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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
Sardar Patel University 2
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
Sardar Patel University 3
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
Sardar Patel University 4
(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
Sardar Patel University 5
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
Sardar Patel University 6
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
Sardar Patel University 7
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
Sardar Patel University 8
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
Sardar Patel University 9
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
Sardar Patel University 10
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
Sardar Patel University 11
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
Sardar Patel University 12
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
Sardar Patel University 13
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
Sardar Patel University 14
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
Sardar Patel University 15
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
Sardar Patel University 16
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
Sardar Patel University 17
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
Sardar Patel University 18
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
Sardar Patel University 19
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
Sardar Patel University 20
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
Sardar Patel University 21
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
Sardar Patel University 22
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
Sardar Patel University 23
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
Sardar Patel University 24
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
Sardar Patel University 25
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
Sardar Patel University 26
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
Sardar Patel University 27
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
Sardar Patel University 28
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
Sardar Patel University 29
(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
Sardar Patel University 30
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
Sardar Patel University 31
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
Sardar Patel University 32
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
Sardar Patel University 33
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
Sardar Patel University 34
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
Sardar Patel University 35
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
Sardar Patel University 36
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Chapter-1
Sardar Patel University 37
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J. Am. Chem. Soc., 1536, 68 (1946)
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