydropyrimidone

B-keto esterAcyl imines

Metal complex of nitrogen containing ring systems have been studied [94,95]

extensively in recent years. Raman N. and others [96] in analogous way have

prepared N–(l-morpholino benzyl) semicarbazide (MBS), formed by the condensation

of morpholine, semicarbazide and benzaldehyde and its Cu(II), Ni(II), Co(II) and

Zn(II) complexes. Their structure was elucidated on the basis of elemental analysis,

magnetic susceptibility, electrical conductivity and spectral study. The complexes

exhibited square-planar geometry. The monomeric and non-electrolyte nature of the

complexes was evident by their magnetic susceptibility and low conductance data.

The proposed structure of the complexes is shown in following structure.

Chapter-1


CHNO

NN

OM

NH2

NH

N

O

NH2

CH N O

H

Metal complex of N-(1-morpholino benzyl) semicarbazide

In addition to the above mentioned applications, literature reports have

revealed many other applications of imidazoles as:

Cationic surfactant [97]

Anti corrosive coating [98]

Explosive [99]

To synthesis two-photon absorption and blue upconversion fluorescence of

novel nitrogen heterocyclic chromophores [100].

Dyes in the development of drugs and pharmaceuticals [101].

1.4 OBJECTIVE

Looking to the above importance of various imidzole derivatives, the objective

of the present work are synthesis, characterization and material applications (i.e.

antibacterial and dyeing assessment) of imidazole derivatives.

1.5 PRESENT WORK

The brief review of organic synthesis of imidazoles and its applicability in

various areas of science prompted the present author to focus on the targets regarding

synthesis of eight different diamines m-phenylenediamine (MPD),

p-phenylenediamine (PPD), benzidine (BD), ortho toluidine (OTD), 4,4’-diamino

diphenyl sulphone (DDS), 4,4’-diamino diphenyl methane (DDM), 4,4’-diamino

diphenyl sulphonamide (DASA) and 2,4’-diamino toluene (DT) to give a series of

eight imidazoles. The details of synthesis and characterization of eight series of

imidazole derivatives are furnished in Chapter-2 of the present thesis.

Chapter-1


The applications of these eight series of imidazoles have been examined as

antimicrobial agents by studying their antimicrobial activity against different bacteria

and fungi micro organisms. This work is described in Chapter-3 of the thesis.

Further, four selected imidazoles have been used as dye precursors (diazonium

component) in synthesis of disperse azo dyes to give four series of disperse azo dyes.

The dyeability of these four series of disperse azo dyes have been studied on polyester

and nylon fabrics. Finally, the dyeing behavior of these dyed patterns have been

evaluated in terms of exhaustion and fixation study as well as by studying their

fastness properties. Thus the work pertaining to synthesis, characterization of these

disperse azo dyes and there applicability in textile dyeing is presented in Chapter-5

and Chapter-6 of the thesis.

Chapter-1


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Chapter-1


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Advance in Organic Chemistry., 9, 225 (1976)

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Advance in Organic Chemistry.,31, 128 (1982)

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Chapter-1


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