H O C O + H N R C N R + H - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/12280/7/07...intermediate such as (A-17) and (A-18). They have different three type of resonating structures,

7

SCHIFF BASE

INTRODUCTION:

This chapter deals with the compounds having structure, R-CH = NR’ or

R-C= NR’ and their related derivatives. These compounds are known as imines,

azomethines, anils or more commonly as Schiff bases (where R=R’ or alkyl or aryl)

[1].

When aldehydes or ketones react with primary amine (R-NH2) to form

compounds with a carbon – nitrogen double bond they are called imines. The reaction

is acid catalyzed. These compound where discovered by Schiff [2] and so they are

commonly known as Schiff bases.

MECHANISM :-

A large number of Schiff bases are known to have useful biological activities

like tuberculostatic, fungicidal [3] and bactericidal [4].

The strong acid catalysts like concentrated protic acid [5], BF3 etherate [24],

ZnCl2 [6-10] or POCl3 [10] are used in the preparation of Schiff bases.

Literature Review:

Certain Schiff bases are derived from 2 amino–4–phenyl thiozole and their

reduction products are known to have diuretic properties [11]. They are also known to

exhibit anesthetic, anticonvulsant and anti tubercular activities [12].

Anticonvulsant activity of the Schiff base derivatives obtained from vanillin

was established by Tiwari et al. [12].

C + H2N RO C N R H2O+H3O

+

C O H2N R+..

CNH2

+R

O.... :

-

-

+

+

CNH

OH

R

CNH R

OH2

NCH

R

+NC RH3O +

+H3O

Aldehyde or Ketone

Primary Amine Dipolarintermidiate

Amino alcohol

Protoneted amino alcohol

IminiumionImine

H2O -H2O

....

8

Dash et al. [13] have synthesized and tested Schiff base derivatives for

fungicidal activity.

Profft [14] reported the synthesis and anthelmintic activity of Schiff base

derivatives.

Schiff base containing the hetero atoms and six membered pyrimidine ring

(S-1) where synthesized and screened for anti cancer activity [15].

Anticancer activity of Schiff base derivatives prepared from benzaldehyde

nitrogen mustard and p-amino phenyl thiazole (S-2) is also reported.

Schiff base containing thiozole nucleuses where reported to have anti fungal

activity (S-3) [16].

N

N

N = CH - R

OH

HO

R = 4-bromo phenyl, 4-methyl phenyl, 2-hydroxy phenyl

(S-1)

NCl -H

2C -H

2C

Cl - H2C -H

2C

CH N

S

N

(S-2)

S

N

CH3

+

CH = N

HO

R1

R2

R3

R1 = R

2 = R

3 = H

(S-3)

9

Pawar et al. [17] have synthesized Schiff base derivatives.

Schiff base having general structure (S-4) have been synthesized [18].

(S-4)

It has been observed that the biological activity of certain organic compounds

is related to their ability to form complexes with metal ions.

It has been also observed that the biological activities of complex compounds

are higher than those of free ligands.

Sahu K. et al. [19] have synthesized (S- 5-6) and tested for anti cancer

activity.

Modi [20] have reported anti cancer activity.

The fungicidal activity of some of the Schiff base compounds has been

evaluated against spore germination of brown spot, pathogen of rice and

Helminthosporium oryzae [21].

Schiff base derivatives of bis (4-amini phenyl) methane (S-7) screened

pesticidal and anti bacterial activity [22].

H3CO

O

OCH

N

M

O

N+

R

N+

O

R(S-6)

R = 4- phenyl thiazole,4- p - Cl- thiazole,

4 - phenyl benzothiazole

CH = N CH2

RRBrBr

R = 4-Chloro, 4-methoxy, 4- Amino

N = HC

(S-7)

10

Several heterocyclic Schiff bases of general structure (S-8) are found to be

responsible for their in vitro anti bacterial activity [23].

Schiff base containing Spiro derivatives (S-9) were studied for their biological

activity [24].

(S-9)

Vansadia et al. [25] have synthesized Schiff base derivatives (S-10) and tested

for anti microbial activity.

Joshi et al. [26] have synthesized Schiff base derivatives and tested for anti

tuber activity.

Mital has synthesized some new coumarin Schiff bases, which possess anti

bacterial and anti fungal activity [27].

Trivedi [28] synthesized 1-[4’-imino (substituted phenyl) phenyl]-2-phenyl-4-

{4”-N, N-dimethyl amino benzylidene}-imidazol-5-one (S-11) and study of their anti

microbial activity.

S

N

HN

H5C

6

Cl

CH = N - R - N = CHS

N

Cl

NH

C6H5(S-8)

NN

N

H3C

N

S

SO2

R - CH = N CO - CH - CO CO - CH - CO - NH = CH - R

R = Aryl(S-10)

11

Some indolyl pyrazolines (S-12) derivatives prepared and screened analgesic,

ulcerogenic activities and those compounds, which showed promising anti

inflammatory activities, were also screened for their cyclooxyglyenase assay. [29]

Sudheendra [30] have synthesized pyrazoline derivatives (S-13) and

evaluation for their biological activity, it can be concluded that, most of the

compounds tested for its anti microbial activity.

Some substituted Schiff base derivatives incorporated with pyrimidine moiety

(S-14) prepared and tested their antimicrobial activity [31].

NN

O(H3C)2N

N =HC

R

R = Different Substituted Phenyl

(S-11)

H3CO

NH

Cl

CH N

N

N

COCH3

R

R = 4-OCH3, 2-Cl, 4-Cl, 2, 4-diCl, 2, 6-diCl, 2-F, 2, 4-diF, 2, 6-diF, 2-OCH3, H

(S-12)

N N

Z Y

OCH2CO

OCH3

CH N F

Cl

Y, Z = Substituted Phenyl

(S-13)

NH N

NN CH

R1

R

R = H, 2-OH, 3-OH, 4-OH, 2-NO2, 3-NO2, 4-NO2, 2-Cl, 3-Cl, 2-OCH3, 3-OCH3, 3, 4, 5-OCH3, N(CH3)2

R1 = H, 2-NO2

(S-14)

12

TuranZitouni et al have synthesized some Salicylaldehyde Schiff bases of 2-

aminopyridine (S-15) and study of their electronic spectra and inhibitory study [32].

(S-15)

Pravin S. Patel prepared (S-16) [33].

(S-16)

Schiff bases [34] are very useful substances for its of microbial and

commercial application they have been checked for its pharmaceutical application like

antimalarial[35], anti cancer[36], antibacterial[37], antifungal[38], antitubercular[39],

anti-inflammatory, antimicrobial[40] and antiviral [41] etc.

N N

OH

R1

R1= -H, Br, -NO2, -OCH3

N

O

O

N N

OH

13

2-AZETIDINONE ( ββββ-LACTAM) DERIVATIVES

INTRODUCTION:

The four membered rings appear to be the smallest cyclic system that is

capable of accommodating the amide function as a constituent. In Cyclo butane, if

one CH2 is replaced by –NH, the compound show formed is known as azetidine. Such

compound with >C=O group with adjacent to-NH are known as Azetidinone (A-1).

Such four member cyclic amide, which contains nitrogen heteroatom, is commonly

referred to as β-Lactam and the literature they are referred 2-azetidinone [42].

(A-1)

In the beginning of the 20th century the β-Lactam compound was prepared by

Staudinger [43] in 1907. Up to 1940 the chemistry of β-Lactam compounds did not

draw much more attention. But suddenly after 1943 when penicillin (A-2) [44] was

discovered which contain β-Lactam ring and was found to have very good antibiotic

activities the chemistry of β-Lactam compounds drew much more interest. Few more

naturally occurring β-Lactam compounds were isolated such as Cephalosporin (A-3)

[45], Pachystermine-A and Pachystermine-B [46] and wildfire toxin 77.

More efforts have been put for synthesis of simpler β-Lactam for testing as

antibiotics, antidepressants, sedatic [47] etc. Herbicidal activity of 4-azetidinone is

also well documented in the literature.

ONH

O

O

NHR

N

COOH

CH3

CH3

S

(A-2)

O

O

NHR

N

COOH

CH2COOH

S

(A-3)

14

Literature Review:

A review by Sheehan J.C. and Corey E.J. [42] reports representative synthetic

procedure. More recently, other aspects of synthesis have been reviewed [48-52].

1. The combination of an imine (A-5) and acid chloride (A-4) in the presence of

tertiary amine it produced β-Lactam (A-6) [53, 54]. This procedure was

developed in connection with the problem of penicillin synthesis.

2. When biphenyl ketene (A-7) reacts readily with benzylidene aniline (A-8) at

room temperature, it produces crystalline β-Lactam, 1, 3, 3, 4-tetraphenyl

Azetidinone (A-9). It was the first known β-Lactam [43].

3. When certain β-acyl amino acid (A-10) is heated at their melting points, ring

closure is affected with the loss of carboxylic acid and produces β-Lactam (A-

11). This procedure was established by Staudinger [55].

4. When phenyl or 4-bromophenyl isocynates (A-12) reacts with diazomethane,

it produces the corresponding β-Lactam (A-13) [56].

O

H2CX Cl

+N

HC

C6H5

C6H

5

C6H6

(C2H5)3N

O

N

X

C6H5H5C6

X = Halo, Alkyl etc

(A-4) (A-5) (A-6)

C6H

5

O

N

C6H

5C6H

5

C6H

5

H5C

6

H5C

6

C C O + N

CH

H5C

6

H5C

6(A-7)(A-8) (A-9)

N

CO CH CH3

CH3

CH C CH3

CH3

CH3

H2C

H5C6

H5C

6H5C

6

H5C6

ON

CH2

CH3

CH3

(A-10) (A-11)

15

5. N-substituted mesoionic oxazolones (A-14) have been reported to react with

schiff base (A-15) to afford Azetidinone (A-16) [57].

MECHANISM:

The synthesis of β-Lactam can be explained by following mechanism [58, 59].

The formation cis and trans β-Lactam takes place via (2+2) cycloaddition involving a

ketone and imine obtained from phenyl glyoxal or phenoxy ketone and phenyl ethyl

amine or N-methylimines. The cis and trans stereo chemistry mainly depends on the

substituents attached with ketone part and imine is believed to exist in more stable E.

Configuration.

The nitrogen atom of azomethine has lone pare of electron. The nitrogen

nucleophillic of azomethine attacks on ketone possessing donor group such as alkoxy

or aryloxy and acceptor groups such as thioalkoxy or thioaryloxy, thereby generate

intermediate such as (A-17) and (A-18). They have different three type of resonating

structures, which on cyclization generate cis β-Lactam through less stable

intermediate (A-18) and also generate more stable trans β-Lactam via more stable

intermediate (A-19) and (A-20) stabilized due to sulfur atom.

H2CN

2+ Ar N C O

ON

Ar

Ar = -C6H

5, 4-BrC

6H

4

(A-12)(A-13)

O

N O

C6H

5

H5C6

R+ C

6H

5C

6H

5N HC

O

NC

6H

5

H5C6

NR

OC

R = Alkyl

(A-14) (A-15) (A-16)

16

BIOLOGICAL IMPORTANCE:

A large number of (A-21) antibiotic contains β-Lactam heterocyclic moiety

[60, 61].

(A-21)

C N

R1

R1

R1

H R2+δ -δ

CPhO

HC O

+δ -δ

Anti to PhO

NC

PhO

O

H

H

+

-

R1

R2

NC

O

O

H

H

+

-

PhO

O

R2

R2

H H

( A - Cis )

C NR

1

H +δ -δ

CH

C O+δ -δ

R2

Ph S

Syn to

Ph S

R1

R2

NC

Ph

O

HH

+

-O

Ph SH R

2 H

R1

N+

-C

S

ON

R1

HH

Ph S R2

PhS

H

R2

H

R1

N

+C

O-

( C - Trans )

( B - Trans )

N

(A-17)

(A-18)

(A-19)

(A-20)

O Cl

N

CH3OC

OH

17

β-Lactam compounds synthesized from N-arylidene-p-amino acetophenone

have been found to possess anti bacterial as well as anti fungal activity [62].

Hogale [63] reported and synthesized 4-azetidinone derivatives (A-22) and

checked its anti bacterial activity.

Patel [64] have combined sulfonyl moiety with 4-azetidinone ring (A-23) for

their eventual anti microbial activity.

The compounds (A-24) were prepared to improve anti bacterial activity of

sulfazecins. Among all these compounds when R= (CH3)2-C-COOH and R1=CONH2,

such compounds having microbial activity [65].

Shah [66] has synthesized 4-aryl-3-chloro-1-N- [(6’-phenyl thione (3-2-d))-

pyrimid-4-yl-amino]-2-azetidinone derivatives and tested for their anti microbial

activity.

NS

O

C

NHO

N

ClR

R = Alkyl or Aryl

(A-22)

O CN

O

RCl

HOC N

O

R Cl

HSO

2 NN

R = Alkyl or Aryl

(A-23)

N

S O

NH O

R 1

SO3HN

N OR

H2N

(A-24)

R = CH3, -CH2COOH

R1 = -CONH2, CONHCH 3

18

Some thiouryl Azetidinone (A-25) derivatives prepared and checked for its anti

parkinsonia application It is found that thiouryl azetidinone having phenyl and 4-

methoxy phenyl group at 2nd and 4th position were most potent [67].

R =H, 4-N (CH3)2, 4-OCH3 etc R = -CH3 Or -C2H5 R1 = Aryl

β-Lactam derivatives (A-26) were synthesized and tested for their Parkinson

activity [68].

Singh [69] has prepared 1-aryl cyclohexyl-3-3-diphenyl-1’-(biphenyl acetyl)-

2-oxospiro-[azetidine-4-3’-indolin-2-one] (A-27) and screened for their anti

convulsant activity.

(A-27) A series of fused and Spiro β-Lactam (A-28) have been synthesized and

studied its anti microbial activities [70].

(A-28)

Dave et al. [71] illustrated the synthesis of novel quaternary ammonium

β-Lactam (A-29) anticipating anti bacterial propertied in the compound.

OCl

NHS

NH2

N

R

(A-25) OCl

N

R N

N

O

R(A-26)

N

O

N

OPh

Ph

R

COCHPh2

R = Substituted aryl

O

N

N CN

CH

R

19

Some azetidinone derivatives (A-30) incorporated with 3-5-6-trichloropyridine

moiety were synthesized and tested for their herbicidal activity [72].

(A-30)

B-Lactam derivatives (A-31) were derived from 1-4-benzothiazine-2-3-diones and

tested their fungal activity [73].

Trivedi prepared A-32 and checked its tuberculostatic [74]

O N CH3

CH3

CH3

+

NR1 R

2

R1 = Thienyl R 2

= 3-Chloro phenyl

(A-29)

N O

O

NH

ClCl

O

R

ClN

R = Alkyl, Aryl and Heteroaryl

N

S

CO - NH

O

Cl

R

NR = -C 6H5, -CH 2-CH2-CH3

(A-31)

NS

Br

Br

Br

Br

CO CH2

NH

O

Cl

R

N

R = Aryl

(A-32)

20

A-33 was screened for their anti microbial activity [75].

(A-33)

Peter [76] have synthesized cephalosporin derivatives of Doxorubicin (A-34)

as pro-drug for activation by monoclonal antibodies β-Lactams conjugates and

showed influence in the activity towards the higher side by the nature of substituent at

7th position.

β-Lactam drugs are still to most widely prescribed anti biotic used in medicine [69].

Patel [77] reported the synthesis of azetidinones derivatives having pyrimidine

moiety (A-35) which have also been evaluated for anti microbial and antitubercular

activity.

CH3

H3C

OH

CH3

O

R

ClN R = Aryl

O

O OH

OH

OH

CO - CH 2 - OH

O

HO

O

NH - COO - CH 2

N

S

O

NH

R

CO2H

R = H, C6H

5CH

2CO

(A-34)

21

Tripti [78] have synthesized some substituted azetidinones derivatives (A-36)

having pyridine moiety and tested for their pesticidal activities.

Azetidinone having general structure (A-37) screen its anti microbial and anti

fungal activity [79].

Ashok Kumar [80] have synthesized compound (A-38) which is used as bio-

active agent.

R= 3-NH2 C6H4, 4-N(CH3)2C6H4, 3-NO2 C6H4, 2-Cl C6H4,...

NR

ClO

NHNH

O

NN

OCH3

OCH3

OCH3

Cl

(A-35)

S

NN NH

R = substituted phenyl

NR

ClO(A-36)

O

R1

N

O

Cl

CH3

R3

R1 = H, CH3

R2 = H, Cl, CH3, OCH3

(A-37)

22

Thore [81] have combined pyridine moiety with Bis-2-azetidinone ring (A-39)

for their eventual anti microbial activity.

Ashok Kumar [82] have synthesized 2-(4’-oxo-3’-chloro-2’-substituted aryl-

azetidinyl) amino methyl-3-substituted aryl-6-substituted/unsubstituted-quinazoline-

4(3H)-ones (A-40) and have tested their anti bacterial activity.

NN

S

NN

S SCH2N

OCl

N

ClO

R

R = H, 4-Cl, 2-OCH3

(A-38)

N

O Cl

R'

NH

R

CH3CH3

N

OCl

R'CH3 CH3

R = C6H45, 2-NO2C6H4, 2-OCH3 C6H4, 4-CH3C6H4, R' = 4-CH3 C6H4

(A-39)

N

N

O

CH2NH N

O Cl

X

R

R'

X = H, Br, I

R = H, p-Cl, p-OCH3

R' = m-N(CH3)2, o-OCH3,

(A-40)

23

CHALCONE DERIVATIVES

INTRODUCTION:

Last many years the publication reflects the importance of chalcone is very

active intermediate substance, having excellent pharmaceutical application and so

some new heterocyclic compound could be prepared. Due to presence of keto

ethylenic linkage they give the substance for its great synthetic values.

The term "Chalcone" was first coined by Kostanecki and Tambor [83], who

did pioneering work in the synthesis of natural colouring compounds. This is well

illustrated by benzal acetonphenone or phenyl styryl ketone or β-phenyl

acrylophenone, γ-oxo-α,γ-diphenyl-α-propylene and α-phenyl-β-benzoyl- ethylene

[84].

SYNTHETIC ASPECT

The most convenient method for the preparation of chalcone consists in

condensing an appropriate aryl methyl ketone with an aromatic aldehyde in presence

of alcoholic KOH [85, 86], that involves the Claisen-Schmidt condensation.

The other condensing agents employed in several cases and sometimes with

advantages are hydrogen chloride[87, 88], anhydrous aluminium chloride[89], weak

bases like piperidine[90], boron trifluoride[91], amino acids[92], organocadmium

compounds[93], phosphorous oxy chloride[94], borax[95], perchloric acid[96] and

zinc chloride and acetic anhydride[97].

Chalcones can also be synthesized by condensing several other reagents

instead of an aldehyde and ketone.

O

+ H2OC

O

CH3R + CHOR' C

O

CH = CH - R'Ralcoholic KOH

24

1. Di azo coupling of phenyl diazonium chloride with benzoyl acrylic acid [98].

2. Friedel craft's cinnamoylation [99].

3. Fries rearrangement of aryl cinnamates [100].

4. Nencki reaction with cinnamic acid on an aromatic compounds [101].

REACTION MECHANISM

The following two mechanisms have been suggested for the synthesis of

chalcones.

(A) Base catalyzed [102] and (B) Acid catalyzed [103]

(A) Base catalyzed:

In presence of base catalyst Aromatic aldehyde and acetophenone reaction

there is two alternative mechanisms were applied

(B) Acid catalyzed:

25

IMPORTANCE OF CHALCONES The chemistry of chalcones has assumed importance, Furthermore, they are

also associated with wide spectrum of pharmacological activities and industrial

applications.

1. Chalcones bearing an active keto-ethylenic linkage and therefore, are reactive

towards a number of reagents, yielding various heterocyclic compounds

exhibiting significant biological activities viz. Pyrimidines [104-106],

Cyanopyridines[107], Cyanopyrans[108], Quinoxalines[109], Indazoles [110],

Pyrazolines[111], Isoxazoles[112], Isothiazoles[113] etc.

2. Chalcones are intermediate compounds for the synthesis of some naturally

occurring heterocyclic compounds like flavones, flavanols, dihydro flavanols,

benzal coumarinones, anthocyanins, etc.

3. Chalcone is very useful for providing the structure of natural products like

cyanomaclurin[114],eriodictoyl[115],hemlocktannin[116],narighenin[117],phl

oretin[118],

4. The structures of some naturally occurring pigments like chrysin, galangin,

kaempferol and quercetrol were established by their synthesis from suitably

substituted chalcones [119].

5. The chalcones are natural biocides [120-122] and are well-known key

intermediate in the synthesis of heterocyclic compounds possessing

biodynamic behaviour [123-126].

6. For detection of ferrous II [127] and calcium II [128]. For analytical reagent

used Trihydroxy for amperometric estimation of copper [129] and for

spectrophotometric study of the germanium [130].

7. Chalcones and their derivatives are also found to be applicable as light-

stabilizing agent [131], sweetening agent [132], organic brightening agent,

photosensitive material, polymerization catalyst, scintillators as well as

fluorescent whitening agent.

26

THERAPEUTIC IMPORTANCE

Chalcone is useful for having broad range of therapeutic activities as shown

below:

1. Antiallergic [133]

2. Anticancer [134-135]

3. Anti-inflammatory [136-137]

4. Antimalarial [138-139]

5. Antitubercular [140-141]

6. Antiviral [142]

7. Antitumor [143-144]

8. Antispasmodic [145]

9. Antiulcer [146-147]

10. Anthelmintic [148-149]

11. Bactericidal [150-151]

12. Cardiovascular [152]

13. Fungicidal [153-155]

14. Germicidal [156]

15. Herbicidal [157]

16. Insecticidal [158-160]

Literature Reviews:

Moreover Mulund V. V. et al. [161] have prepared some chalcones (C-1) from

coumarine derivatives which possess significant antimicrobial activity.

(C-1)

Bowden K. [162] prepared substituted 3-(4-phenyl benzoyl)-Chalcone/2-

hydroxy chalcone / α-bromo chalcones as potential antibacterial agents. Badami B.

V. and co-workers [163] have reported some new chalcone derivatives (C-2) as

antifungal agent.

O

OOH

O R

27

(C-2)

R, R’ = Substituted Phenyl

Some of the chalcones have been patented for their use as antifungal [164],

antimicrobial [165, 166] and anticancer [167] agents.

Solankee Anjani et al. [168] synthesized chalcone derivatives (C-3) which

have been tested for antibacterial activity.

(C-3)

Duck Sylvie [169] have synthesized chalcone derivatives (C-4) possessing

cytotoxic activity against the K-562 human leukemia cell lines.

Ezio and co-workers [170] have been reported chalcones having a valuable

antiproliferation activity both on sensitive cancerous cell and on cell which are

resistant to common chemotherapeutic drugs. Denny, William Alexander et. al. [171]

has prepared chalcones for use in antibody.

Furthermore, Tanaka, Masayuki et al. [172] have prepared α, β unsaturated

quinolinyl-ketones as inhibitor of inter-leukin 1 production. Sreenivasulu, Sharma

[173] have reported di chalcones with 100% antifeedant activity. Bradsher et al.

[174, 175] synthesized chalcones, which have been suggested as remedy for cancer.

R N

NO

O

R'

O-

+

N

N

N

NH-CH 2CH3H3CH2C-HN

NH CO-CH = CH-R

OOH

OCH3

H3CO

H3CO

OCH3

CH3

OH

(C-4)

28

Synthesis and insecticidal property of aryl-ω-(methyl-1, 2, 4-triazol/imidazol-1-yl)

chalcones (C-5) have been documented by R. Seele et al. [176].

(C-5)

M. R. Jayapalandn, Y. Sreedhar synthesis and characterization of 4- Hydroxy

chalcones by aldol condensation using SOCl2/EtOH. [177](C-6)

(C-6)

J. R. Patel et al. synthesized 4'-aminochalcone-based dibromomaleimides (C-

7) and scanned them for antibacterial activity. [178]

(C-7)

To synthesize some novel chalcone derivatives bearing substituted

benzaldehyde moiety, in order to achieving better therapeutic agents.

XN

N

O

R1 R2

R1= Alkayl, R2= Substituted phenyl

OH

O

CH3

CHO

OH

O

+SOCl2

EtOH.r.t.

R

R

R= 2

N

O

OBr

Br

O

R1

R2

R3

29

OVERALL EVALUATION (SECTION-I)

Recently the increasing interest for the use of chalcone in biological

application like antibacterial, anticancer, anti-inflammatory, anti fungal,

anticonvulsant, hypolipidemic, antitumor, anti ulcer, analgesic etc.. [179]

So that, we decide to find out some new chalcones derivatives and taste its

antimicrobial and therapeutic activities. Research in chalcones derivatives are worth

tested for more and more possible biological importance,

These wide varieties of anti-microbial activities of Chalcones group

containing compounds prompted us to synthesize the following compounds.

SECTION-I

Synthesis and biological evaluation of the…

SH-01 to SH-10

NCl

O

OH

O

R

The compounds of this section have been prepared reaction between SH-B1

with different substituted aldehyde.

30

Biological screening result of SH-01 to SH-10 shows that compound (SH-02

& SH-05) better against E. coli, lefts all in the range of 125-250 µg/ml.

Substitution 4-hydroxy SH-09 and SH-07 shown good antibacterial activity

against S. pyogenus

SH-01 and SH-08 is found excellent antifungal activities against C. albicans,

31

CHO

OH

4-hydroxybenzaldehyde

Methanole COCH3NH2

N

OH

COCH3

ClCH2COCl Et3N

OHN

O

Cl

COCH3

1-(4-acetylphenyl)-3-chloro-4-(4-hydroxyphenyl)azetidin-2-one

Ethanol

Reflux for 10 hours OHC

OH

N

O

Cl

O

3-chloro-1-{4-[3-(substitutedphenyl)prop-2-enoyl]phenyl}-4-(4-hydroxyphenyl)azetidin-2-one

SH 01 to SH -10

SH-B1

SH-A1

Reaction Scheme

R

R

1-(4-[(4-hydroxyphenyl)methylidene]amino}phenyl)ethanone

32

Structure of Chalcones of SH-01 to SH-10

N

O

Cl

O

Cl

OH

SH-01

.

N

O

Cl

OH

O

OH

SH-02

N

O

Cl

OH

O

H3CO OCH3

SH-03

N

O

Cl

OH

O

O2N

SH-04

33

N

O

Cl

OH

O

Cl

SH-05

N

O

Cl

OH

O

N C2H5

H5C2

SH-06

N

O

Cl

OH

O

OH

SH-07

N

O

Cl

OH

O

N

CH3

CH3

SH-08

34

N

O

Cl

OH

O

SH-09

N

O

Cl

OH

O

H3CO

OH

SH-10

35

EXPERIMENTAL WORK

Synthesis of SH-A1

A mixture of 4-hydroxybenzaldehyde (0.01M), pera amino acetophenone 0.01 M and

35 ml of methanol heated for some times for getting clear solution and kept it

overnight. Then it was recrystallized by ethanol to obtain Schiff base SH-A1, the

yield was 75% and the M.P. of the products at 1950C

Molecular Formula = C15H13NO2

Formula Weight = 239.26

Composition Required = Carbon (75.30%) Hydrogen (5.48%) Nitrogen (5.85%)

Composition Founded = Carbon (75.28%) Hydrogen (5.45%) Nitrogen (5.82%)

Synthesis of SH-B1

In a 250 ml RBF take SH-A1 (0.01M) in 60ml benzene was taken. Cl-CH3-COCl

(0.01M) and tri ethyl amine 1 ml added with stirring and refluxed for 7 hours. When

the reaction was complete. Product was recrystallized by suitable solvent. % of yield

was 60% and the M.P. of the Product at 1190C

Molecular Formula = C17H14ClNO3


Composition Required = Carbon 64.67 % Hydrogen 4.47% Nitrogen 4.44%

Composition Founded = Carbon 64.64% Hydrogen (4.44%) Nitrogen 4.42%

36

Synthesis of SH-01

SH-B1 0.011M in 55 ml absolute Ethanol, 2-chlorobenzaldehyde 0.011 M and

12 ml alkalis was refluxed for 9h. Then obtain mixture was collected, filtered and

neutralized. Obtained product was crystallized by absolute ethanol. The product yield

was 65 % and M.P. of the product at 2180C.

Molecular Formula = C24H17Cl2NO3


Composition Required= Carbon (65.77%) Hydrogen (3.91%) Nitrogen (3.20%)


Synthesis of SH-02

SH-B1 0.011 M in 55 ml absolute ethanol, Salicyldehyde 0.011 M and 12 ml

alkali refluxed 9 h. obtain substance collected, filtered & neutralized. A product was

crystallized with the help of absolute ethanol. The product yield was 72% and M.P. of

the product 1780C.



Composition Required = Carbon (68.66%) Hydrogen (4.32%) Nitrogen (3.34%)


37

Synthesis of SH-03

SH-B1 0.011 M in 55 ml ethanol, 3, 4-dimethoxybenzaldehyde 0.011 M and

12 ml alkali was 9 h refluxed. Then obtain Substance collected, & neutralized. A

Product crystallized by the help of absolute ethanol. % yield was 68% and M.P. of the

product 1180C.



Composition Required = Carbon (67.31%) Hydrogen (4.78%) N (3.02%)

Composition Founded = Carbon (67.28%) Hydrogen (4.75%) N (3.01%)

Synthesis of SH-04

SH-B1 0.011 M in 55 ml ethanol, 3-nitrobenzaldehyde 0.011 M and 12 ml

alkali 9 h refluxed. Then refluxing substance collected, Filtered, & neutralized by the

help of dil. HCl. A Product was crystallized by absolute ethanol. The Product Yield

was 74% and M.P. of the Product at 2300C.

Molecular Formula = C24H17ClN2O5




38

Synthesis of SH-05

SH-B1 0.011 M in 55 ml ethanol, 4-chlorobenzaldehyde 0.011 M and 12 ml

alkali 9 h refluxed. obtain Refluxing substance collected, filtered & Neutralized with

the help of dil. HCl. A Product was crystallized by absolute ethanol. The Product

Yield was 66% and the M.P. of the product at 2450C.





Synthesis of SH-06

SH-B1 0.011 M in 55 ml ethanol, 4-di-ethyl amino aromatic aldehyde 0.011

M and 12 ml alkali 9 h refluxed. Then obtain refluxing substance collected, &

Neutralized with help of dil. HCl. A product was crystallized by absolute ethanol. The

Product yield was 69% and M.P. of the Product at 2780C.



Composition Required = Carbon 70.80% Hydrogen 5.73% Nitrogen 5.90%

Composition Founded = Carbon 70.78% Hydrogen 5.72% Nitrogen 5.87%

39

Synthesis of SH-07

SH-B1 0.011 M in 55 ml ethanol, 4-hydroxybenzaldehyde 0.011 M and 12 ml

alkali 9 h refluxed. After that refluxing substance collected, & neutralized with help

of dil. HCl. A Product was crystallized by absolute ethanol. Percentage of yield was

75% and M.P. of substance 2190C.





Synthesis of SH-08

SH-B1 0.011 M in 55 ml ethanol, pera-di-methyl- amino Benzaldehyde 0.01

M and 12 ml alkali 9 h refluxed. Obtain refluxing substance collected, filtered &

neutralized. The obtain Product was crystallized by absolute ethanol. The Product

Yield was 67% and M.P. of the Product at 2000C.




Composition Founded =Carbon 69.83% Hydrogen 5.18% Nitrogen 6.24%

40

Synthesis of SH-09

SH-B1 0.011 M in 55 ml ethanol, aromatic aldehyde 0.011 M and 12 ml alkali

9 h refluxed. Then collected, & Neutralized by the help of dil.HCl. The obtain

substance was crystallized by absolute ethanol. The Product Yield was 78% and M.P.

of the Product at 2280C.





Synthesis of SH-10

SH-B1 0.011 M in 55 ml ethanol, 2-hydroxy- 3-methoxybenzaldehyde 0.011

M and 12 ml alkali 9 h refluxed. Then substance collected, & Neutralized. The obtain

substance crystallized by absolute ethanol. The Product Yield was 75% and M.P. of

the Product at 1200C.





41

Physical constant of SH-01 to SH-10

TABLE NO. 1

Sr. Comp.

No. R M.F. M.W % °C

% C %N % H

Found Calcd Found Calcd Found Calcd

1 SH-01 -2-Cl C24H17Cl2NO3 438.30 65 218 65.74 65.77 3.18 3.20 3.89 3.91

2 SH-02 -2-OH C24H18ClNO4 419.86 72 178 68.62 68.66 3.32 3.34 4.30 4.32

3 SH-03 -3,4-(OCH3)2 C26H22ClNO5 463.91 68 118 67.28 67.31 3.01 3.02 4.75 4.78

4 SH-04 -3-NO2 C24H17ClN2O5 448.86 74 230 64.18 64.22 6.22 6.24 3.80 3.82

5 SH-05 -4-Cl C24H17Cl2NO3 438.30 66 245 65.72 65.77 3.17 3.20 3.89 3.91

6 SH-06 -4-N(C2H5)2 C28H27ClN2O3 474.98 69 278 70.78 70.80 5.87 5.90 5.72 5.73

7 SH-07 -4-OH C24H18ClNO4 419.86 75 219 68.63 68.66 3.33 3.34 4.30 4.32

8 SH-08 -4-N(CH3)2 C26H23ClN2O3 446.93 67 200 69.83 69.87 6.24 6.27 5.18 5.19

9 SH-09 CHO C24H18ClNO3 403.86 78 228 71.35 71.38 3.45 3.47 4.47 4.49

10 SH-10 -2-OH-3-OCH3 C25H20ClNO5 449.88 75 120 66.71 66.74 3.09 3.11 4.45 4.48

42

Table No.2

IR Interpretation of SH-01 to SH-10

No. Sub. No. -OH =C-H -C-H

(Stretch) >C=O

(Stretch) >C=C<

aromatic -CH2- (bend)

-CH3 (bend) C-N C-CO-C -C-O -N=O C-O-C C-Cl

1 SH- 1 3340 3050 1730 1580 1280 1250 685

2 SH- 2 3360 3045 1725 1610 1290 1260 1190 760

3 SH- 3 3350 3050 2935 1720 1590 1360 1305 1270 1085 785

4 SH- 4 3360 3060 1715 1610 1290 1260 1445 775

5 SH- 5 3370 3050 1720 1590 1290 1250 755

6 SH- 6 3380 3060 2940 1720 1560 1450 1380 1280 1260 770

7 SH- 7 3380 3050 1725 1580 1310 1260 1180 785

8 SH- 8 3340 3060 2940 1720 1590 1370 1290 1250 780

9 SH- 9 3345 3070 1725 1540 1290 1250 685

10 SH- 10

3360 3070 2930 1720 1610 1390 1305 1270 1230 1090 695

43

OVERALL EVALUATION (SECTION-II)

These wide varieties of anti-microbial activities of Chalcones group

containing compounds prompted us to synthesize the following compounds.

Section – II

Preparation and Microbial evaluation of the….

SH-11 to SH-20

NCl

O

Cl

O

R

The compounds of this section have been prepared reaction between 1-(4-

acetyl phenyl)-3-chloro-4-(4-chlorophenyl) azetidin-2-one with difference aromatic

aldehydes.

Biological screening result of above synthesized Derivatives shows that

compound (SH-14, SH-15) have shown better activity against E. coli, (SH-14 and

SH-20 ) against S. aureus, remaining all the compounds Good active against S.aureus

.Compounds with substitution hydrogen (SH-19) is good antibacterial against S.

pyogenus, Remaining all compounds having good to very good against S.pyogenes.

Compound (SH-14) is shawn excellent antifungal active against C. albicans,

remaining are very poor for remains antifungal activities like A. niger, and

A.clavatus.

44

CHO

Cl

Methanole COCH3NH2

N

Cl

COCH3

ClCH2COCl Et3N

ClN

O

Cl

COCH3

Ethanol

Reflux for 10 hours OHC

Cl

N

O

Cl

O

SH-11 to SH-20

SH-B2

SH-A2

4-chlorobenzaldehyde

1-{4-[(4-chlorobenzylidene)amino]phenyl}ethanone

1-(4-acetylphenyl)-3-chloro-4-(4-chlorophenyl)azetidin-2-one

3-chloro-1-{4-[3-(substitutedphenyl)prop-2-enoyl]phenyl}-4-(4-chlorophenyl)azetidin-2-one

Reaction Scheme

R

R

45

Structure of Chalcone of SH-11 to SH-20

N

O

Cl

Cl

O

Cl

SH-11

N

O

Cl

O

OH

Cl

SH-12

N

O

Cl

Cl

O

H3CO OCH3

SH-13

N

O

Cl

Cl

O

O2N

SH-14

46

N

O

Cl

Cl

O

Cl

SH-15

N

O

Cl

Cl

O

N

H5C2

C2H5

SH-16

N

O

Cl

Cl

O

OH

SH-17

N

O

Cl

Cl

O

N

CH3CH3

SH-18

47

N

O

Cl

Cl

O

SH-19

N

O

Cl

Cl

O

H3CO

OH

SH-20

48

EXPERIMENTAL WORK

Synthesis of SH-A2

4-Chloro benzaldehyde 0.011M, pera amino acetophenone 0.01 M and 35 ml

of alcohol heated for some times for getting clear solution and kept it overnight. Then

it was recrystallized by ethanol to obtain SH-A2. The % of Yield was 75% and M.P.

of the composition at 1200C.

Molecular Formula = C15H12ClNO




Synthesis of SH-B2

In a 250 ml RBF SH-A2 0.011M in 60ml benzene was taken. Cl-CH3-COCl

0.01M and tri ethyl amine 1 ml added with stirring Refluxed 8 hours. When the

reaction was complete. Product was recrystallized by suitable solvent. The Product

Yield was 60% and M.P. of the Product at 1080C.





49

Synthesis of SH-11


alkali 9 h refluxed. Then refluxed material collected & neutralized by the help of

dil.HCl. Obtain Substance crystallized. The Product Yield was 68% and M.P. of the

Product at 1320C.



Composition required = Carbon (63.11%) Hydrogen (3.53%) N (3.07%)

Composition founded = Carbon (63.07%) Hydrogen (3.51%) N (3.04%)

Synthesis of SH-12

SH-B2 0.011 M in 55 ml ethanol, salicylaldehyde 0.011 M and 12 ml alkali

was refluxed 9 h. Then the refluxed substance collected, reacts with dil.HCl. obtain

material crystallized by absolute alcohol. The Product Yield was 74% and M.P. of the

Product at 1580C.





50

Synthesis of SH-13

SH-B2 0.011 M in 55 ml ethanol, 3, 4-dimethoxybenzaldehyde 0.011 M and

12 ml alkali 9 h refluxed. Then refluxed material collected, & reacts dil.HCl. Obtain

Product was crystallized by absolute alcohol. The % of yield was72% and M.P. of the

Product at 1670c.





Synthesis of SH-14

SH-B2 0.011 m in 55 ml absolute ethanol, 3-nitrobenzaldehyde 0.011 M and

12 ml alkali 9 h refluxed. Then refluxed material collected & reacts dil.HCl. Thus

obtain product was crystallized by absolute alcohol. The product yield was 78% and

the Product M.P. at 1140C.

Molecular Formula = C24H16Cl2N2O4




51

Synthesis of SH-15


alkali 9 h R. Then refluxed material collected & reacts with dil.HCl. Thus obtain

product was crystallized by absolute alcohol. The Product yield was 69% and the

Product M.P. at 1480C.





Synthesis of SH-16

SH-B2 0.011 M in 55 ml ethanol, 4-(di-ethyl amino) benzaldehyde 0.011M

and 12 ml alkali 9 h refluxed. Then refluxed material collected & reacts with dil.HCl.

Thus obtain Product was crystallized by absolute ethanol. The Product yield was 72%

and M.P. of the Product at 1330C.





52

Synthesis of SH-17

SH-B2 0.011 M in 55 ml ethanol, 4-hydroxybenzaldehyde 0.011 M and 12 ml

alkali was refluxed for it 9 h. Then the refluxed product was collected filtered and

reacts with dil.HCl. Thus obtain product was crystallized by absolute ethanol. The

product yield was 78% and M.P. of the product at 1420C.





Synthesis of SH-18

SH-B2 0.011 M in 55 ml ethanol, 4-(di-methyl amino) benzaldehyde 0.011 M

and 12 ml alkali 9 h refluxed. Then refluxed material collected, & reacts with dil.HCl.

Thus obtain Product was crystallized by absolute ethanol. The Product yield was 76%

and the M.P. of the Product at 2120C.





53

Synthesis of SH-19

SH-B2 0.011 M in 55 ml ethanol, benzaldehyde 0.011 m and 12 ml alkali 9 h

refluxed. Then refluxed material collected, & reacts dil.HCl. Thus obtain product was

crystallized by absolute ethanol. The Product yield was 79% and M.P. of the Product

at 1650C.



Composition Required =Carbon (68.26%) Hydrogen (4.06%) N (3.32%)


Synthesis of SH-20

SH-B2 0.011 M in 55 ml ethanol, 2-hydroxy- 3-methoxybenzaldehyde 0.011

M and 12 ml alkali 9 h refluxed. Then refluxed material collected & reacts dil.HCl.

Thus obtain product was crystallized by absolute ethanol. The product yield was 73%

and M.P. of the product at 1830C.





54

Physical constant of SH-11 to SH-20

TABLE No. 3

No Compd R M.F. M.W. % °C % C %N % H

Found Calcd Found Calcd Found Calcd

1 SH-11 -2-Cl C24H16Cl3NO2 456.75 68 132 63.07 63.11 3.04 3.07 3.51 3.53

2 SH-12 -2-OH C24H17Cl2NO3 438.30 74 158 65.75 65.77 3.18 3.20 3.88 3.91

3 SH-13 -3,4-(OCH3)2 C26H21Cl2NO4 482.36 72 167 64.68 64.74 2.88 2.90 4.36 4.39

4 SH-14 -3-NO2 C24H16Cl2N2O4 467.30 78 114 61.65 61.69 5.97 5.99 3.43 3.45

5 SH-15 -4-Cl C24H16Cl3NO2 456.75 69 148 63.08 63.11 3.05 3.07 3.50 3.53

6 SH-16 -4-N(C2H5)2 C28H26Cl2N2O2 493.42 72 133 68.13 68.16 5.65 5.68 5.28 5.31

7 SH-17 -4-OH C24H17Cl2NO3 438.30 78 142 65.73 65.77 3.17 3.20 3.88 3.91

8 SH-18 -4-N(CH3)2 C26H22Cl2N2O2 465.37 76 212 67.06 67.10 6.00 6.02 4.73 4.76

9 SH-19 CHO C24H17Cl2NO2 422.30 79 165 68.23 68.26 3.28 3.32 4.04 4.06

10 SH-20 -2-OH-3-OCH3 C25H19Cl2NO4 468.33 73 183 64.08 64.11 2.95 2.99 4.05 4.09

55

Table No.4

IR Interpretation of SH-11 to SH-20

No. Sub. No. -OH =C-H -C-H

(Stretch) >C=O

(Stretch) >C=C<

aromatic -CH2- (bend)

-CH3 (bend) C-N C-CO-C -C-O -N=O C-O-C C-Cl

1 SH- 11 3060 1715 1540 1290

1240 680

2 SH- 12 3350 3055 1710 1555 1305

1240 1180 730

3 SH- 13 3055 2940 1720 1560 1365 1290

1240 1085 670

4 SH- 14 3045 1720 1625 1285

1230 1450 685

5 SH- 15 3050 1725 1610 1285

1250 695

6 SH-1 6 3065 2950 1715 1610 1460 1370 1280

1255 690

7 SH- 17 3360 3065 1710 1590 1305

1245 1205 690

8 SH-1 8 3065 2955 1715 1580 1375 1305

1245 705

9 SH- 19 3080 1725 1575 1315

1240 730

10 SH- 20 3380 3080 2950 1720 1570 1380 1305

1245 1220 1090 715

Documents

H O C O + H N R C N R + H - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/12280/7/07...intermediate such as (A-17) and (A-18). They have different three type of resonating structures,