chapter-4 chromen-2-one derivatives -...

Chapter-4 Chromen-2-one derivatives

Department of Chemistry, Dr. H.S. Gour Central University, Sagar (M.P.) 79

oumarin is a chemical compound, especially a

benzopyrone, which is found in many plants notably in high

concentration in the tonka bean (Dipteryx odorata), Vanilla grass

(Anthoxanthum odoratum). The name comes from a french word,

“coumarou”, for the tonka bean. It has a sweet odour, and has been

used in perfumes since 1882.

Although coumarin itself has no anticoagulant properties, yet it

is transformed in to the natural anticoagulant dicoumarol by a

number of species of fungi. This proceeds through production of 4-

hydroxy coumarin, then further into the actual anticoagulant

dicoumarol, fermentation product and mycotoxin.1

Coumarin(2H-Chromen-2-one) is a phytochemical with vanilla

like flavor, it is a oxygen containing heterocycle. Coumarin can occur

either free or combined with glucose.

Coumarin is used in the pharmaceutical industry as a

precursor molecule in the synthesis of a number of synthetic

anticoagulant. Pharmaceuticals similar to dicoumarol, notably warfarin

(which has a common and confusing, brand name Coumadin) and

some even more potent rodenticides that works by the same

anticoagulant mechanism.

Coumarin has clinical and medicinal value in itself, as an

edema modifier. Coumarin and other Benzopyrones, such as 5,6

benzopyrone, 1,2 benzopyrone, diosmin and others are known to

C



stimulate macrophages to degrade extracellular albumen,allowing

faster resorption of edematous fluids.2-3

Coumarin is also used as a gain medium in some dye lasers.4-6

Coumarin has been used in the treatment of lymphedema.7 Coumarin

is a potent rodenticide; Rats and other rodents largely metabolize it to

3,4 coumarin epoxide, a toxic compound that can cause internal

hemorrhage and death. Human largely metabolize it to 7-hydroxy-

coumarin, a compound of lower toxicity (The German Federal

institute) for risk assessment has established a tolerable daily intake

of 1 mg coumarin per kg body weight but also advises that (if) this

level exceeds for a short time only, there is no threat to the health.8

Dicoumarins derivatives of coumarin, are potent rodenticides because

they block the synthesis of vitamin K especially in rodents, giving it

strong anticoagulatory and rodenticidal properties. Death occurs after

a period of two weeks, usually from internal hemorrhaging.

Vitamin K is a true antidote for poisoning by 4-hydroxy

coumarin such as bromadiolone. Treatment usually comprises a large

dose of vitamin K given intravenously immediately, followed by doses

in pills for a period of at least two weeks, though usually three to four

afterword’s. If caught early, prognosis is good even when large

amounts are injected. Transfusion with fresh frozen plasma to provide

clotting factors also provides time for vitamin K to reverse enzyme

poisoning in the liver and allow new clotting factors to be synthesized

there.



Synthesis: The Biosynthesis of coumarin in plants via

hydroxylation, glycolysis and cyclization of cinnamic acid. Coumarin

can be prepared in a laboratory by perkin reaction between

salicyldehyde and acetic anhydride.

The pechmann condensation provides another synthesis of

coumarin and its derivatives.

Biological function: Coumarin has appetite suppressing

properties, suggesting one reason for its widespread occurrence in

plants, especially grasses and clovers, because of its effect of reducing

the impact of grazing animals. Although the compound has a pleasant

sweet odour, it has bitter taste and animals may avoid eating.9

Naturally and biologically active coumarin compounds:

Coumarin derivatives have been reported to show anticoagulant,

antiinflammatory,10 antimicrobial,11 anti-HIV, antioxidant,12 anti-

allergic anticancer, anti-proliferative and antiviral13 activity.

Coumarin is a simple allelopathic compound found in many

plants14. It plays an important role in Plant interactions and

biocommunication.15-17 Some allelochemical Such as phenolic compounds

released from living plants into the environment.18

Some chromen-2-one-derivatives: Some novel coumarin

derivatives(I) have been synthesized by Sandeep. et al.19 and screened

for their biological activity.



O

CH3ON O

Ar

O

CH3

(I)

Review of literature reveals several pharmacological activites of

coumarin derivatives including anticancer,20 anti-tubercular,21 anti-

inflammatory,22 and anticoagulant activities, chemically synthesized

derivatives of coumarins have been reported earlier for anti-anxiety,23

anti-convulsant,24 analgesic25 activities.

Some Benzopyran-2-one derivatives by PT2 induced seizure

model in mice and their anti-convulsant activity (II) has been

described by KOTI et al.26

O O

F

N

(II)

7-(4-fluorobenzylindene amino)-4-methyl-2H-chromen-2-one).

Some benzopyran-2 one have been synthesized and tested

for their anti-inflammatory activity(III) by Bhalla et al.27

OOH O

CH N

NC

COCH3

A

(III)



Some new methyl coumarines (iv) were reported by K.

Shivashankar et al.28 Which exhibited potent antimicrobial activity.

+

(IV)

CH2

CH3

O O

Synthesis and characterization of some novel coumarin

derivatives and their pharmacological evaluation (V) have been

described by selvam et al.29

O O

CH2

N X

(V)

Synthesis of some Novel coumarin by Boron trifluoride

dihydrate with pachmann reaction (VI) has been described by

Stoyanou et al.30

O

CH3

OR

R

R1

23

(VI)

Furocoumarins, such as psoralene and the angelicine

derivatives are naturally occuring compounds. They are known to

possess for high photobiological activity. A new route of synthesis of

furocoumarines and their analogs (VII),(VIII), have been described by

Traven.31



O O O

CH3

CH3

C2H5O

O

(VII)

O

O

O

CH3

O

O

O (VIII)

Some novel 7-Hydroxy 4-methyl coumarin derivatives (IX) have

been synthesized by Pankaj et al,32 and screened for their

antipsychotic activity.

O

CH3

O OCH2CH2NR

R

(IX)

R = CH3, C2H5, CH(CH3)2, (CH2)2CH3, (CH2)3CH3, C6H5

Novobiocin, a known DNA gyrase inhibitor-binds to a nucleotide

binding site located on the C-terminal of HSP90 and induces

degradable Hsp90 dependant client proteins at as 700 μm is breast

cancer cells, Although many analogues of Novobiocin have been

synthesized. Some Novobion scaffold derivatives (X) have been

synthesized by Donnely33 and screened for their antiproliferative

activity.



OMEO

OO

NH2

OH

O O O

NH

O

OHOH

(X)

Novobiocin

During the last twenty years, the study of the biological

activities of chromen derivatives have been the aim of many scientists.

Recently the anticoagulant, anthelmintic, hypothermal and

vasodilatory properties of chromen have been reviewed.34 Some fused

chromenes derivatives (XI) have been synthesized by Ahmed Saghier et

al.35 and reported for their antibacterial activity.

O O

OHCOOEtCN

Ph

(XI)

Design and synthesis of a coumarin based acidichromic (XII)

colorant have been described by shih-Lun Lin et al.36

O

HO O

NOX

(XII)



Some 4-Hydroxy-(trimethoxy phenyl) prop-2-enoyl-2H-chromen-

2-one has been synthesized by Mechi et al.37

O OH

O

Ome

O

(XIII)

Synthesis and characterization of Benzoyl hydrazone (XIV) has

been described by Kotali et al.38 and screened for this antileucemic

activity.

OOH

me NHNCOPh

O

(XIV)

Discovery, characterization and comparison of inhibitors of

Bacillus ampracis and staphylococy aures Replicative DNA Helicases

(XV) has been described by Aiello et al.39

O O O

OH

O

Br

F

(XV)



Various chromen-2-one derivatives have been synthesized by

Kumar et al.40 and screened (XVI) for their antitubercular, anticancer

and antiviral activity.

OO

N

S

NNN

CH2SCH2COPh

R

(XVI)

1

R1 = H R1 = - NO2

Synthesis and antimicrobial activity of some new coumarin

derivatives have been described by Prasad et al.41

Synthesis of chromen-2-one derivatives: The compounds

synthesized in this series can be summarized as follows, RR37-RR50.

O O

CH3

CCH3

N

R

RR.37 R=o-NO2 RR.44 R= p-NO2

RR.38 R=H RR.45 R=p-CH3O

RR.39 R=o-NH2 RR.46 R=p-Br

RR.40 R=p-CH3 RR.47 R=m-Cl

RR.41 R=o-CH3 RR.48 R=o-Cl

RR.42 R=m-CH3 RR.49 R=o-nephthyl

RR.43 R=m-NO2 RR.50 R=p-Cl



REACTION SEQUENCE:

CCH3

O

OH

+ H3C - C - CH2 - C - OC2H5

O

O

Con. H2SO4

ethanol

O O

CH3

CCH3

O

(1)

NH2R

O O

CH3

CCH3

N

(2)

6-acetyl,

Subsituted aromatic amine

6-{1-(-substituted-phenyl)imino)ethyl)-4-methyl-2H-chromen-2-one

4- methyl coumarin

ethanol

R



Experimental section:

Synthesis of 6-acetyl, 4-methyl, coumarin(1):

To the mixture of para hydroxy acetophenone (0.01 mol), ethyl

acetoacetate (.02 mol) and 20 ml of precooled conc. H2SO4, was added

slowly, with stirring, After the addition, stirring continued for about 30

min. and the reaction mixture was poured into crushed ice, the product

separated was filtered, washed, dried and recrystallized from hot

methanol.

Synthesis of 6-{1-(-substituted-phenyl)imino)ethyl)-4-methyl-2H-

chromen-2-one (2):

6-acetyl,4-methyl,coumarin (2.38g, 0.01 mol) was dissolved in

ethanol (50 ml) and substituted aromatic amines (0.06 mol) was

added. Reaction mixture was refluxed for about 5 hrs. It was cooled

and product separated was filtered, washed with cold water, dried and

recrystallized from ethanol. and the purity of the compound was

checked by TLC. IR (KBR in CM-1), 6-{1-(-2-nitrophenyl)imino)ethyl)-

4-methyl-2H-chromen-2-one(RR-37); 3107.43 Aro (C-H Str.), 2848.96

Ali (C-H Str.), 1624.12 (C=0 Str.), 1105.25 (C-0 Str.), 1064.74 (C-O-C

Str.), 1166.97 (C=N Str.), 1282.71 (C-N Str.), 779.27 (N-O Str.),

1435.09 (C-H bending in the plane), 698.53 (C-H bending out of

plane). Similarly other compounds (RR38-RR50) were also synthesized

and their characteristic analytical data are given below.



6-{1-(-phenyl)imino)ethyl)-4-methyl-2H-chromen-2-one(RR-38):

3012.91 Aro (C-H Str.), 2980.12 All (C-H Str.), 1690.2 (C = O Str.),

1536.39 (C-O Str.), 1657.03 (C-O-C Str.), 1498.74 (C=N Str.), 1138.04

(C-N Str.), 1402.56 (C-H bending in the plane), 736.83 (C-H bending

out of plane).

6-{1-(-2-aminophenyl)imino)ethyl)-4-methyl-2H-chromen-2-one

(RR-39) : 3446.91 (N-H Str.), 2970.48 Ali (C-H Str.), 3117.07 Aro (C-H

Str.), 1678.24 (C-O Str.), 1635.69 (C=O Str.), 1321.28 (C=N Str.),

1112.96 (C-N Str.), 1458.23 (C-H bending in the plane), 740.69 (C-H

bending out of plane).

6-{1-(-4-methylphenyl)imino)ethyl)-4-methyl-2H-chromen-2-one

(RR-40) : 2951.19 Aro (C-H Str.), 2904.89 Ali (C-H Str.), 1696.32 (C=O

Str.), 1558.54 (C-O Str.), 1326.1 (C=N Str.), 111.03 (C-N str.), 1437.02

(C-H bending in the plane), 775.41 (C-H bending out of plane).


(RR-41) : 3059.2 Ar(C-H Str.), 1541.18 (C-O Str.), 1852.12 (C-N Str.),

1111.04 (C-N Str.), 815.61 (N-O Str.), 1481.38 (C-H bending in plane),

669.32 (C-H bending out of plane).



Str.), 1570.11 (C-O Str.), 1278.85 (C=N Str.), 1132.25 (C-N Str.),

956.72 (N-O Str.), 1437.25 (C-H bending in plane), 748.41 (C-H

bending out of plane).



6-{1-(-3-nitrophenyl)imino)ethyl)-4-methyl-2H-chromen-2-one (RR-

43) : 3059.27 Aro (C-H Str.), 2953.12 Ali (C-H Str.), 1701.36 (C=) Str.),

1134.18 (C-O Str.), 1278.85 (C-N Str.), 1091.75 (C-O-C Str.), 1440.87

(C-H bending in plane), 703.21 (C-H bending out of plane).

6-{1-(-4-nitrophenyl)imino)ethyl)-4-methyl-2H-chromen-2-one (RR-

44) : 3128.64 Aro (C-H Str.), 2987.84 Ali (C-H Str.), 1660.77 (C=O

Str.), 1276.92(C-N Str.), 817.85 (Aro-Br), 1432.02 (C-H bending in

plane), 640.39 (C-H bending out of plane).

6-{1-(-3-methoxyphenyl)imino)ethyl)-4-methyl-2H-chromen-2-one

(RR-45) : 3001.56 Aro(C-H); 2902.82 Ali (C-H), 1692.1 (C=O Str.),

1550.8 (C-O Str.), 1300.07 (C=N Str.), 1278.85 (C-N Str.), 745.23 (C-

Cl Str.), 669.81 (C-H bending in plane), 1386.86 (C-H bending out of

plane).

6-{1-(-4-bromophenyl)imino)ethyl)-4-methyl-2H-chromen-2-one

(RR-46): 3070.78 Aro (C-H Str.), 2914.54 Ali (C-H Str.), 1649.19 (C=O

Str.), 1581.68 (C-O Str.), 837.13 (C-Cl Str.), 1437.02 (C-H bending in

plane), 675.11 (C-H bending in plane), 675.11 (C-H bending out of

plane).

6-{1-(-3-chlorophenyl)imino)ethyl)-4-methyl-2H-chromen-2-one


Str.), 1502.81 (C-O Str.), 1302.51 (C-N Str.), 1196.31 (C=N Str.),

1402.31 (C-H bending in plane), 758.31 (C-H bending out of plane).





Str.) 1550.31 (C-O Str.), 1360.18 (C=N Str.), 1256.32 (C-N Str.), 756

(C-Cl Str.), 1401.81 (C-H bending in plane.), 695.21 (C-H bending out

of plane).

6-{1-(-2-napthyl)imino)ethyl)-4-methyl-2H-chromen-2-one(RR-49);

2996.31 Aro(C-H str.), 2901.50 Ali(C-H str.), 1705.31 (C=0 str.),

1196.31 (C=N str), 1502.81(C-O str.),1402.31 (C-H bending in plane),

758.31 (C-H bending out of plane).


(RR-50); 3006.82 Aro(C-H str.), 2954.65 Ali(C-H str.), 1695.21(C=0

str.), 1360.18(C=N str.) 1256(C-N str.), 1550.31(C-O str.), 756.31(C-Cl

str.), 1401.21 (C-H bending in plane), 695.21 (C-H bending out of

plane).

1HNMR spectra of the compounds: (DMSO-d6) RR-38 : 5.795 (6H, S,

2CH3 protons), 4.839 (5H, multi sub. benzene ring), 4.756. (5H,

multi., subs. coumarin ring).

RR-44 : 6.032 (6H, singlet.2CH3), 4.027 (4H, sym multi, Nitro subs.

benzene ring), 5.123 (5H, multi subs, benzene ring), 5.123 (5H, multi,

subs coumarin ring).

RR-45 : 2.478 (3H, singlet, OCH3 methoxy protons), 4.977 (6H,

singlet, 2CH3), 3.304 (4H.OCH3 subs. benzene ring multi), 3.299 (4H,

multi CH3 subs. coumarin ring).

RR-48 : 3.738 (4H. multi. chloro subs. benzene ring), 3.711 (4H.

Multiplate methyl subs. coumarin ring) 5.625 (6H. Singlet, 2 methyl

group).



Physical Data and Characterization

Compound RR-37

Name 6-{1-(-2-nitrophenyl)imino)ethyl)-4-methyl-2H-chromen-

2-one

M.F. C18H14N2 O4

O O

CH3

CCH3

N

O2N

M.wt. 322

M.P. 211ºC

Yield 65%

Elemental

Analysis

C% H% N%

Cal Found Cal Found Cal Found

67.07 67.06 4.38 4.37 8.69 8.68

Compound RR-38

Name 6-{1-(-phenyl)imino)ethyl)-4-methyl-2H-chromen-2-one.

M.F. C18H15N O2

O O

CH3

CCH3

N

M.wt. 277

M.P. 207ºC

Yield 75%

Elemental

Analysis

C% H% N%


77.96 77.95 5.45 5.44 5.05 5.04



Compound RR-39

Name 6-{1-(-2-aminophenyl)imino)ethyl)-4-methyl-2H-

chromen-2-one.

M.F. C18H16N2O2

O O

CH3

CCH3

N

H2N

M.wt. 292

M.P. 265ºC

Yield 69%

Elemental

Analysis

C% H% N%


73.95 73.94 5.52 5.51 9.58 9.57

Compound RR-40

Name 6-{1-(-4-methyl-phenyl)imino)ethyl)-4-methyl-2H-

chromen-2-one.

M.F. C19H17NO2

O O

CH3

CCH3

N

CH3

M.wt. 291

M.P. 216ºC

Yield 59%

Elemental

Analysis

C% H% N%


78.33 78.31 5.88 5.84 4.81 4.80



Compound RR-41


chromen-2-one

M.F. C19H17NO2

O O

CH3

CCH3

N

H3C

M.wt. 291

M.P. 206ºC

Yield 70%

Elemental

Analysis

C% H% N%


78.33 78.31 5.88 5.84 4.81 4.80

Compound RR-42


chromen-2-one.

M.F. C19H17NO2

O O

CH3

CCH3

N

CH3

M.wt. 291

M.P. 205ºC

Yield 75%

Elemental

Analysis

C% H% N%


78.33 78.31 5.88 5.84 4.81 4.80



Compound RR-43


2-one.

M.F. C18H14O4N2

O O

CH3

CCH3

N

O2N

M.wt. 322

M.P. 281ºC

Yield 65%

Elemental

Analysis

C% H% N%


67.07 67.06 4.38 4.37 8.69 8.68

Compound RR-44


2-one.

M.F. C18H14O4N2

O O

CH3

CCH3

N

NO2

M.wt. 322

M.P. 261ºC

Yield 60%

Elemental

Analysis

C% H% N%


67.07 67.06 4.38 4.37 8.69 8.68



Compound RR-45

Name 6-{1-(-3-methoxy-phenyl)imino)ethyl)-4-methyl-2H-

chromen-2-one.

M.F. C19H17N O3

O O

CH3

CCH3

N

MeO

M.wt. 307

M.P. 215ºC

Yield 65%

Elemental

Analysis

C% H% N%


74.25 74.23 5.58 5.57 4.56 4.55

Compound RR-46

Name 6-{1-(-4-bromo-phenyl)imino)ethyl)-4-methyl-2H-

chromen-2-one.

M.F. C18H14NO2Br

O O

CH3

CCH3

N

Br

M.wt. 356

M.P. 212ºC

Yield 55%

Elemental

Analysis

C% H% N%


60.19 60.08 3.86 3.75 3.83 3.81



Compound RR-47

Name 6-{1-(-3-chloro-phenyl)imino)ethyl)-4-methyl-2H-

chromen-2-one..

M.F. C18H14N O2Cl

O O

CH3

CCH3

N

Cl

M.wt. 311

M.P. 205ºC

Yield 72%

Elemental

Analysis

C% H% N%


69.35 69.33 4.53 4.51 4.49 4.48

Compound RR-48


chromen-2-one..

M.F. C18H14NO2Cl

O O

CH3

CCH3

N

Cl

M.wt. 311

M.P. 215ºC

Yield 69%

Elemental

Analysis

C% H% N%


69.35 69.33 4.53 4.51 4.49 4.48



Compound RR-49

Name 6-{1-(-2-naphthalen)imino)ethyl)-4-methyl-2H-

chromen-2-one.

M.F. C22H17NO2

N

O O

CH3

CCH3

M.wt. 329

M.P. 275ºC

Yield 65%

Elemental

Analysis

C% H% N%


80.20 80.11 5.81 5.79 4.25 4.23

Compound RR-50


chromen-2-one..

M.F. C18H14O2NCl

O O

CH3

CCH3

N

Cl

M.wt. 311

M.P. 220ºC

Yield 65%

Elemental

Analysis

C% H% N%


69.35 69.33 4.53 4.51 4.49 4.48



Results and Discussion :

The structures of all the synthesized coumarin derivatives have

been confirmed on the basis of elemental analysis (IR and 1HNMR

spectral data studies).

Para hydroxy acetophenone on reaction with ethyl acetoacetate

with precooled conc. H2SO4. yielded 6-acetyl,4-methyl, coumarin(I).

This compound on treatment with different substituted aromatic

amines in the ethanol gave different Schiff bases or final products

(RR37-RR50).

All the synthesized derivatives (RR37-RR50), were purified

through recrystallization with suitable solvents and purity of the

synthesized derivatives have been checked by TLC using silica gel-G

(activated).

All the synthesized chromen-2-one derivatives have given

appreciable yield with satisfactory elemental analysis and structures

of all the synthesized derivatives have been confirmed on the basis of

the spectral datas.



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