SYNTHESIS OF ISOXAZOLE CHAPTER I …shodhganga.inflibnet.ac.in/bitstream/10603/50064/7/07...Part III...

Part III

SYNTHESIS OF ISOXAZOLE

CHAPTER I

INTRODUCTION

Importance ofisoxazoles:

Isoxazoles derivatives have been reported to possess antiiubercular'. aniiviraF and

antibacteriaP activity. Isoxazoles have also been reported as herbicides^ \ Chlorosubsiiuiled

isoxazoles*"' possess antibacterial activity. Sharan el al' synthesised chlorosiibsiiuiicd

isoxazole derivatives as very effective antibacterial agents. Recently Den Uma and Ashok

Rao'" reported l,4-bis-(5-aryl-3-isoxazoIyl) benzenes to be antibacterial agenis.

Structure ofisoxazoles :

The isoxazole (la) is a five membered heterocyclic ring system containing both oxy

gen and nitrogen atoms in the 1,3-positions. The oxazole nucleus may be regarded as a

furan nucleus in which the -CH= grouping. Isoxazole (lb) is isomeric with oxa/ole (la) .

with oxygen and nitrogen atoms in the 1,2-positions.

(la) (lb)

Synthesis in isoxazole :

3,5-Disubstituted isoxazoles'"* are synthesised from 1,3-dicarbonyl compounds with

hydroxylamine involving the intermediates dikeloneoxime (Ic). its tauiomer (Id), and 5-

hydroxyisoxazoline(Ie).

Recently the intermediate (le) has been isolated"* from the reaction mixture.

135

NH,()H

R-C=CH Vr«'-OH NOH

^ R-C-CH,-C-R' '6 l\

R-C - CH,- C -R II () K< )H

(Id) Ic)

R' R' l ' < R ^ / OH

(le)

Isomeric isoxazoles could often be formed when the unsymmetrical 1.3-dicarhiinyl

compounds are made to react with NH^.OH.HCl and theri proportion depends on the reac

tivity of 1,3-dicarbonyl compounds. From the enolic structure of 1,3-dicarbi>nyl compound

(10, it is considered that, if R'=H, the inductive effect of alkyl (R"=alkyl) will make carbon

atom-3 less positive, so nucleophilic attack of NH.OH will be on carbon aioip -1 lo give 5-

substituted isoxazole (Ig), as the major prodllCt"'"'^ It has been reported thai'" only a single

isoxazole could be isolated if R' and R" both are substituted phenyl groups with a sufficieni

difference in substituents. For example, the electron withdrawing effect of meianiuophenyl

group (R') will make C-1 sufficiently positive so that the reaction occurs only ai this posi

tion.

. H .

O

> i ^

0

H

(If)

R'

'R'

(Ig)

136

Substituted isoxazoles are synthesised Irom the enolelhers of B-dikelones by the ac

tion of hydroxylamine in allcaline or acidic medium. The example of this type ol reaction is

the formation of the mixture of isomeric 3-melhyl and 5-melhyl isoxa/.oles by the action ol

NH^.OH.HCl on hydroxymethyl acetone in alcoholic sodium hydroxide solution while the

alkyl ether of hydroxymethylene acetone in acetic acid gave only 3-methylisoxa/ole-'^'.

CH-C-CH = C-H ^•™ = SH" ^

N

H,C-

.N CH-C-CH = C-H - C- CH = C"M O OH

NH,()H N K

• ^

NH.OH -1^ /Alc.NaOH

N > H,

AcOH H,C^

NH,()H /AcOH

CH,- C- CH = (|'-H O OR

Weygand et al" have reported the formation of isoxa/.ole Irom the two isomeric eihers

of anisoylacetophenone in acid medium. It may therefore be considered that the B-dikeione

is formed by the hydrolysis of enol eihers in acid medium, which in turn is converted m ti

isoxazole.

^ C -CH = p - < 0 > O C H , ' ^ r -CH = p - / Q ) O O C H " ' — ^ 0 O C H ^ ^

C-CH = p - < @ > -O OH ^ ^

OCH

Nk

HCO

l-^-%<o>

NHOH NHOH

137

H , C C K ^ ^

""-ono

In alkaline medium the position ol'enol elher group is responsible lor the lormaiion ol

isoxazole from the turn isomeric melhylethers of anisoylaceiopheiione. Il lias been suj;-

gested that, the reaction proceeds by 1.4-addilion in alkaline medium. This is also sup

ported by the isolation of B-hydroxyl amine -chalcone (11) in neutral solution, which in turn

is converted in to isoxazole by acid or alkali treatment. Hvidence for 1.2-addiiion rather

than 1,4-addition in alkaline medium has been suggested by liistart and Markel.

\ -CH = p Y O > — > \^f^-CH, - p — \ ^ 5 OCH^-^ OH O NftOH^-^

C^-r. ^ tL "-CO^Q^ O C H

' '• * 6 ' N H O H OCH,

Acetylenic ketone like p-anisoylphenylketone is converted to isoxazole (111) in acid

medium, while in basic medium it yields isoxazole (IV). Ben/.oylanisoylaceiylene in acid

medium yields (IV) where as in basic medium it yields (II). Hence 1.2 or 1.4-addition

depends on the experimental conditions. Since 1,4-addition to P-unsaluraied sysieni lo be

of Michael type, this must be carried out in alkaline medium. It has been observed thai

138

acetylenic ketones on 1,2-addilion form the normal oximes. which are immediately con

verted in to respective isoxazoles-"*, by cycli/.alion and rearrangement (See scheme 1).

H,CO

g - c = - c ^ NH,OH/H' HCO

f-c=-c<g> NOH

HCO

O NHOH

N

H,CO

f?-cH3 - f -(g) O NOH

" • ^ ' ^ o

(w)

H . C O ^

HC m o.

/ N

(111)

H C O

Itn-^

HCO

NOH O o

/K

c = c-{9—<P NHOH/H* ' l O .

NOH f- O

(Scheme 1)

The most widely applicable method tor the preparation ofisoxa/.ole derivative is the

139

action of fuming nitric acid on acetylenes in presence of acetone. The fulminic acid is the

reactive intermediate in the formation of isoxa/.ole, therefore it is known as luhiiinic acid

synthesis of isoxazoles. This work was published by A. Quilico and associates' -\ Before

1942, these isoxazoles were regarded as mixtures of 5-subslituted derivatives bui later there

were identified and confirmed as 3-substituled isoxa/oles'"" -"

Isoxazole is synthesised^" by the action of nilrolic acid on acetylenic compounds. Il is

believed that the reaction proceeds by the elimination of nitrous acid from nilrolic acid.

forming a nitrileoxide intermediate which reacts in a usual manner with acetylenes.

R'-C=CH

R-C-NO, > R-C=N-->0 > R - C CH -UNO, II I

R'

NOH N

R - C CH II 11 /

3,5-Disubstituted isoxazole of unequivocal structure was synihe.sised-' by the action

of .sodiophenyl acetylide on chlorooxime (hydroximic chloride).

Ph-C = C-Na + Cl -CH-qH^- (OCH,) -P > Ph-C^^^N

NoH ' K : , H , - ( { r H j - P

A Quilico el af'" studied the mechanism of this reaction and reported ihal

benzhydroximic chloride in basic medium gave benzniirileoxide which could reaci u iih

acetylenic compound or even with a compound containing reactive methylene group. But

no condensation products were isolated from ihe reaction of ben/.nitrile -oxide on Ph-C=C-

140

Ph, Me-C=C-Me or Me-CsC-Ph.

t Ph-C-Cl lOH

NaOH -> Ph-C=N-CH,

CH = CR

CH,-C-CH,-(j]-()C\H,

6 0

Ph -I LcoocH,

Schlubach and Repenning have reported thai 3,5-diaryl-isoxa/.ole can he ohatined hy

the action of nitrolic acid or aciphenyl nitromelhane or acetylene in presence of horoniri fluo

ride.

Ph - CH

OH O -H,0 N

O

HC = CPh / ( i s^ /Ph

Thus from the above examples, it can be stated that the niirile oxide is the ullmiate

intermediate which reacts with acetylonic triple bond to form isoxazole. If aceiylenic com

pounds are used with intrileoxide, isoxa/.oline, the reduced form of isoxazole being formed',

Sammour el al" have reported the formation of 3,5-diarylisoxazole by the action of

chalcone epoxide with NH/)H.

R<0> , -C-CH-CH-

R'

> R'

141

3,5-Diarylisoxa7.oles of unequivocal slruciurcs have been synlhesised " Irom 2.4.5-

iriphenyl pyrilium salts by the action of hydroxylamine. A mechanism has been proposed

and it is observed that, the pyrilium ring is opened to lorm oxime as an intermediate which

then isomerises to isoxazoline. The isoxa/.oline on successive ti'eatnient with acid and alkali

affords isoxazole and acelophenone as the .side product. The .same reactions al.so lead lo the

formation of the same isoxazole by proto-elimination reaction*".

Ph y^^'h

Ph

NH,OH ^

H'

HOHN Ph Qx.-Ph

P h , ^ / ^ , P h HOHNT ^

Ph

Ph Qv^Ph

^ c ^

Ph.

' ( \ / P h

or

H ^ / ^ / I ' h 4- HN x '

CoPh or

'll pCoPh

+

PhCOCH,

The formation of 3,5-diaryli.soxazole from chalcone epoxide and NH,.()H.HCi in dif

ferent media has been reported by Roth and Sohwarz^\ From the mechanism of the reac

tion, it has been .stated that, epoxideoxinie or 3,.'i-diaryI-4-hydroxyisoxazoline are the mter-

142

mediate which are easily converted in to isoxa/ole. liul it has been concluded from further

work on oximation on chalconeoxide, that 3.5-diaryl-5-hydroxyisoxa/.oline instead ol 3.5-

diaryl-4-hydroxyisoxazoline is the intermediate in the formation of isoxazole.

Fh-CH-CH-C-Ar NH,.OH.HCi Dioxane ^ i 30 min 660C

NK

NH,.OH.HP alkalised with Na COj

/ O N Ph-CH-CH-C-Ar

k3H t AcOH+H,S(),

2 4

^ ^ / I ' h

OH

Ae()H+ H,S(), 25 minutes

^ \ / P h

25 minutes

It is found that the direct synthesis of 3.5-dimethyl-isoxazole from 3.5-diniiroheptane

can be effected on treatment with KOH".

.CH

H,CVCH

NO,

CH-C^H^

NO,

KOH <>v./C\H,

^

HX\

A direct and most suitable of 3,5-diaryl-isoxa/.ole and 3-aryl-5-methylisoxa/ole ol

definite structure is from the action of NH.OH. HCl on ^avanones'^ thiochromones'".

chromones*'.

143

NH.OHOHHC

Pyridine

OH

C _

O" -R

Flavone (R=An X=()), Thichrome (R=CH,, X=C) Chromone (R=CH,. X=())

a-Bromostyrene or o-nilroslyrene reacts with nitride oxide to give 5-brom- or 4-

nitro-isoxazoline respectively. These isoxazolines are converted in to the same isoxa/ole on

alkaline treatment and heating respectively"'.

Ph -C =CH, + C- Ph Br "O^N"

Ph-1' Vi: ^k/Ph ir > f 1

Heal -HNO,

Ph -CH=CH-NO, O <-• J-" A ' f ^ / P h

Ph-^^ ^ NO,

The reaction of chalconedibromide with NH,OH in presence of alkali provided an

unambiguous synthesis of isoxazole(v) 22.3y.42-44 Similarly the monobromochaicone which

can be obtained from chalcone dibromidc by elimation of HBr, reacts with NH^.OH.HCI.

under similar conditions to yield isoxa/.ole (VI)"-'""''

Br Br NH^.OH.HCl/OH-

R-C-CH-CH-R'

II I I O Br Br N - O-

I H

•^ R-C-CH-CH-R'

144

R-C -C = CH-R' > R-C-C-Br J» R || i Br > R

IJL O Br NCH ^O R' ' ^^o^~ R'

W O R' (Vl) I H

No definite mechanism has been reported to far for these reactions . though it appears

to proceed through 1,2-addition by way of intermediate oximes. It can be proposed that 4-

bromo-isoxazoline could be the possible intermediate which isoxa/.ole (Vl).

Waygand et al"* reported that P-ethoxychalcone oii treatment with NH .OH.HC'l af

fords isoxazole (V) of definite structure.

NHj.OH.HCl _ ^ ^

R'-C-CH=C-R 3> ' ^ ' 1 il

O OC,H,

iV)

Thus the reaction of chalcone dibromide or p-ethoxychalcone with NH,.()H.HC'I can

be employed to determine with of two isoxazole (V) and (VI) is obtained from related P-

diketone on reaction with NH,0H.HC1.

I E - NH OHHri NH^.OH.HCl N IL „, ^ - O ^ R c NH^.QH.HU K.^^cH,-C-R' ^ > " " ^ O ^ R'

II "II

o o

(V) (VI)

Borkhade"^ (1970), has been reported from this laboratory the formation of the mix-

145

ture of three compounds, viz, 3-(2-hydi"oxy-5-iTiethylphenyl)-.'i-phenylisoxa/()line: ^-{2-

hydroxy-3-bromo-5-melhylphcnyl)-5-pheny! isoxa/olinc and 3-(2-liydi()xy-3-hiom()-5-

niethylphenyl)-5-phenylisoxazole on Ireatmenl or2'-hydroxy-5'-mclhylchalc()nedihi()mide

with hydroxylamine hydrochloride in pyridium medium. The mechanisniproposed by

Borkhade for the above reaction is based on that proposed by (ihiya and IVIaralhey•*

H,cY^.^H-,„.<0>

HX-i OH

^ - C H ^ C H - ^

Br

H,C-OH

| ; - C H - C H - < ^

H,C

Same isoxazoles^^ were obtained by the interaction of RCR-=NOH (R-=CI) which

R'COCH .NG, in presence of tertiary amine and shown to be corrosion inhibitors for I'uels

and lubricants

146

RCR2=N0H +R'COCH2N02 > J |1

Sokolor el al"" were prepared subsliluled isoxazoles by the nitrogen ol (R=l-I, lodo.

Br, CI) in AcO containing catalyst and amount of H^SO .

R-rp^Me

Arena et al" were synthesised isoxazoles substituted with 4-pyridyl and 3-chiorophenyl

groups by cyclization of hydraxamoyl chlorides with ketoacetates.

R=H-pyridyl, 0=ClCgH^; R,=H-pyridyl, 0-ClC\H^; R,=H. COR,, R,=()H. OHT.

NHCH^CH^Et, OCH^CHjNEt^ etc.)

Perkin etaF^ synthesised 3-(4-Ghlorophenyl)-5-(4-methoxyphenyI) isoxazole by treat

ing P-ClC^H^Me : NOH with Buli at ()"C and followed by cyclization of inlermediaie with

p-MeOC^,H,CO,Me in THF containing HCl.

Ibragimove et al" prepared substituted isoxazoles by treating RCOCH :CH.CICH,-C1

with NH.OH in Dioxane.

147

R-Ns O ^ " CH,CI

(R=alkyl, cycloakyl, aiyl)

Nicolaides et al' '* prepared isoxa/.oles from nitrileoxide and irimcthylsilyloxy---

pyrazolines in MeOH.

• >

OSiMe

Elkasaby et al'*'* have obtained new isoxa/.oles from chalcone by more than one route.

The isoxazolines were conveniently converted into the corresponding isoxa/oles by the

action of NBS and trcjaling the crude product with base. The isoxa/.oles were also obaiained

from chalconedibromides by the action of NH,.()H.HCl/Na()H and from chalcone epoxides

by the action of NH,.OH.HCl/pyridine.

NH.OHy Py. Ar,-C-CH=CH-Ar3 - L ^

O

(Chalcone)

r Ar

Ar-C-CH-Br-CH-Br-Ar, II O

(Chalcone dibromide)

Ar - C-CH-CH-Ar, II \ / " O O

(Chalcone epoxide)

NROH.OH.HCl

%$S9

Ar,

(Isoxa/.oline)

NBS /Base

NH.OH.HCl / Py. •^ Ar U Ar,

(Isoxazole)

148

Thakre el al *" synlhesised 3-(2'-ruryl or 2'-lhionyl)-5-(2-hyclroxyphcnyl) isoxa/oles

by condensation ofcorressponding 1,3-propanediones with NH^.OH.HCI in mclhanol.

R,

R,yA?OH

R, V ^ C -CH3-(f;

K 6 c

NK.OH.HCl R

CH,-(fJ-R O

MeOH • >

(A)

R, R,yAs^OH

O (B)

Judging the structure of 1,3-propanediones and hence its direction olenoii/ation the

structure of isoxazole formed would be (A) and not (B). In structure (c) the carbonyl-carbon

atom attached to the aryl moiety will be more negative than the other carbonyl-carbon due

to the inductive and resonance effect of the aryl group. It can therefore enoli/.e and only type

of isomer having the possible structure (A) is obtained.

Jamode" has synlhesised several 3-(o-hydroxyaryl)-5-aryIiosxa/.oles by ihe action ol

NH^.OH.HCl in ethalenediamine on diben/.oylmethanes, llavones and 3-bromonavanones.

OH

V''l'^ NH.OH.HCI

°r<o> o o NH,(CH,), NH.

\ l /

149

OH

^J^ Wododkar"*** reported the formalion ofisoxa/oles from D-hydroxydiben/oylmclhaiiL's

and 3-iodonavanones by reaction with NH^.OH.HCl in l)M17pyridine.

OH NH,.OH.HCl [ O

:o> — ^ ^ .^ H

o

NH,.{)H.HC1/

Pyridine

V<2>

Trisubstituted isoxazoles ** were prepared by chemical and electrochemical reduction

of a-acetyl-P-nitrostilbenes.

O.NCPh : CRH.COR •^ Ph I' . 'I I'h

1.3-Cycloaddition ofbenzonitrile oxide and 2.6-dichloroben/.onitrile oxide and with

trimelhylsilyl enol ethers of manoketones and (3-diketone.s and also with enolbenzoaies ol

50

benzoylacetone was studied"', l- nol ben/.oalcs gave dircclly the corresponding isoxa/.oles.

U l + CHXOCH.COCR > \^Q—rrCOMe

CI ^ -O-^Me

Chincholkar and Jamode*' iTom this laboratory reported by the synthesis of 3-(2-

hydroxyaryl)-4-aroyl-5-arylisoxa/,oles by interaction of 3-aroyl flavones and NH,.()H.HC'I

in pyridine.

"^ ]^V<P> '^^ NH..OH.HC, ^ R r ^ ^ ^ C - < 0 > ^ '^.'^-Al^C-<?7yR, Pyridine N.,. , .^ ,

•R, S ' ^ @ ^ ^ ' Pyridine ^ ^ O - ^ f p

Chincholkar and Jamode*- afforded the synthesis of 3-aryl-4-aroyl-5-(2-hydroxyaryl

isoxazoles by the condensation of 3-aroyinavones and NH .OH.HCI in methanol.

^ ^ ' V ^ ' ^ NH.OH HC. R r ^ C = ^ ^ < ^ '

V ^ ^ - < P ) ^ R 3 MeOH ^ N ^ ( p

Sankya Co.Ltd." prepared isoxazoles by adding Cu(OAc) to Fd(t)Ac), in McSO^

followed by heating with 3-(p-Tosyloxy)-5-methylisoxa/.ole in benzene.

151

R

(R=H, alkyl alkoxy. halo

R,=arylsuIfonyl. HOCH„ etc.

R, = alkyl, aryl)

Rajnarender el aP'* prepared isoxazole (R=NHC()CH2CI) hy the aciion ol 4-

henzalaminoisoxazole (R=N:CHPh) with ClCH.COCl.

Me N.

R

0^~ CH=CH-Ph

Kakade'''' reported the synthesis of 3,5-diaryl-isoxa/.oles from 2-

hydroxybenzoylmethanes on treatment with NH^.OH.HCl in DMSO solvent.

OH

Lohiya has studied the reaction or2'-hydroxy-dibenzoyImethane and NH,.()H.HCI in

various solvents such as pyridine, ethylenediamine. aqueous DMF, methanol containing

excess of KOH and reported two products. 3-(2-hydroxy-5-methylphenyl)-5-(4-

methoxyphenyl)-iosxazol (a) and .3-(a-hydroxylamino-4-melhoxysiryryi)-.S-

methylbenzoisoxazole (b).

1.S2

H,C

.o H

CH,- P-<@)-OCH, NH.OH.HCl AQX

OCII

(a)

HA CH=C-<!^Q\-OVH.

HNOH

(b)

Hlango el al' ^ reporied the synlhcsis orsuhslilulcd isoxu/.oles by coiidcnsaiion ol 4-

HOCgHpCHMeCO, et with 2,6 dichloioben/.oisoxa/.olc in DMl-.

CHMeCORt

CI

Gaggad '** has prepared 3-(2-hydr()xyphenyl)-.'S-,slyryl-i.soxaz()le Ironi l-(2-

hydroxyphenyr)-5-phenyI-4-peniene-1 .^-diones by the aelion of hydroxylamine hydrochlo

ride in pyridine.

R

H

C - CH,-C-CH= CH < g > - R , NH,0HHC1

Pyridine

V

R^e -OH

O" -CH-C •H<0>-l<,

153

SaraF^ synthesised isomeric 5-(2-hydr()xyphcnyl)-3-.slyiylis()xa/.olc.s by ihe aciion ol

NH,.{)H.HC1 on l-(2-hydroxyphenyl)-3-phcnyl-4-pcnlene-I..Vdioncs in elhanol.

R

H

C - CH,-C-CH= C H ^ ^ y R, NH OHHCI

EtOH

R-K).

^ ,OH

-CH=CH <g>-,

Basinski and Jarzmanowaska'" have reported the Ibrmalion i)liwo isomeric isoxa/.oies

(al) and (bl) from co-formyl-o-hydroxyacetophenone or chromone with hydroxylamituv

or

O

y ^ , H NH,OH.HCl

C-CH,-CHO 6 -

OH

N •0

(al)

&L K'^ (b!)

Witzak'" '- has reported the formation of two isomeric isoxa/oles (a2) and <h2) alon^

with other products from o-hydrox} chalcones and hydroxyiamine hydrochloride in ilk-

presence of sodium hydroxide.

154

\ -CH =CH-/o)-o

NH,()H.HCI [ p ) R ^ > I s ^ j .

OH

NaOH N.o>^0>-'<

(;i2) OH

•N

(b2)

Nair" has reported the synthesis ot" isomeric isoxa/oles (a3) and (b3) Irom I-(2'

furyl)-3-(2-hydroxyphenyl)-l,3-propanedione in pyridine and methanol respeeiivciy.

R-40 ^-cH.g-g

NH,()H.HC1 / ^ V O H

Pyridine Ijui

NH,OH.HCl f^-fe

MeOH

'OH

N /,

Recently more aniimycotic formation" have been reported containing isoxa/oles.

X=Cl,Br, I

R,=H, alkyl. phenyl, ihienyK furyl.

R, = H, alkyl, alkoxy or halo

R3 = H, alkyl, alkenyl

155

It was found that (R,. R, and R, =H and X = CI) conirollcd lk)iryii.s cinercaon cucum

bers'

Isoxazole'^' has been found lo have anliviral properlies against. Heres type 2-virus

I'l ()

Penicillin derivatives containing isoxa/.ole ring, isoxa/.oic carhonyl penicillins" syn-

ihesised by Eguchi et al were antibacterial Pseudomonas aeruginosa.

R, •CONHCHRCONH

^ - ^ - Q \ ^

(R, R,,R, =H, alkyl, arylkyl, aryl)

Steven et al" have been reported the synthesis of i.soxa/oles by the action of Ph.C:C/

NOH with H,C:C1, and EtN followed by NaOHCH.Ph treatment.

Ph

C N NaOCH.Ph "D CI OCRPh

Grabowask et af' prepared chlorosubstituted isoxa/.oles by cyclocondcn.sation ol

CIC^H^CH.NOH with MeC.OCH.Co^Ht in presence of NaOCI and NaOH.

CI

O'

-CO,R

-Me

156

Cabre Caslellvi el aP" synlhesised chlorosubsliUiied isoxa/.oles by the action ol acid

chlorides with NaN^ in presence of a catalyst 4-niethylpyiidine liydiochlonde

Ph.CHjN^Bn^CI and 15 crown-5.

:o: X,—n-coR,

^' N,^;^Me

Odakengo el al"' have been reported the synthesis of isoxa/.ole by the action ol' .V(3-

chlorophenyl)-4-Chloro-5-aceloxy-2-isoxa/oline with 1 .H-dia/.obicycio (5.4 - 0) undencanc

in THI'.

Xn ^ ^ p

X=halo, haloalkyl, halo alcoxy

n = l-5

y = halo, Ar', etc.

Malyula N.G. and Khismutadinov" synthesised substituted isoxazoles by halogena-

tion of the corresponding derivatives (X=H) by CI, Br. I-Kl and dehydrohalogenation o\

resulting intermediate in dioxane or MeOH with pyridine, ()lU,NH.

Ph X

NO, p\^ NO

O" R ^ N . Q J - ^

157

Barluenga el al" reporlcd the synthesis tjfdihydroisoxa/oles and their derivatives by

cyclizalionof R,N:C(Ph)C(R,)(Cl)C(R,): NH with NH.OH in pyridineloHowed hy |-,aX)H

treatment.

R, CI

R

-Ph F3CCO3H

N'

CI • ^

Ph

R-^^X)

Chiriano et a^ reported the synthesis ofisoxa/oles Irom R'C:CH, H.C( K'( ),l I. H( )N()

and CI.

CI ir^ Ns. O-^R'

(R,=CH,OH, Ph. CH.Br, CH(()H) Me, CH(()H)Ph. C\H,,)

Sharan et al**' have synthesised isoxazole having fungicidal activity towards Aspergillus

niger by the condensation of substituted aldehydes with 8-acetyl-7-hydroxy-4-

methylcoumarin following by cycli/ation with NH,()H.

0=C-CH=CH-R

0 - ^ R

Dannhardt et aP ' reported the synthesis ol' 4-amini)-3-p-(Chlorophenyl)-5-(B-

aminoethylthio) isoxazole by the treatment of NaOlU.lUOH. HCI. lUher on 4-(p-

chlorophenyl)-3-methyl furoxane followed hy condensation with Li(CH,),NH,.

158

CI O.

Cj—^SCCH^X

N.

NH

or- NH,

Millal and Singhal** synthcsised anliniicrohial isoxa/olcs IVom dilTerftnl subsliiLilcd

benzene diazonium chlorides coupled with some reactive methylene compounds and then

condensed with NR.OH.HCl.

R, R.

R,COCH,COCH, ^'~^(^y /

N N-CH

CO

R, R. CO •R'

NH,OII HCl

sk

R

R oL,= i-N=N n-CH

\ K x'^o-^

Zong et aP" reported the synthesis of a mixture of isomeric isoxazoles I'rom

unsymmeirical P-diketones(l-aryl-3-tolypropane-,3dionesand l-aryl-butane-l.3-dioneand

NH,.0H.HC1.

Me^ Me^.

C

O R N rf^R

Den Uma and Ashok K. Rao**'' synthesised antimicrobial isoxazoles from 1.4 Bis (3-

59

aroyl-2.3-dibromopropanoyl) ben/onc with NH,.()H.HC'I

i- > n I 1 . I V I I 1 I I I I K

Bich el al' " reported the preparation of novel amino methyl derivatives ol' S-niiro-1.2-

benzisoxazole-3-(2H)-one.

(R=Morphino, Q;R=H,Me)

Werner el aP' reported synthesis and antifungal study of isoxa/.ole carhoxylic acid

derivative, N-(l-phenylethyl)-5-teributyl-3-isoxa/.ole earboxylamide (H) by aminating the

acid herbicide (I).

O U O Me

^:ir O-^ M e , C - V Q ^ H

A=Alkanediyl, Q=Oxygen. sulphur, imio etc.

R,=alkyl etc. R2=H,X, alkyi, etc. R,=cyclohexyl, heteroary! etc.

Bard et al''- reported the synthesis of isoxazole, by the condensation of 5-ch!oro-4-

tbnnyl-3-methyl-phenylpyrazole (I) with dilTerenl active methylene compt)unds U) Ibrm an

a,P-unsaturated ketone intermediate which was then cyclocondensed with hydrazine and

160

hydroxylamine lo yield title compound.

Koenig et al' ^ reported the preparation of 5-rormyl-3-isopropyli.soxa/.ole (1) hy ih oxi

dation of 5-(chloronielhyl)-3-isopropylisoxa/o!e in the presence oC N- melhyl-niorphine.

The compounds thus prepared are found lo he elTeclive herhicides.

Sonare el al' " reported the direct synthesis of 3.5-disubstiluted 4-hroinoisoxa/,oles 11)

by the condensation ofeither 3-bromonavones (11) or 2-bromo-1,3-diaryipropane-1.3-di()nes

(III). (P-dikelones) with hydroxylamine hydrochloride.

Oy^R-

NH.OH.HCl : >

UU man conditions

Lin. siiow, Tao and Yang, Fu. Mey' \ reported the derivatization of 5-halogen-3-(4-

nitrophenyl) isoxazoles. Treatment or.'S-halo-3-(4-nitrophenyl isoxa/.oles with various rea

gents demonstrated competative substitution between the hydrogen ol" arene and ihe halo

gens of the isoxazoles.

A facile synthesis of 3-aryl-4-hydroxyalkylisoxazo)es was reported by Venn (iupalan

and Co workers' '. 1,3-Dipolar cycloaddition reaction of benzonitrileoxide was used tor ihe

preparation of 5-substituted isoxazoles. Tetrahydrofuro, {3,2-d) isoxa/ole and

telrahydrapyrano(3.2-d) i.soxazolegive 4-hydroxyalkyalisoxazoles upon ireaimeni with Cone.

HCl.

Hanson el al'* synthesised 4-oximino-4.5-dihyclroisoxa/,()le from isomeric syn-oximi

along with pyrazoles, a, P-unsaluraled keloximes K1CH:C'H (:N()H)k, were nilrosaled

using Bu-nitriie in aqueous elhanol in the presence of copper (II) - sulpliaie and pyridine.

For Ihe syn-oximes where R|=Ph and K,=Me or el conversion ol ihe oxnne lo Ihe

pareni kelone was also observed.

Rajpul' '* have synlhcsisod chlorosuhsliluled isoxa/.oles from llavoncs & 2.^-

propanediones in elhanol coniaining liule piperidine.

S-™^5H 0>Rn

°r^^

NH OH/HCl

EtOH/piperidine

Palil' ' have synlhesised some new chlorosubstituted 4-aroylisoxa/.oles by ihe con

densation of NH.,.0H.HC1 with 3-aroylflvanones in DMF coniaining liille piperidine.

HX

V - ' CI

NH,.0H/HC1

^ ~\P/-^' Piperidine

(R, & R = H, OCH,)

O

.R

I

162

Deshmukh'"" has reported the synthesis 3,5-(Jiarylisoxa/()lcs trom 2-

hydroxychalconedibromidcs with NHpH-HCl in DMSO containing little piperidine.

H

a^n.rM = n./nN ^"=°""" - JO ltT<2> ^--^ H

DMSO/piperidine o ^

Recently, Kedar"" synlhesised 3,5-diarylisoxa/oles from 1.3-diphenyl-1.3-

propanediones and NH,.OH.HCI in presence of aqueous .sodium hydroxide in elhanol.

CI PlTr^^ . /7^ NH,0H/HC1 ^^£Q g-cH,9^-^

)H

EtOH/aq. NaOH ^l 1 ] / ^ -

163

ORIGIN OF THE PROBLEM

Lsoxazoles are generally prepared by ihe action ot NH^OH.HCl on l,3-(Jicarbonyl

compounds''^ 3,5-Diaryl isoxa/.oles arc reported to be formed from llavones'"-

chromones*'chalconedibromides or a-bromochalcones. The synihesis ol ^,5-

diarylisoxazoles by the action ofNHjOH.Hcl on (J-diketones llavonesand ^-hronioHavanones

in pyridine''^ and ethylenediamine as a reaction medium has also been reported. I'alil" re-

ptiried the synthesis of 3,5-diarylisoxa/.oles from chlorosubsiiiuled .^-aroylflavaones and

NH,OH.HCI in DMF solvent containing few drops of piperidine, while Kajpui"" carried out

the same reaction using elhanol containing a little piperidine as a solvent.

Kakade * reported the synthesis of isomeric 3-phenyl-5-(2-hydroxyphenyl) i.si)xa/oles

from l-(2-hydroxyphenyl)-3-phenyl-1,3-propanediones and hydroxylaminehydrochlohde

in DMSO in presence of sodium acetate. Recently Deshmukh'"" reported the use of piperidine

in DMSO as a solvent for the preparation of 3,5-diarylisoxa/.oles from chalconedibroinide

on treatment with NHjOH.HCl.

Literature survey has thus prompted us for the present study involving the use of

DMSO solvent containing few drops of piperidine as a medium for the first lime in the

synthesis of 3,5-diaryl-4-aroyl isoxazoles from 3-aroyinavones.

PROBLEM

The present work deals with the synthesis of 3.5-diaryI-4-aroylisoxa/.oles Irom V

aroylflavones and NH,0H.HC1 in DMSO solvent containing a few drops of piperidine as a

medium. It has been revealed that the use of piperidine in DMSO as the solvent in the above

164

reaciion influence ihe rate of the reaction and also the yield of the products. The structures

and identify of the compounds synlhesised have been cofirmed by spectral and elemental

analysis. The probable mechanism has been al.so di.scus.sed.

SUMMARY OF THE WORK

2-hydroxyacetophenone (1) :

2-hydroxy-5-methylacetophenone (la) and 2-hydroxyacetophenone (lb) were obtained

respectively from p-cresylacetale and phenylacetate by I'ries Migration.

2-Aroyloxy acetophenone (2) :

2-Benzoyloxy-5-methylacetophenone (2a) and 2-ben/,oyloxyacelophenone (2b) were

obtained by benzoylation of respective acetophenone using benzoic acid and POCf in

pyridine medium.

l-(2-Hydroxy-5-methylphenyl)-3-aryl-l ,3-propanedi(mes(3):

l-(2-Hydroxy-5-melhylphenyl)-3-phenyl-l.3-pr()panedione (.3a) m.p. 90" and l-(2-

hydroxyphenyl)-3-phenyl-l,3-propanedione (3h) m.p. 125"C were prepared by Baker-

Venkataraman Transformation of corresponding 2-aroyloxyacetophenones. The structure

of (3a) was confirmed on the besis of IR, U V, PMR spectra and discussed in Part I. Chapter

11 of the thesis.

3-Aroylflavanone (4) :

3-Aroyltlavanones (4a-f) were prepared from l-(2-hydroxy-5-methylphenyl)-3-phe-

nyl-l,3-propanediones (3a) and l-(2-hydroxyphenyl)-3-phenyl-l,3-propanedit)ne (3b) by

ileraction with appropriate ai'omatic aldehydes in ethanol containing few drops ol'piperidine.

The structure of 3-benzoyl-6-methyl-navanone (4a) was confirmed on the basis of IR. U V

165

and PMR spectra and discussed in the Pari I, Chapter II ol the thesis. The compounds (4a 1)

thus prepared are tabulated in Table 1:1

3-Aroylflavones (5):

3-Aroyinavones (Sa-f) were prepared by relluxing 3-aroyinavones {4a-l) wiihcfysial

of iodine in DMSO solvent. The structure of 3-ben/.oyl-4'-methoxy-6-niethyiriavt)ne(5h)

was confirmed on the basis of IR. UV and PMR spectra and discussed in Part IV . Chapter

11 of the thesis. The compounds (5a-r) thus prepared are tabulated in Table 1.2.

4-Aroylisoxazoles (6) :

3-Aroyinavones (5a-0 on treatment with NH^OH.HC'l in DMSO coniainmg a liule

piperidine , gave 3,5-diaryl-4-aroylisoxazoles ( 6a-r). The structure of 3-{2-hydroxy-.'S-

,methylphenyl)-4-benzoyl-5-phenyl)isoxazole (6a) was c.onnrmed on the basis of (K. L'V

and PMR spectra and discussed in Part HI, Chapter 11 of the thesis. The sompounds (6a-r)

thus prepared are tabulated in Table 1.3.

Table 1.1

Comp. No. Expt. No. Flavanone M.P. ("C)

3-Benzoyl-6-methyinavanone 14K

3-Benzoyl-4'-methoxy-6-methyl-navanone 15S

3-Benzoyl-2-(2'-ruryl)-6-methylchronianone 125

3-Benzoyinavun()nc ISS

3-Benzoyl-4'-methoxynavanone 122

3-Benzoyl-2-(2'-ruryl)chromanone 144

4a

4b

4c

4d

4e

41*

7

8

9

10

11

12

166

Table 1.2 - 3-Aroyinavone.s

Conip.No. Expt.No. Flavone (VI.P.C'C)

3-Ben/,oyl-6-nielhyinav()ne IK(i

3-Ben/,oyl-4'-meihoxy-6-melhi)xynavone 165

3-Benzoyl-2-(2'-ruryl)chn)ni()ne I ^ I

3-lienzoyinav()ne 132

3-lien/.()yl-4'-nielli()xyriav()nc 137

3-Ben/.()yl-2-(2'-ruryl)chromoiu' 211)

5a

5b

5c

5d

5t"

51"

13

14

15

16

17

18

167

http://Expt.No

1.3

4-Aroyllsoxazoles

Comp. No. Expt. No. Isoxazole M.P.C'C)

6a 19 3-(2-Hydioxy-5-melhylphenyl)-4 175 «

-benzoyl-5-phenylisoxazole

6b 20 3-(2-Hydroxy-5-melhylphenyl)-4-hen/.()yl-5 163

-(4'-melhoxyphcnyl)is()xa/.ole.

6c 21 3-(2-Hydroxy-5-iTielhyIphenyi)-4-bcn/.()yl I5S

-5-(2'-ruryl)i>soxa/ole

6d 22 3-(2-Hydroxyphcnyl)-4-ben/,oyl 146

-5-phenylisoxa/ole

6e 23 3-(2-Hydroxyphcnyl)-4-bcnzoyl-5 134

-(4'-melh()xyphenyl)isoxa/ole

6r 24 3-{2-Hydroxyphenyl)-4-bcn/A)yl-5 171

-(2'-ruryl)isoxa/.olc

168

r

'Fart III

CHAPTER -II

Contents • Page No.

Discussion of the Results and Experimental 169

References 209*

DISCUSSION OF THE RESULTS AND EXPERIMENTAL

The historical accouni of the lileralurc shows thai ihc reaction olchalconedihromitle

with different nitrogen nucleophiles like hydroxylaminehydrochloride, hydra/.inehydrochlo-

ride and semicarbazide in alkaline medium provides differeni nitrogen heterocyclic com

pounds. Various solvents like pyridine"' ethylenediamine". I)M1'''\ melhanoP' etc. were

used in the synthesis of 3,5-diarylisoxazoles. Kakade'''* reported the synthesis of isomeric 3-

phenyl-5-(2-hydroxyphenyl)isoxazoles from 1 -(2-hydroxyphenyl)-3-phenyl-1.3-

propanediones and hydroxylaminehydrochloride in DMSO in presence of sodium acetate.

Recently Deshmukh"* has reported the fomiation of 3-(2-hydroxy-3.5-3',5'-dichlorophenyl)-

5-sub.stituted phenylisoxazoles and their acetoxy derivatives. '

The work presented in this section deals with the use of DMSO containing few drops

of piperidine. for the first time, as a medium, for the synthesis of new 3-{2-hydroxyaryl)-4-

aroyl-5-aryl substituted isoxazoles by condensing 3-aroyinavones with hydroxylamine hy

drochloride.

The structures of these compounds have been e.slabli.shed on the basis of chemical

properties, spectral and elemental analysis. The melting points were recorded on 'Tempo'

melting point apparatus and are uncorrected. The infrared spectra were .scanned on 'Nicolei

Magna - I.R. 550' Spectrophotometer in KBr pellets. The proton magnetic resonance spec

tra were drawn on 'Bruker AC-3()()1' NMR Spectrometer' in CDCl, using TMS as iilcr-

ence. The UV-visible spectra were recorded in methanol on 'Ferkin BImer 202' specuxMiicier.

The carbon and hydrogen analyses were carried out on 'Carlo -lirba-1106' analy.ser. The

nitrogen estimation was done on 'Coleman N-analy.ser-29'. The elemental and spectral analy-

169

ses were carried out at R.S.l.C, I.I.T. Mumhai. R.S.l.C. Chandigrah, R.S.l.C. Nagpur and

UDCT Mumbai. The chemicals used were ol laboratory reagents garde. The puriiy ol ihe

compounds prepared was tested by TLC on microscopic slides with Silica gel-(i layers ol

().3mm thickness.

170

Section - A

Preparation of starting Materials

The preparation of starting material involves the lollowing steps :

, 1. The preparation of 2-hydroxyacetophenones (1 a and I h)

2. The preparation of 2-benzoyloxyacetophenones (2a and 2b) from 2-hydroxyaceiophenones

(la and lb)

3. The preparation of 1 -(2-hydroxyphenyl)-3-phenyl-1,3 propanediones (3a and 3b) from 2-

benzoyloxy-aeetophenones.

4. The preparation of 3-ben/.oylflavanones (4a-f) from l-(2-hydroxyphenyl)-3-phenyl-1,3-

propanediones.

5. The preparation of 3-ben/.oyinavones (5a-f) from 3-ben/.oyinavanones (4a-l)

The detailed production & connected accounts for the preparation of above com

pounds (tto 4.) is given in the section A of Chapter II in part I of this thesis under experi

ment No. 1 to 12.

171

FLAVONES

The name tlavonc lor the then unknown 2-phenylben/.opyrone (I) was lirsi suggesied

by Von Kostanecki andTaniboi"'\ The numbering shown is llial universally accepted ol ihe

derivatives of fiavone hydroxyderivalives and their ethers are by for the mosi imporiani

ones.

(I)

The rings A and B in the flavone molecule react more or less normally as aromatic

rings. This is particularly true of the hydroxyllavones and their ethers, which behave as

phenols and their ethers in substitution reactions. Thus nitration o 5-'"'^ and 7-

hydroxynavone'"\ chrysin""^, apigenin"", etc. have been reported. Al.so coupling with

diazonium salts has been successfully applied to hydroxyllavones. e.g. 5""' and 6-hydroxy""'

'''\ 5-hydroxy-6-methoxynavone'"'*, chrysin'", etc.

Although the structures of all of the.se derivatives have not been established, ii can

safely be said that if ring A has hydroxyl groups, as in the ca.se in all the examples given

above, this ring is preferrentially attacked.

The pyrone ring C, on the other hand, is responsible for most of the reactions typical

of llavones.

Chromones with 2-arylsubstituent occur in nature and po.s.se.ss a variety of biological

activities"-"^ ''*''. It has been claimed that they behave like auxins in stimulating the germina

tion of wheat seeds' ' \

172

http://the.se

http://ca.se

Chromones with heterocyclic subsliluenl at 2-posili()n are reported to possess

bronchodilatory, coronary spasmolytic, CNS depressant and antisarcoma"*" properties' '^'''".

2-(2'-pyridyl) and 2-(3'-pyridyl) chromone have been reported to possess analgesic and coro

nary dialatory activity'^".

It has been known for long time that the pyrone ring has distinctive basic properties'-'

and it is therefore not surprising that basicity is encountered also in llavones. Thus llavone

forms a crystalline, although somewhat unstable, hydrochloride'--. The structure ol such

pyrylium and Havylium salLs has in the past been the subject of controversy.*In the light of

present - day knowledge it can safely be concluded that the structure of flavone hydn)chlo-

ride is the resonance hybrid represented as (II).

CI

Introduction of a substiluent such as hydroxyl or alkoxyl, which is capable ol

accomodating the positive charge into positions 5.7 or 4' will give rise to further contribut

ing structures such as (III), (IV) or (V).

H,CO

H,CO

(III) IV) (V)

173

The basicity should accordingly be enhanced by such a substitution. [|, has also been

known for a long time that certain naturally occuring polyhydroxyllavones form crystalline

salt with strong acids. Briggs and Locker'-^ have reported thai 3.-'>-dimelhoxy-6.7.3'.4'-

bismethylendioxytlavones forms crystalline salt even with organic acids such as picric acid.

Unfortunately there seems to be very little inllamation available regarding the quanti

tative intluence of various substituents in different po.sitions on the basicity of llavones. The

only investigation pertaining to this question appears to be the one by Devis and (Icissman'-''.

They showed that Whilst llavone has a pKa of -1.2, 4'-methoxyflavone is a stronger ha.se

having pKa = -().8.

Although the pyrone ring formally has a carbonyl group, llavone does noi react nor

mally with such carbonyl reagents as hydroxylamine. .semicarba/.ide or phenylhydra/ine.

The corresponding derivatives of llavones can, however, be prepared Irom 4-thionollavone'-"

or. better , from its methiodide. The alleged llavone oxime obtained from llavone with

hydroxylamine hydrochloride in pyridine'-^ has been shown to be ."^-O-hydroxyphenyl-S-

phenylisoxazole. The only example of a normally formed carbonyl derivatives appears lo be

llavone 2,4-dinitrophenylhydrazone'-^''-^

Upon treatment with alkali the pyrone ring opened giving a 1,.1-dikeione. which ihen

usually undergoes further degradation. This reaction has been of very great importance m

elucidating the structure of llavone derivatives.

The synthetic methods available for the .synthesis of llavones and its derivatives can

be roughly divided into three groups :

1) Methods in which the heterocyclic ring is formed during the reaction.

2) Methods in which the starting material contains the heterocyclic ring, but in a differeni

174

http://ha.se

state of oxidation or of a different size.

3) Methods in which starting material is a Havone.

Methods belonging to group I

[n these reactions the pyrone ring is formed during the reaction without isolation ol

any intermediate containing the heterocyclic ring. Formally the methods using a chalcune

either as starting material or as an intermediate also belongs to this group, hui hccau>o of

these close connection between the chalcones and llavanones these methods are considered

to belong to group 2.

The carbon skeleton of the Havones is usually formed from two aromatic compounds,

each containing one of the aromatic rings. There exists foimally four po.ssibilities for achieving

this :

r. j ^ m. o V C

(A) (B)

n" c. c/-\ ^^^^c" •!:0

(C) (D)

No method based on scheme B is known, but the three others have been successfully

used.

The earliest method is dealkylation of a 2-alkoxy-diben/oylmethane with simultane

ous ring closure to the tlavone, by treatment with hydroiodic acid, as demonstrated by the

175

synthesis of chrysin 129

yOMe M e O / n V -CH = /7^ HI

(VI)

HO o

The necessary starling material can be obalained by a Claisen condcnsaiidn of either

o-alkoxyacetophenone with an ester of"an aromatic caiboxylic acid or an o-alkoxycarboxylic

ester with an acetophenone'^"; thus corresponding to scheme C or I).

The ring closure ofo-hydroxydibenzoylmelhanes is not always unambiguous, when

both aromatic rings have o-illkoxy groups, or one aromatic rings has two o-alkoxy groups

the ring closure can some -times proceed in two directions, although usually only one prod

uct is obtained. For instance (VIII) gives (IX) and not (X) ' ' and (XI) gives (XII) and noi

(XIII)''-.

(X) (VIII) S.'

'76

pCH,

OCH

(XIII) (Xl) H'

V<o>

(XII)

By keeping the reaction time short enough , it has been possible U) achieve ring clo

sure without dealkylation ol' the alkoxy groups'". A belter procedure is lo dealkylaic o-

alkoxy group by aluminium Chloride in nitrobenzene followed by ring closure with dilule

acids' ". Ring closure of a o-hydroxydiben/,oylmethane to a llavone can also be achieved al

pH 8-9 in dilute solution''\ When o-hydroxydibenzoylmethanes are treated with performic

acid they are converted into 3-hydroxynavones ' ^

Only two examples'"'''*' of conversion of an o-aroyloxy-acetophenone diieclly inu) a

llavone were known until Whealer and Collaborators''""*' showed thai this can generally he

brought about by heating in anhydrous glycerol.

Another variation of the same method is the Allan -Robinson synthesis. In this ihe o-

hydroxyacetophenone is heated with anhydride and sodium salt of an aromatic acid, fol

lowed by alkaline hydrolysis'"*'. The method gives the best results when ihe ketone has an

oxygen, either as an alkoxy group or aroyloxy group, in the w-position, and is ihus suiiable

for the synthesis of 3- hydroxy- and 3-alkoxynavones, without this group 3-aroyinavones

177

is formed and although the aroylgroup can be removed by hydrolysis the reaction is ollen

incomplele'"- or may lake other courses'^'. Kuhn and [.ow'"*" reported belter yields when

using trielhyl amine as a catalyst instead of the salt of the acid.

Unexcepied products have in certain cases been reported from Allan -Robinson syn

theses. Thus, attempted use of o-acetoxyben/oic anhydride with the corresponding salt gave

the corresponding 2-methylchromone"'\ Aceiylvinillic and acelylisovinillic anhydride have

on the other hand been sucessfully used with triethylamine as catalyst'^'. Wessely and

Mosser'^' reported that2,4-dihydroxy3,6-dimethoxyacetophenone with anisic anhydride ni

most cases gave 5,7-dihydroxy-6,4'-dimethoxynavone instead of the expected 7-hydroxy-

5,8,4'-irimethoxy-flavones, although in one experiment the normal product was obtained.

The abnormal reaction of Wessely and Moser involves demethylaiion. Such

demethylations during Allan-Robinson synthesis have been reported in other ca.ses as well'*

ISO

The first step in the Allan -Robinson synthesis is evidently the formation of an o-

aroyloxyacetophenone. which then reacts as in Ihe Baker-Venkatraman transformation the

intermediate (XVI) then loses water and gives the llavone (XVH).

(XVI)

— > L H _ " '^ —

BH • ^

'COCH,

(XV)

< ^ y^^^s + (4 () ^IJ-

(XVII)

178

The formation of 3-aroyl derivatives has been assumed it) take place through further

aroylalion of the o-hydroxydibenzoylmethanes and subsequent ring closure. Opinions thai

this further aroylation takes place on the o-hydroxy group'^"'-. and on Ch, group'"" have

both been expressed. That o-hydroxydiben/oylnielhanes can he formed under Allan -Robin

son synthesis has been experimently proved'""''^.

The systematic methods corresponding to scheme a have received much less atten

tion. Ruhemann''*'* prepared B-phenoxycinamic acid from the ester of phenylpropiolic acid

and sodium phenolate. Ring closure of the acid chloride with aluminium chloride gave

flavones. Seka and Prosche'""* obtained hydroxyllavones directly from phloroglucinol,

reborcinol, pyrogallo with phenylpropiolic acid chloride and aluminium chloride. The yields

were, however, low neither of these methods is of much value for synthesis of Havones.

Of somewhat greater importance is the reaction between phenol and ben/.oylacelale.

Originally phosphorus pentoxide was used as dehydrating agent in this reaction''^ But the

discovery by Menster and Fillon''**"'' that the reaction can be brought about simply healing

the benzoylaceltae derivative with the appropriate phenol to a temperature of 24()-25()"C'

first made this workable procedure. A recent improvement to carry out the reaction in boil

ing nitrobenzene in an atmosphere of nitrogen"'".

The 5,7,3',4'-tetrahydroxy-9-methoxyflavone and 5.7,3',4'-tetrahydroxy-S-.5'-

dimethoxy-flavone (XVIII)"^' were prepared from 2,4-dihydroxy-3',6'-dimethoxy-

acetophenone using modified Baker-Venkataraman method to give corresponding deiben-

zoylmethanes which underwent cyclizalion.

179

)Me /_J0H

XVIII R=H, OCH,

5-Hy(lroxy-3'.4',7,8-telramethoxynavonc" '' was prepared by liakcr-Vcnkaiaraman

rearrangement of 2-veralrt)yloxy-4,6-climelhoxyacet()phenone. followed by meihylaiioii.

persulphate oxidation and methylation with CH.N,

Prolonged heating of 2,3,6-iriacetoxyacetophenone in AC^O-NaOAC yield a mixiiire

of chromones (XIX)'^\ The latter with methanol in acidic medium gave (XX) which has

inert to oxidation by Ag,0.

OCOCH3 /N/OCOCH, /^:V^^''CH, MeOH y\J^

. . . n . . . '^^ OCOCH, OAco OH o

(XIX) (XX)

Kostanecki-Robinson butyrylation of P-orcacetophenone followed by iieaimeni with

H,SO_, gave propylchromone (XXI)' '*.

(XXI)

Substituted 2-(2'-furyl)-3-hydroxychromones (XXII) were prepared by Thakare ei al"'"

180

by cyclodehydralion of 1,3-propandionc (XXI[[) and shown lo posses no any significani

biological activity.

,RrV^-cH.-g-V

(XXII)

K o

(XXHI)

a-Heteroarylhydroxyacetophenones'", 2,4-(OH),C^H,COCH,R, by aceiylaiion in

xylene at 130"C, yielded 2-methyl-chromones (XXIV) in 46-74% yield.

Ha/N>«JH AC^O

OCH^R

R=2-benzofuryl,5(ethoxycaibonyl)-2-furyl-etc.

Kastanecki-Robinson propionylalions'^'^ and B-orcacetopehnone and its 4-o-

methylether and subsequent treatment of" the product with cone. H^SO^ gave 7-hydroxy-2-

ethyl-5-methyl-3-propionylchromone and 7-me thoxy-2-ethyl-.5-methyl-3-

propionylchromone.

Methods beloning to group 2

In the reatcions belonging to this group the starting material is usually llavanone (or

corresponding chalkone) or an aurone, and their convension into llavones. I'"or original method

of Kostanecki involved addition of bromine at the double bond followed by ii-eaimeni with

alcoholic potash. This has been found to be successful in a few simple cases, since parlicu-

181

larly if side phenyl ring substituted the isomeric benzalcoumoranone (XXVII) are often

produced"'^ Hence the method is not suitable for general preparation of tlavtines.

Dehydrogenation of chalkone with selenium dioxide proceeds satisfactory just as in

the case of flavanones'*' .

/OH

<°>s (XXV)

CH =CH-R Br, /OH

CHK

(XXVII)

Flavone Prosogerin-A (XXIX)'™ was obtained by oxidative cyclizalion of chalkone

(XXVII), Prosogerin-B, with SeO^ and debenzylation.

R O ^ O / C -CH = C H - < ^ y O Dir» O R'O

SeO, ^

^^^\-(d>^ R'

O

(XXVIII)

R=CH2Ph, R'=CH,

(XXIX)

R=H, R'=CH,

182

Oxidation of chalkone (XXX)'^' with SeO, gave milletenin-C. (XXXI)

Me Me

SeO, MeO-i

• >

X:H.

(XXX)

Reaction of 2,3-dichloro-5,6-dicyano-l,4-ben/,oquinone (DDQ)'" in boiling dioxanc

with flavanones, (e.g. 5,6,7-trimethoxynavanone (XXXH) gave the corresponding llavoncs

(XXXIII) in excellent yields.

MeO-r

Me o v^

MeO o

dioxane

DDQ

MeO-i V ^ MeO Y ^ r

MeO o

(XXXII) (XXXIII)

The oxidation of 2-phenyl-2H-l-ben/.opyrone'", with KMnOin acetone gave cone-

spending flavones in 8-73% yield. The reaction niechanism has been discussed on the basis

of substituent effect and the oxidation of related compounds. Baker and Glockring'" have

synthesised 3-aroyltlavones (XXXV) by oxidative cyclization of arylidine derivatives

(XXXIV) id\' 2-hydroxydibenzoylmethanes by SeO, in amyl alcohol.

/<o> , _ . 0 H CH' ^ - ^ , SeO,

-> amyl alcohol o ^-^

(XXXIV) (XXXV )

183

Simple C-3-derivatives of flavones (XXXVII)'" were oblained by rellirxing arylidine

derivatives (XXXVI) and resublimed SeO, in dioxane.

X)H ^ H - < 0 > R s^o

<2>i-'-g -> dioxane

(XXXVI) (XXX Vll)

Several a-aroylchalkones"\ obtained by Knoevenegal reaction between

diaroylmethanes and aromatic aldehydes , were converted into 3-aroyinavones (XXXIX)

by oxidation with SeO,.

/OH CH.C,RR(P) SeO,

— ^ •

O

(XXXVIII) (XXXIX)

3-Aroyl-2-arylchromones (XXXII)'" were prepared by oxidative cycii/.aiion of 2-

aroyl-3-arylacrylophenones (XXXL) using SeO, in isomyl alcohol.

yOH CH-R Con

^H isoamyl alcohol

(XXXL) (XXXLI)

184

Methods belonging to group 3 »

In these reactions tlavones derivatives is obtained by change in substitution pattern ol

pre-formed tlavone skeleton.

The flavylium salts (XXXLII)' ** (R=H,OMe.Me) with Ti(NO,), in methanol gave

-70% of corresponding tlavones (XXXLIII).

o (XXXLII) (XXXLIII)

The furo (5",4",7,8) tlavones (XXXLV)' ' (R=H,Me,Fh) were synthesised by cyclization

of 8-allyl-7-hydroxyflavones (XXXLIV) using dichlorobis (benzonitrile) palladium syn

thesis.

H a ^ X ^ O v / n ^ Me %<o)

(XXXLIV) (XXXLV)

185

Synthesis of 3-aroylflavones

Chalcones and flavanones are reported to give corresponding llavones by SeO,

dehydrogenation. Baker and Venkataraman"*" rearranged o-aroyloxy-acelophenones with

bases like K^CO,, Na^CO,, NaNH , pyridine etc. to obtain O-hydroxydibenzoylmethanes

which on cyclisation give flavone. Thakre et al"* synthesised 2-(2'-ruryl)-3-hydroxychroiTione

by cyclodehydration of 1,3-propanediones with acetic acid and HCl. 3-Aroyltlavones were

"synthesised by oxidation of arylidene derivatives of 2-hydroxy-dibenzoylmeihanes with

SeOj in amyl alcohol' ''.

Jerzmahoska et al'" obtained simple C-3-derivatives of llavones from the arylidene

derivatives and resublimed SeO^ in dioxane. 3-Aroyinavones have also been prepared from

3-aroyinavanones by subjecting them to SeO, oxidation in dioxane. Thakar and Ingle pre

pared 3-aroyl-2-arylacrylophenones using SeO^ in isoamyl alcohol. Flavones were prepared

by Voigtlander et al"".by heating corresponding llavanones with I in pyridine.

PatiP' reported the synthesis of chlorosubstituted 3-aroyinavones using [,/DMSO

mixture.

In this part, synthesis of 3-aroylflavones from 3-aroyinavanones have been carried

out by oxidation with SeO^ involves a loss of certain amount of product in the process of

removal of selenium from the reaction, this has been therefore avoided using iodine-

dimethylsulphoxide mixture for the conversion of 3-aroyinavanones to 3-aroyinavones.

Experiment No. 13

Preparation of 3-benzoyl-6-methylflavone (5a) from 3-benzoyl-6-methylflavanone (4a) :

A mixture of 3-benzoyl-6-methyinavanone (4a) (0.01 mol, 3.42 g.) and a crystal of

iodine was refluxed in dimethylsulphoxide (20 ml) for 10 minutes. The product was ob-

186

lained on diluting the reaction mixture with water. It was washed with the solution of so

dium thiosulphate (10%) and then with water and llnaliy crystallised from elhanol acetic

acid mixture . m.p. 180°c, yield 75%.

Reaction:

L

DMSO

(4a) (5a)

Properties and constitution of the compound (5a) :

1. The compound (5a) is a creamy white shining crystalline solid melting at IHO'C.

2. TLC : solvent (CCg height 1.9 cm, solute height 1.4 cm, Kl" value = 0.73.

3. The alcoholic solution of these compounds did not give any colouration with leCl, indi

cating the absence of pheolic -OH group. However, it gave yellow colouration with cone.

2 4

4. The compound (5a) formed red colour with Mg/HCl.

5. With bromine water and KMnO^ solution, the compound (5a) showed unsaturation test.

6. The analytical results agreed with the molecular formula C HjgO .

7. Elemental analysis of compound (5a):

Analysis %C %H

Found 80.18 4.62

Calculated 81.17 4.70

Thus, from the analytical results and chemical properties, the compound (5a) was

187

assinged the structure of 3-benzoyl-6-methyinavonc.

orV<S>

(5u)

Experiment No. 14

Preparation of 3-benzoyl-4'-methoxy-6-methylflavone (5b) from 3-benzoyl-4''

methoxyflavanone (4b) :

A mixture of 3-benzoyl-4'-methoxy-6-melhylflavanone (4b) (0.01 mol, 3.72g.) and a

crystal of iodine was refluxed in dimethylsulphoxide (2()ml) for 10 minutes. The product

was obtained by diluting the reaction mixture with water and processed as in Hxpl. No. 13.

The product thus obtained was crystallised from ethanol acetic acid mixture to gel the crys

tals of compound (5b) m.p. 165"C, yield 85%.

Reaction:

V^y DMso j ; 6 \ ^

(4b) (5b)

Properties and Constitution of the compound (5b):

1. The compounds (5b) melted at 165"C.

2. The other properties of the compound (5b) were similar to those given in Ivxpi. No. 13

188

3. Analytical results of the compound (5b) agreed with the molecular formula C, H, () .

4. Elemental analysis of the compound (5b):

Analysis C% H%

Found 77.64 4.71


5. Spectral data:

IR, UV and PMR spectras of the compound (5b) were recorded and showed the fol

lowing results (IR : spectrum No.16 , UV: Spectrum No. 17, PMR: Spectrum No. 18 )

a) The IR spectrum of the compound (5b) (Spectrum No. 16) was recorded and showed

the following absorption bands'** '".

Region Frequency cm' Intensity Correlation

3700-3000

1700-1600

1600-1450

1500-1200

1200-1100

3400

1650

1610

1590

1243

m

m

w

0-H stretching

C=0 stretching

C=0 stretching

C=C stretching

C-O-C stretching in ethers.

b) The UV-VIS spectrum of the compound (5b) (Spectrum No. 17) recorded in CHCl, showed

X max. at 320 nm corresponding to n- it* transition.

c) The PMR spectra of the compound (5b) (Specturm No. 18) recorded in CDCl, showed the

following absorption peaks'*^"''''*'

189

o o CD

O O CD

O O O

O O CM

o o

o o CD

O O CD

O O O

O O lO

o -o o

CD

6 z 2: Z) DC t-U UJ Q. t/1

O

0 0

0 en

0 00

0 0 CD

0 IT)

0 0 CO

0 0 c

0 0

D-^

cc LU

o 2: O 3 in z n UJ

<

o o

o

o 00

o

o U3

O

O

O 00

O CM

Q h C u Q U

S^ecfci-UYrt. M > ' 17 o o

i

• <

o

If)

o CM

in

CM

o CO 00

in O 2

O

in

4 o

o ih

in

in

o i£>

in

lb

o

in

O CO

Chemical Shift Nature of peak No. of Protons types of Protons

2.33

3.78

6.8-8.2

S

S

m

3H

3H

IIH

Ai-CH,

Ar-O-CH,

Ar-H

From the chemical properties, analytical results and spectral data the compound (5b)

was assigned the structure as 3-benzoyl-4'-methoxy-6-methylflavone.

H.

QA-<b>cH3

n<2> (5b)

Experiment No. 15

Preparation of3-benzoyl-2-(2'-furyl)-6-methylchromone (5c) from 3-benzoyl-2-(2'-furyl)-

6-methylchromanone (4c):

A mixture of 3-benzoyl-2-(2'furyl)-6-melhyl-chromanone (0.01 mol, 3.32 g.) and a

crystal of iodine was refluxed in dimethylsulphide (20 ml) for 10 minutes. The product was

obtained by diluting the reaction mixture with water and processed as in expi. No. 13. The

product thus obtained was crystallised from elhanol and acetic acid mixture to get the crys

tals of compound (5c) m.p. 13()-131"C, yield 75%.

190

Reaction :

> DMSO

(4c) (5c)

Properties and Constitution of the compound (5c) :

1. The compound (5c) melted at 13()-13r'C.

2. The other properties of the compound (5c) were similar to these given in expi. No. 13

3. Analytical results of the cornpound (5c) agreed with the molecular formula C,|H, () .

4.Elemental analysis of the compound (5c):

Analysis C% H.%

Found 75.26% 4.02%

Calculated 76.34% 4.24%.

Thus from the chemical properties and analyticaal results, the compound (5c) was

assinged the structure as 3-benzoyl-2-(2'-furyl)-6-melhylchromone.

(5c)

191

Experiment No. 16

Preparation of 3-benzoylflavones (5d)from 3-benzoyl-flavanone (4d) :

A mixture of 3-benzoyinavanone (4d) (0.01 mol, 3.28 g ) and acry.sial of iodine was

reOuxed in dimethylsulphoxide (20 ml) for 10 minules. The produet was obtained by dilut

ing the reaction mixture with water and processed as in lixpt. No. 13. The product thus

obtained was crystallised from ethanol acetic acid mixture, to get the crystals of the com

pounds (5d). m.p. 132"C, yield 15'/>

Reaction :

(4d) (5d)

Properties and Constitution of the compound (5d):

1. The compound (5d) melted at 132"C.

2. The other properties of the compound (5d) were similar to those given in Hxpi. No. 13.

3. Analytical results of the compound (5d) agreed with the molecular formu'la C„H|_j(),.

Thus from the chemical properties and analytical results, the compound (5d) was

assinged the structure as 3-benzoyinavone.

(5d)

192

Experiment No. 17

Preparation of 3-benzoyl-4'-methoxyflavone (Se) from 3-benz.oyl-4'-metho7.yjlavanoe

(4e):

A mixture of 3-benzoyl-4'-mclhoxynavanonc (4c) (o.o 1 mol. 3.58 g) and a crystal DI

iodine was refluxed in dimelhyl-sulphoxidc (2()ml) for 10 minutes. The product was ob

tained by diluting the reaction mixture with water and processed as in lixpi. Mo. 13. The

product thus obtained was crystallised from ethanol and acetic acid mixture to get the crys

tals of the compound (5e), m.p. 137"C.. yield 85%.

Reaction :

DMSO

(4e)

OCH

(5e)

Properties and Constitution of the compound (5e) :

1. The compound (5e) melted at 137"C.

2. The other properties of the compound (5e) were similar to lho.se given m Ivxpi. No. 13 .

3. Analytical results of the compound (5e) agreed with the molecular lormula C^Hj^Oj.

4. Elemental analysis of the compound (5c):

Analysis C% H%

Found 77.12% 4.18


Thus from the chemical properties and analytical results, the compound (5e) was

193

http://lho.se

assinged the slruclure as 3-hcn/,oyI-4-melhoxynav()ne.

(5e)

Experiment No. 1 8

Preparation of 3-benzoyl-2-(2'-furyl) chromone (5f) from 3-benzoyl-2-(2'-furyl)

chromanone (4f):

A mixture of 3-bcnzoyI-2-(2'-riiryl) chromanone (41) (0.01 mol, 3.18 g) and a crysiai

of iodine was relluxed in dimethylsulphoxide (2()ml) for 10 minutes. The product was ob

tained by diluting the reaction mixture with water and processed as in lixpi. No. 13. The

product thus obtained was crystallised from elhaivol and acetic acid mixture to gel the crys

tals of the compound (5f) m.p. 21()"C. yield 757r..

Reaction :

DMSO

(4f) (50

Properties and Constitution of the compound (5f)

1. The compound 5f melted at 21 ()"C.

194

2. The other properties of the compound (50 were similar to those given in !• xpi. No i \

3. Analytical results of the compound (51) agreed-with the molecular formula (,\ H ^,(),.

4. Elemental analysis of the compound (51) :

Analysis C% H%

Found 75.76 3.62


Thus from the chemical properties and analytical results , the compound (51) was

assigned the structure as 3-ben/,oyl-2-(2'-furyl) chn)mone.

(5n

195

Synthesis of Isoxazoles (6) :

Isoxazoles have been usually obiained Irom chalconedihromide and dikcionc' and

alsi) from acetylenic ketones ''" or llavones wiili NH,()H.HCI. Chincholkar and Jamode"

used 3-aroylflavones for the sysnthesis of isomeric isoxa/oles in pyridine and meihanol. .V

furoylchromones have been used for the synthesis of 4-luroylisoxa/.oles in pyridine me

dium Raipuf'*synthesisedor3,5-diarylisoxa/.olesrorm llavones,and NH.OH.HCI meihanol

conlaining Utile piperidine medium. Palil''' reported the synthesis ol 3.5-diaryl-4-

aroylisoxazoles from 3-aroyinavones and NH,.()H.HC1 in l)Ml7piperidine. Deshmukh'

used 2'-hydroxychalconedibromide and NH.OH.HCl in DMSO/pipcridine for the synthesis

of 3,5-diarylisoxazoles. Recently Kedar"" reported the formation o\' 3-5-diaryiisoxa/i>k's

from l-(2-hydroxyphenyl)-3-aryl-1.3-propanediones and NH^OH.HC! in alkaline medium.

• The work presented here deals with the results of action of NH,()H.Ht'! on ''>-

Aroylilavones by using DMSO and little piperidine as a reaction medium.

Experiment No. 19

Action of NHpH.HCl on 3-benzoyl-6-inethylflavone (5a) :

Synthesis of3-(2-hydroxy5-methylphenyl)-4-benzoyl-5-phenylisoxazole (6a):

A mixture of 3-ben/.oyl-6-melhyinavone(5a) (0.01 mol. 3.40 g) and hydroxylamine

hydrochloride {0.02 mol, 1.40 g) was relluxed in dimelhylsulphoxide (DMSO) (30 ml)

conlaining piperidine (0.5 ml) for 3-4 hours. The reaction mixture was poured in water and

acidified with 5()'/r HCI. The .semisolid obtained was triturated with and crystallised lri)m

ethanol to give while shining needles of the compound (6a). m.p. I75"C. yield 55'/(.

196

Reaction :

+ NH,0H.HC1 DMSO

Piperidine H

o OH

O

O

o:

{5a) (6a)

Properties and Constitution of the compound (6a) :

1. TLC studies showed the Rf Value = 0.77 in CC1_,. Solvent height l.H cm . soluic height

1.4 cm.

2. It did not gave any colouration with ethanolic I'cCI, solution hut it was tounci lo soluble

in dil. NaOH solution and gave acetyl derivatives indicating the presence of free phe

nolic OH group.

3. The analytical daiacontliTned the molecular Ibmiula of the compound {6a) U) be C\,H|,(),N.

4. Elemental analysis of the compound (6a) :

Analysis C% H% N%

l-ound 77.54 4.59 4.61 «

Calculated 77.75 4.78 3.94

Discussion ofIR, UV and PMR spectra of the compound (6a) :

The .spectral data of the compound (6a) is as follows

a) IR spectrum :

The IR spectrum of the compound (6a) (Spectrum No. 19) Showed the following

abst)rption bands.

197

Region(cin') Frequency Intensity Correlation

37(M)-3(){)()

3()()()-25()()

1790-1600

1700-1550

3434

2927

16H3

1611

(w,b)

(m)

(s)

(s)

O-H siiciching

C-H sirelching ( aliphatic I'H, group I

C=() sitviching oi(X)l,'li group.

C=N aiiUCM'

(aromalic sireich )

b) UV spectrum :

The UV-VIS specirum of the compound {6a) (spectrum No. 20) showed ^^niax. corre

sponding lo 380 nm, corresponding to n - > n* transition.

c) PMR spectrum :

The PMR spectrum of the compound (6a) (Spectrum No.2l) showed peak as listed

below.

Chemical

Shift in 5

1.6

7.3-8.0

Nature of

Peak

(s)

(m)

No.of

Protons

3H

13H

Types of

Protons

Ar-CH,

Ar-H

Thus from the chemical properties , analytical results and spectral data the compound

198

6 z

3

Q:

( j

to

o-h -» - o c « £ — * - - » - o c o<lJ

o o o

c o

o (ft XI

<

o o in d

o o

220 300 wavelength SPECTRUM NQ-ZD-!

AOO

_ _ J 1—1

E a a

1.

T] — CM

in

CM

6 z

OC H O UJ

a 01 - CD

- 00

CD

(6a) was assigned the slruclure as 3-(2-hy(Jroxy-5-inelhyIphciiyh-4-ben/,()yl-.S-

phenylisDxazole.

.OH

(6a)

Probable Mechanism :

Flavone (5a) on treatmenl with NH,()H.HCI in DMSO and pipcridine medium gave

3.5-diaryl-4-aroylisoxazole (6a). The formaiion of isoxazoleinvolves a niicleophilic 1.2-

addilion of H.NH.OH lo carbonyl group leading to the lormalion ol an adduci. This ihen

io.ses water molecule lo give oxime which under experimenial conditions cycli/es to give ^-

5-dia]'yl-4-aroy[isoxazole.

The dilTereni steps of 1.2-addition type of mechanism are given below :

H,C

OH Qt COPh

Q l^-L<2> ^ HC

OH COPh

O O H ^ - ^

NH,OH

Nk

199

H,C

OH , COPh

H I ^ ^ H H(/ ^

HC \o OH

OH - ^ I

H-N OH HO

f ^ -H,0

NK

Isoxazole

-H,0 HC

OH COPh

\ h

Iniermedialc oximc

Experiment No. 20

Action of NHpH.HCl on 3-benzoyl-4'-methoxy-6-methyl-flavone (5b) :

Synthesis of 3-(2-hydroxy-5-methylphenyl)-4-benzoyl-5-(4-methoxyphenyl)isoxazole

(6b) :

A mixture of 3-benzoyl-4'-melhoxy-6-melhyinavone (5h) (0.01 niol. 3.70 g) and

hydroxyl-amine hydrochloride (0.02 mol, 1.4 g) wa.s relliixed in dimelhyl-.sulphoxide (30

ml) containing piperidine (0.5 ml) for 3-4 hours and processed as in lixpt. No. 19 lo give the

compound (6b), m.p. 163"C, yield 85%.

200

Reaction :

OCH _.0H

DM SO JA^ NROHHCI ^ H,CX/^Cj ^

Piperidine

=0

• oKo) OCH,

(5b) (6b)

Properties and Constitution of the compound (6b): '

1. The chemical properlies of the compound (6b) were found lo be ideniical lo ihose given

in Expl. No. 19.

2. The analytical data of the compound (6b) agreed with the molecular formula t\^H,, 0_,N.

3. Elemental analysis of the compound (6b):

Analysis C% H% N%

Found 74.72 4.83 3.14

Calculated 74.80 4.94 3.63

On the basis of chemical properties analytical results and by analogy with (6a). com

pound (6b) was assigned the structure as 3-(2-hydroxy-5-methyIphenyl)-4-ben/.oyl-5-(4-

methoxyphenyl)isoxazole.

,0H Sy)

H , C \ ^ C — r f " ^ H y — \

(6b)

It has. been observed that the presence of activating melhoxy group at 4-posiiion in

201

jliiwat. ilnmi .^ librarfj

phenyl ring of flavone (5b) increases the yield of ise)xa/.ole (6b). This is due lo ihe electron

donating nature ormethoxy group. This may be attributed lo the increase in electron density

on oxygen of carbonyl group, due to electron How from -OCH^ group. This increa.sed elec

tron density accelarales the process of 1,2-addirion of NH,.()H.HC1 which results in the

formation of an intermediate adduct. This then loses the molecule of water to give oxime

which undergoes cyclizalion and rearrangement to give isoxa/ole (6b).

Reaction Mechanism :

\^<2y^ OCH, -^ H,C

OH O^' COPh

j;-tH.j;-.<g>ocH, /N

H,C

OH Q] COPh

Q l-t-^ôcn,^

NH^.OH

R C

OH Qi COPh

'^-tyC^ÔCH

OH

" ( T O H H O '

COPh

e=:*(3)=ocH3 H,C

OH OH

I ÔPh

T H-N

ÔH HO^ o OCH

-HO

^

202

H,C

OH

N

-Ph

M/^OCH,

-H,0 H,C-'

OH

N

:oph

^OH HO^ 'k 'IcH,

(6b)

Experiment No. 21

Action ofNHflH.HClon 3-benzoyl-2-(2'-furyi)-6-methylflamne (5c) :

Synthesis of3-(2-hydroxy-5-methylphenyl)-4-benzoyl-5'(2'-furyl)isoxaz.ole (6c):

A mixture ol" 3-benzoyl-2-(2'-ruryl)-6-mclhyinav()ne (5c) (0.01 mol. 3.. 0 g) and

hydroxylamine hydrochloride (0.02 mol, 1.4g) was relluxed in dimelhylsulphoxide (30 ml)

containing piperidine (0.5 ml) for 3-4 hours and processed as in lixpt. No. 19 lo give the

compound (6c) m.p. 158"C. yield W%.

Reaction :

H.d .oA-^

O l<2>

(5c)

+ NR.OH.HCl DM SO

Piperidine

• i O j ^ ' c=o

(6c)

Properties and Constitution of the Compound (6c) :

1. The compound (6c) showed the properties similar to those given in lixpi. No. 19.

2. The analytical data of the compound (6c) agreed with the molecualr formula C,|H|X)jN.

203

3. Elemental analysis of the compound (6c):

Analysis C% H% N%

Found 72.92 4.12 4.01

Calculated 73.04 4.34 4.05

On the basis of chemical properties, analytical results and by analogy with (6a) com

pound (6c) was assigned the structure as 3-(2-hydroxy-5-methylphenyl)-4-ben/.oyl-5-(2'-

furyl)isoxazole.

H

H

' c 11 I

N.

C=0

O'

(6c)

Experiment No. 22

Action of NHfiH.HCl on 3-benzoylflavone (5d) :

Synthesis of3-(2-hydroxyphenyl)-4^benzoyl-5-phenyliosxazole (6d):

A mixture of 3-benzoyiriavone (5d) (0.01 mol, 32.6 g) and hydroxylamine hydro

chloride (0.02 mol, 1.4g) wasrefluxed in dimelhyl-sulphoxide (30 ml) containing piperidine

(0.05 ml) for 3-4 hours and processed as in lixpt. No. 19 to give white crystals oi the com

pound (6d) m.p. 146"C, yield 60%.

Reaction :

204

n<o> DMSO

+ NH^OHHCl ^ Piperidine

(5d)

OH

N

=0

-Jko) (6d)

Properties and Constitution of the compound (6d) :

1. The compound (6d) showed Ihe properties similar lo those given in lixpi. No. 19

2. The analytical data of the.compound (6d) agreed with the molecular formula C\,H| (),N.

3. Elemental analysis of the compound (6d)

Analysis C% H% N%

Found 77.12 4.15 4.01

Calculated • 77.41 4.39 4.10

On the basis of chemical properties, analytical results and by analogy with (6a) com

pound (6d) was assigned the structure as 3-(2-hydroxyphenyl)-4-ben/,oyl-5-phenylisoxa/.ole.

,OHIOJ of Xo

(6d)

Experiment No. 23

Action ofNHpH.HCl on 3-benzoyl-4'-methoxyflavone (5e) :

Synthesis of3-(2-hydroxyphenyl)-4-benzoyl-5-(4-methoxy-phenyl) isoxazole (6e)

205

A mixture of 3-benzoyl-4'-methoxytlavone (5e) (0.01 mol 3.56 g) and hydroxylamine

hydrochloride (0.02 mol, 1.4 g) was relluxed in dimelhylsulphoxide (30 ml) containing

piperidine (0.5 ml) for 3-4 hours and processed as in Expt. No. 19 lo give while crystals of

the compound (6e) m.p. 134"C, yield 80%.

Reaction :

\y(OyOCH^ DM.SO ^ O j II — +NH,0H.HC1

Piperidme j - ^ j i ^ o C H ,

(5e) (6e)

Properties and Constitution of the compound (6e) :

1. The compound (6e) showed the properties similar to those given in Hxpl. No. 19

2. The analytical data of the compound (6e) agreed with the molecular formula

23 17 4

3. Elemental analysis of the compound (6e): . «

Analysis C% H% N%

Found 74.02 4.41 3.56

Calculated 74.39 4.58 3.77

On the basis of analytical results, chemical properties and by analogy with (6a) com

pound (6e) was assigned the structure as 3-(2-hydroxyphenyl)-4-hcn/oyl-5-(4-

methoxyphenyl) isoxazole.

206

o H.O

^^J^<o> =0

^ OCH,

(6e)

Experiment No. 24

Action ofNHftH.HClon 3-benzoyl-2-(2'-furyl)flavone (5f) :

Synthesis of3-(2-hydroxyphenyl)'4-benzoyl-5-(2'-furyl)isoxazole (6f) :

A mixture of 3-benzoyl-2-(2'-furyl) flavone (50 (0.01 mol, 3.16 g) and hydioxylamine

hydrochloride (0.02 mol, 1.4g) was refluxed in dimethylsulphoxide (30 ml) containing

piperidine (0.5 ml) for 3-4 hours and processed as in Expt. No. 19 to give the compound (6f)

m.p. 171«C,yield65%.

Reaction

DMSO Ol r=0 ^ ^ C rlrr

Piperidine J - ^ +NH2.OH.HCI ^ \ ^ C O ) Pioeridine J! I

OH ^^•

(50 (60

Properties and Constitution of the compound (6f) :

1. The compound (6f) showed the properties similar to those given in lixpt. No. 19

2. The analytical data of the compound agreed with the molecular formula C,„H|,()^N.

3. Elemental analysis of the compound (5f):

207

Analysis

Found

Calculated

C%

72.39

72.50

H%

3.71

3.92

N%

4.06

4.22

On the basis of analytical results, chemical properties and by analogy with (6a) com

pound (6f) was assigned the structure as 3-(2-hydroxyphenyl)-4-ben/()yl-.'S-(2'-

furyl)isoxazole.

@C"Y^ (60

208

REFERENCES

1. Caradonna C & Stein M L,

2. Stelger N,

3. Okuda T. Kitamura J & Azika K A,

4. Schlubach H H & Repening K,

5. Qulico A , D'Alcotres, G. Stange

& Grunanger P,

6. Krentzberger,

7. Kumai, Chem Indus Ltd Jpn,

8. Ishihara Sangyo Kaisha Ltd Jpn.,

9. Nihon Nohyaky Co. Ltd Jpn,

10. Nissan Chem Indus Ltd Jpn.,

11. Nissan Chem Indus Ltd Jpn.,

12Cecchi L,

13. Sharan,

14. Den Uma, Ashok K Rao,

15. Claisen L,

16. CastellsA&ColombAD,

17. Johnson W S & Shelber W E,

18. Claisen L,

19. Barnes RP&Spriggs AS.

20 Ponizzi L & Strillo-Siena,

21. Claisen L,

I'amiaco Hdn Sci. L , 1960. 674

Chem Ahstr 45. 1951.' 10259.

Proc Gil'u coll phami. 5. 1955. 208.

Liebig'sAnn, 614. 1958.37

(iazzchimital,80, 1950.479.

Chem Ab.str, 92. 1980, 19834464 h.

Chem Abstr, 95, 1981, 62199s.

Chem Ab.str, 99, 1983. i 3999a.

ChemAb.str, 101, 1984. 230516r.

Chem Ab.str, 100, 1984. 5L569li.

ChemAb.slr. 102, 1985.220872a

Chem Abstr, 102, 1985. 2I079y.

Chem Abstr, 112, 1990. 1388662.

ChemAb.str, 114, 1991.

Ber dt Chem Ges, 24, 1891. 3900

J ChemSoc, 18, 1969, I062.-

J Am Chem Soc, 67. 1945. 1745.

BerdtchemGes., 42, 1909. 59.

J Chem Soc, 67, 1945. 134.

Gazzchimilal.73. 1943.335.

Ber dl Chem Ges. 44. 1911. 1961

209

22. Waygand C & Bauier E,

23. Eistart & Market,

24. Claisen L,

25. Quilico Z & Pinizzil L,

26. Quilico Z & Simonetta M,

27. Quilico A,

28. Qulico A & Freri Sigma M,

29. Qulico A & Simonetta M,

30. Qulico A & Simonetta M,

31 Qulico A & Speroni G,

32. Sammour A, Selium M & Hamed A A ,

33. CalbenAT,

34. Kurmel, Philip L, Foderson,

Chrisiain & Buchardt Ole,

35. Roth J M & Schwarz M,

36. Roiche L & Naubauer A.

37. Anspon H A ,

38. Baker W, Harborne J B & Dllis W D ,

39. Pond P J & Shaffslell R G,

40. Alberti C,

41. Grunanger P,

42. Barnes R P and Brandon A,

43. Shenoi R E, Shah R C & Wheeler T S,

LiebigsAnn,459, 1927. 127.

Chem Bcr, 86. 1953.895.

Ber dl Chem Cks, 36. 1903. 3665.

Gazz chim ital. 72, 1942. 458.

ibid, 76, 1946.285.

ibid, 62, 1932,505.

ibid, 76, 1946,3.

ibid, 77, 1947,586.

ibid,76, 1946, 200.

ibid, 76, 1946, 148.

Egypt .1 Chem. 16(2). 1973. 101.

Telrahedran 24(14), 1948. 5059.

Acta chem scand, 22(b), 1968. 287.

Arch pharm, 294. 1961.769.

Z. chem..4(12), 1964.459.

Chem Abstr, 57, 1962, 13618 h.

JChemSoc, 1952, 1303.

.1 Am Chem Soc, 22, 1900,658.

Gazzchimital,97, 19.57,720.

Gazz chim ital, 84, 1954. 359.

.1 Am Chem Soc, 65,1947. 1070.

JChemSoc, 1940,247.

210

44. Barnes R P and Dodson L B,

45. Barnes R P & Sheed J L ,

46. Weggand C & Manning H,

47. Borkhade K T & Marathey M G,

48. Ghiya B T & Marathey M G,

49. Love Richard P & Durenlee R G,

50. Sokolov S D,

51. Arena F ,

52. Perkin,

53. Ibragimov,

54. Nicolaides D N , Kanelakis M A

& Litinas K E ,

55. Elkasaby M A and Salem M A,

56. Thakre K A & Muley R P.

57. Jamode V S,

58. Wadodkar K N,

59. Bellec, Chrislein, Berlin B ,

Golan R, Des Warle S, Mitle P & Viel C,

60. Johnson K M & Stonier R G,

.lAm.soc, 67.1945. 1^2.

J Am Chem soc, 67. 1945. 138.

Ber dt Chem Ges, 59, 1926. 2244.

J scient Industri Res. 218. 1962, 28.

Indian .1 Chem, 8. 1970. 796, .1 scieni,

Industri Res., 218, 1962.28.

Chem Abstr, 92, 1980. 76487 j .

Chem Absir, 80, 1974. 27150n.

Chem Abstr, 83, 1975, 114266k.

Chem Abstr, 85, 1976. 32906w.

Chem Abstr, 84, 1976, I7317r.

Chem Chron, 8(3), 1979, 187.

Indina .1 chem , 19(B), 1980,571.

Indian .1 Chem. 14 (B), 1976. 224.

Ph.D thesis "Synthetic studies of

nitrogen and oxygen heterocyclic

compounds" Nagpur Uni, 1977.

Ph D thesis"Synthesis in heterocyclic

compounds". Nag Uni, 1977.

J Heterocycle Chem. 16(B), 1979,

1957.

.1 Am Chem Soc, 14(c), 1968, 1774.

211

61. Chincholkar M M & Jamode V S

61a. NairSB,

62. Chincholkar M M & Jamode V S

63. Sankyo Co Ltd Japan,

64. Rajnarender E & Rao C,

65. Kakade B S,

66. LohiyaSB&GhiyaBJ ,

67.ElanoVaradrai,

68. Gaggad H L , Wadodkar K N & Ghiya B J,

69. Saraf B D ,

70. Basinski W & Jarzmanowka M,

71. Witezak Z & Krolikowska,

72. Witezak Z,

73. Nair S B & Wadodkar K N,

Indian J Chem, 17(B) 1979.510.

Ph D Thesis "Furylanalogs of substi

tuted llavanoids in the synthesis ol

oxygen and nitrogen heterocyclics".

NagUni, 1986.

ActaCinecia Indica. IXC No. 1.

1983,28.

Chem Abstr, 94, 1981, 103341 g.

Chem Abstr, 99, 1983. 105162 h.

Ph D thesis "Synthesis in heterocyclic

compounds (Role of DMSO as a

solvent)" Nag. Uni., 1983.

Indian J. chem., 26(B). 1987.

873-76.

Chem Abstr, 110, 1989.

Indian J Chem, 24(B), 1985. 1244.

Ph D Thesis "Reactivity ol l-(2-

hydroxyphenyl)-5-phenyl-4-peniene.

1,3-propandedione". Ami Uni, 1988.

Chem Abstr, 91, 1979, 5140 j .

Pol J Chem, 55(1), 1981,89-100.

Chem Abstr, 86, 1977, 43602 r.

Indian J Chem. 21(B). 1982. 573-4.

212

74. Shionogi & Co Ltd Jpn,

75. Shionogi & Ceo Ltd Jpn,

76. Sterling Dreeg Inc,

77. Eguchi C, Vasuda N, Iwagomo H , Takigawa E,

Okutsu M, Onuki J & Nakamiya T,

78. Stevens R V & Albizatt K A ,

79. Grabowask,

8U. Cabre Castellvi,

Sl.OdaKenyo,

82. Malyula N G & Khisamuldinov,

83. Barluenga,

84. Chiriano,

85. Sharanetal,

86. Dannhardi Gerd,

87. Mittal A K & Singhat O P,

88. Zang,

89. Den Uma & Ashok K Rao,

90. Bich, Irena, Slavik, Tomasz,

91. Hallenbach Werner,

ChemAbslr, 101, 1984. 216413 p.

Chem Ahslr, 101, 1984. 206083 s.

Chem Abstr, 98(7). 1983. 107281 i.

Jpn. Kokali Tokkyo Koho. 7.984.592,

197.9.

Chem Abstr, 102. 1985. 62128 1".

Pol. pi 122.81 (ClCo 7d 261/10). 31

Mar, 1984, Appl, 220. 212. 07, Dec

1979 4pp.

ChemAbslr, 107, 1987. 154273 i.

Chem Abstr, 109, 1988, 14951 c.

ChemAbslr, 108, 1988. 150351 c.

Chem Abstr, 108, 1988, 37707 h.

ChemAbslr, 110, 23774 j .

Chem Abstr, 112, 1990. 138866 /..

ChemAbslr, 112, 7409 e.

J. Indian chem soc, LXIII, 1981,

1089-90.

ChemAbslr. 114, 1991.61975.

ChemAbslr, 114, 1991.

Chem Abstr, 119, 1993, 180760 e.

Chem Abstr, 119, 1993. 271147 b.

213

92. Bard M A Z , Barsy M M & Seliuni M

93. Koenig, Latif F M L, Hartmann

Goetz & Norbert,

94. Sonare S S , Doshi A G & Ghiya B J,

95. Lin Show Tao & Yang fu Mey.

96. Venugopaian et al,

97. Hansen et al,

98. Rajput P R.

99. Patil K N,

100. Deshmukh M S,

lOl.KedarRM,

102. D. Alcontres & G Satngo,

Abd lit.. Chem Abslr. 119. 1993.

160174 p.

Chem Abslr, 120, 1994. 1045 p.

Chem Abstr, 120, 1994. 323334 c.

ChemAbsir, 121, 1995. 2.55700 n.

ChemAhsir, 121, 1995.255701 p.

Chem Abslr. 122, 1995. 18747H q.

"Synlhe.sis in nitrogen and oxygen

Heterocyclic compound.s". I'h I)

Thesi.s, Ami Uni, 1993.

"Synthesis and Reactions of 3-Aroyl

chlorollavanoids " Ph 1) thesis. Ami

Uni, 1993.

"Synthesis and study of physico-

chemical aspects of some substituted

Heterocycles, Ph D thesis. Ami

Uni. 1996.

"Synthesis of oxygen - Nitrogen and

Niliogen sulphur Heterocyclic

compounds and their physico-chemi

cal .study", Ph D Ihe.sis. Ami uni. 199K.

Ga/./.chemilal,80. 1950,441.

214

103. Von Kostanecki S & Tambre

104. Naik R M, Mehla A M, Thakur V M,

Jadhav G V & Shah R C,

105. Mehta A M, Jadhav G V & Shah R C.

106.DarierG,

107. Parkin AG,

108. Iyer R N & Venkalaraman K,

109. Mahai H S & Venkataraman K,

110. Iyer R N & Venkataraman K,

111. Parkin A G ,

112 KolheH& Folia

113. FukudaT.,

114.WillianJJ,

115,DimaggioG,

116. Wiley PM,

117. JongebreurG,

J, Ber, 28. 1895.2302.

Proc. Indian Acad Sci. 38A.

1953,31.

Proc. Ind Acad sci. 29A. 1949.

314.

Ber, 27. 1894, 21

JChemSoc, 77, 1900.416.

Proc Ind Acad Sci. 37 A, 1953.

629.

Current Sci (India). 6, 1938,4

50.

Proc Ind Acad Sci, 23A, 1946,

278.

JChemSoc, 73, 1898.666.

Phamiacoi,.lapan, 12.1931,89.

Arch expt. Pathol. Pharmakol,

166, 1932,505.

J Am Pharm Ass Sci, 44, 1955,

404

Chem Ab.str. 48. 19.54.8888.

J Am Chem SCO, 74. 1952.

4359.

Phann Weekblad. 86,1951,661.

215

118. KooJ,

119. Donnelly D, Goochegan R, O' Brien C\

PhilbinE& Wheeler TS ,

120. Schmutz J, Hirt Kunzie F, Eicheenbarger li

& Laucher H,

121 Collie J N&TikleT,

122. BlasdaleWC,

123. Briggs L H , G Locker R H ,

124. Davis C T & Geissman T A ,

125. De Diesbach H & Kramer H,

126. Baker W, Harbome J B & Ollis N D .

127. Gulati K C & Rav J N,

128.AdkinsH&MozingoR,

129. Emilewicz T, Von Kostonecki S & Tambor.

130. Von Kostanecki S & Tambor,

131. Von Kostanecki S & Webel, F

132. BaigelliniG,

133. Czajkowaski J. Von Kostanecki S & Tambor

134. Gulati K C & Vankataraman K ,

135. Raichel L & Henning H G,

136. Fletcher R, Philbin E M, Thornton F D

& Wheeler T S .

137. Simonis H Zangew

.lOrgchcm. 26. 1965.872.

.IMedChem.8, 1965.872.

Helv chim Acta. 36. 1953.620.

JChemSco,75. 1899.710

JAmChemSoc..67.1945.491.

JChemSoc. 1949.2157.

.1 Am Chem Soc..76.1954.3507.

Helv Chim Acia. 28, 1945. 1399.

.IChemSoc. 1952, 1303.

Current Sci (India), 5.1936,75.

J Am Chem Soc. 60. 1938.675.

JBer ,32. 1899.2448.

.1 Ber. 33. 1900.330.

Ber, 34, 1901. 1454.

(Jazz Chim Hal. 451. 1915.69.

.1. Ber. 33. 1900. 1988.

.IChemSoc. 1936,267.

Ann, 621, 1959.72.

TeU-ahedron I^tleis No. 6,1959,9.

Chem, 39, 1926, 1461.

216

138. Chavan J J & Robinson R,

139. Dunne A T M , Gowan J E , Keane J,

O' Kelly B M , O'Sullivan D, Roche M M.

RyanPM&WheelerTS,

140. Lynch H M, O'Tool TM & Wheeler T S,

141. Allan J & Robinson R,

142. Anderson J A Can

143. Baker W, Flamons G F & Winter R,

144. KuhnR&Low

145. Kalff J & Robinson R,

146. Daulofau V & Schopflocher N,

147.WasselyF&MoserGH,

148. Baker W,

149. Zamplen G, Bognar R & Mechner,

150. Rao K V & Seshadari T R,

151. Wawzonak S,

J Chem Soc. 368. 1933.

.IChemSoc, 1950. 1252.

152. Wittig G, Bangert F & Richler H E.

152 a. Baker W,

153. Doporio M L, Gallagher K M, Gowan .1 H,

Hughes A C, Philbin E M , Swain T & Wheeler T S,

.1 Chem Soc, 2063. 1952.

.IChemSoc, 125,1924,2192.

J Research. 7. 1932.285.

.IChemSoc, 1560. 1949.

.1 Ber,77, 1944. 196.

J. ChemSoc, 127. 1925, 1968

Gazz chim ilal, 83, 1953, 449.

Monalsh Chem, .56, 1930,97.

.1 Chem Soc, 956. 19.39.

.IBer, 77,1944,99

Proc Indian Acad Sci. 224,

1945,383. t

In Re Elderfield (Ediior).

Heterocyclic compounds. Vol 2,

P. 229, New york. 1951.

Ann, 446, 1926. 1.55.

.1 Chem,Soc. 1933. 1381

.IChemSoc. 1955.4249.

217

154. Jerzmanweke Z I & Michalske M J,

155. Ruhamann S,

156. SekaR&ProscheG.

157. Simonis H & Remmert P,

158. MentzerC&PillonD.

159. PillonD,

160.TeculaR,

161. Chhabra S C, Gupta S R & Sharma N D.

162. Devi Geela, Kapil R S & Popli S P.

163. Rybertl J & Vaiderrama J,

164. Ahluwalia V K & Rani Nimmi.,

165. Thakare K A & Muley R P,

166. Kiss A, Szabo V, Grishko L G & Khilya V P

167. Ahluwalia V.K.&Sunita.,

168. Kesselkaul L & Von Kostanecki S,

169. Mahal H S, Rai H S & Venkalraman K,

Chem & Ind (I^indon). 1958.132.

Bcr.46, 1913,2188.

Manatch Chem, 69, 1936. 284.

Ber,47, 1914,229.

Comptrnd, 234,1952,444.

Bull Soc.Chim. France. 19.54.9

Bull. SocChim, Prance, 19.59.

423.

Indian J Chem, 16B, 1978,

1079.

Indian J Chem, 17,,. 1979,75.

.1 Rev Lalinoam Chim, 9(4),

1978, 220, Chem Ab.slr, 90,

1970, 1867921".

Indian J Chem, 15B, 1977.

1003. •

IndianJChem,14B. 1976,226.

Khim, Bio Nauki,.3, 1977,231,

Chem Abslr, 87, 1977, 39328J.

Indian J Chem., 14B. 1976,

6821'.

Ber,29, 1896, 1886.

.! Chem Soc, 1936, 866

218

170. Bhardwaj D K, jain R K, MehlaC K

&SharmaGC,

171. Jain A C & Khazanchi R,

172. Matsuura S, linuma M, Ishikawa K

& Kogel K,

173. Ashihana Y, Nagata Y & Kurosawa K,

174. Baker W&GlocklingF,

175. Jerzmahoska Zofia, Podawinski Bohra Roz

176. GiriS& Singh VK,

177. Thakare K A «fe Ingle V N, Indian V N,

178. Meyer-Dayan M, Bodo B, Deschamps-

VallelCMolhoD.,

179. Krupadanama G L D, Shimannarayan G

& Suba Rao , M V ,

180. Mahal H S & Venkatraman,

18.1. Voigtlander H W and Haerlner Harlmul,

Currcni Sci. (India) 4X(9). 1979

381.

Indian J. Chem. 16B, 1978.

1125.

Chem Fharm Bull. 26(1).

1978,305. Chem Absu-, 88.

1978, 1364111.

BullChemSoc. .Ipn. .50(12).

1977, 3298, Chem Ahsu. 88.

1978,74269h.

JChemSoc, 19.50.2759.

Chemi,42, 1968. 7. Chem

AbsU-,7(). 1969, 37612x.

IndianJChem,14B. 1976,135.

IndianJChem,15B, 1977.571.

Teu-ahedran Leu. .36. 1970.

3359. Chem Absu-. 90. 1979.

186732b.

lndianJChem.l'5B. 1977.933.

Curr Sci, 2,1933, 214

Arch Pharm. Weinhein Ger.

316(3). 1983, 219-22; Chem

Ab.sU, 98(6). 1983. 197827c.

219

182. Creewell C J, Runquist O A & Cambell M M, "Spectral analysis of org. CJim-

pounds" Longman, 2nd Hd.. 1972.

183. Dyer J R, "Application of absorption

spectroscopy of organic compounds"

Printice Halls of India, New Delhi,

1971.

184. Dean J A Ed "Langs Hand Book of Chemistry 12th

Hd, Mcgraw Hill, New York

220

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