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Synthesis of indoleFischer's synthesis

NH

NNH

CH3

C - CH3CH3

anhyZnCl2(Acid)

+ NH3

acetonphenyl hydrazone

This the most important method of preparing indole is carried out by heating the phenylhydrazone or subistituted phenylhydrazone of an

aldehyde or ketone with zinc chloride as catalyst .The mechanism is uncertain but a highly favored is that Robinson .According to him acetone

phenyl hydrazone form 2 – methyl indole by first tautomerising the tautomer then undergoing the O – benzidine rearrangement and the

diamine compound so produced eliminating a molecule of ammonia with ring closure

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NH

N

C - CH3H - CH2

NH

NH

C - CH3CH2

H+

C - CH3CH2

NH

NH

H

+CH2

NH

H

C - CH3NH2+

-H+

C - H

NH

H

CH3NH2

-NH3

NH

CH3

[O]

NH

COOH-CO2

NH

Mechanism

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Madelung synthesis

NH

C - CH3

CH3 ONaNH2250 c0

-H2O NH

CH3

2 - methyl indole

It is the cyclisation of O – acetamide toluene by an alkaline reagent

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NH

C - H

CH3 OK.T.butoxide

-H 2O NH

Indole itself is prepared from O – formamide toluene when heated with potassium t-butoxide at 350 cº

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Lipp synthesis

NH2

CH = CH - ClNaOEt

-HCl NH

This is carried out by heating O – aminochlorostyrene with sodium ethoxide

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COOEt

COOEt

CH2 - H

NO2

+NaOEt-EtOH

HCl

CH2

NO2

C = OCOOEt

CH2

NO2

C = OCOOH

ZnCH3COOH

CH2

NH2

C = OCOOH

CH = C - OHCOOH

NH2

-H2O

C - COOHNH

CH

NH

- CO2

Reissert synthesis This is a very good method and is carried out with o- nitrotoluene (or its derivative ) and ethyloxalate as follows .

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x - CH - R | O = C - R'

PhNH2

-XHNH

CH - R

O = C - R'

-H2O

PhNH2 N

H

NH

CH - R

C - R'

- aryl aminoketone

-PhNH2

NH

R'

R

α

|

Bischler's synthesis

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Benzothiophene

Physical properties and structure Thianaphthene (1) also known as benzothiophene was first obtained by difficult synthesis in 1883 and in 1902 it was isolated from coal tar Thianaphthene has little commercial value , but derivatives in the form of thioindigo dyes have great value and have been much investigated Thianaphthene is colourless solid , m.p 32º , bp 220 – 221 .it is best presented as

a resonance hybrid of 1 and charged structure 1a , 1b and 1c in order of decreasing important

S..

S+

-

S+

-

S+

-

1 1a 1b 1c

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SH

CH = CHCl

KOH

S

2 ) - 2 - chlorovinyl (thiophenol

Chemical Reaction The electrophilic substitution of these system is much less regioselective than that of indole(effectively complete selectivity for attack at carbon – 3 ) .for example nitration gives mixture of more than half of the product is the 3 – nitro , 2,4,6 and 7 are also produced

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S

HNO3

S

NO2

+ 2 , 4 , 6 , 7nitro derivative

55 %

3 - nitro benzothiophene

Treatment of benzothiophene with halogene

S

Br2

S

Br

3 - bromo thiophene

S

H

HCH O / H Cl-H2O

S

CH2Cl

3 - Chlor methyl benzothiophene

Chloromethylation

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Reduction : The sulphur – containing ring can be opened in several ways the most useful being desulphurization with Range nickel

S

2,3 - dihydrothionaphthene

S HH

+EtSH

Na , EtOHRanegNiH2

Et

+ H2S

Oxidation Thianaphthene doesn't react with methyl iodide but with hydrogen peroxide in refluxing acetic acid yield a 1,1 – dioxide or sulphone (2)

S

1,1 - dioxo2,3 - dihydrothionaphthane

S

H2O2,ACOH

LiAlH 4

Zn/NaOH100 c0

O2O2

S

(2)1,1-dioxothianhthane

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Addition reaction: Dioxide is much more stable than thiophene 1,1 – dioxide .It under goes a Diels – Alder reaction with it self only at 220 cºSulphur dioxide is lost giving 3 , the structure of wich was proved by conversion to 4

2SO2

(3)

220c0

-SO2Diels - Alder

O2

S

(2)

a)Br2b)Et3N

O2

S

(4)

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The Thianaphthene 1,1 – dioxide also give (5) with butadiene , the 2,3 double bond of (2) has the very interesting property of adding

SO2

+

O2

S

(5)

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Synthetic methodsGeneral method for preparation of benzothiophene and benzofuran

XH+ ClCH 2COOH

-HClH

X

HOC=OCH2

-H2OAlCl 3 X

O

X

OH

Znalkaline

X

chloroacetic acidx = S or O

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XH-HCl

H

X

ClC=OC=O

CoCl|CoCl

+

oxalylechloride

-HCl

X

O

O

3 –Thianaphthene is possibly prepared from ethyl benzene in the vapour phase

2-

CH2CH3 H2SCr2O3/Al2O3 S

H

H

CH2 - CH

H

H

H H S

CHCH

S + 3H2

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4 – I can also be prepared in 71% yield from thiophenol and acetylene at 600 – 650 cº

SH+ CH CH

600 / 650 c0

SH

CH = CH2 Cr2O3/Al2O3

-H2

S

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Li

SH

SCH2

S[CH2CH(OMe)2]2

di(dimethoxyethyl)sulphide

CH(OMe) 2

-2MeOH

Polyphosphoricacid

BrCH2CH(OMe)21,1-dimethoxybromo ethane

thiophenol

S

5 -

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6 – Diels – Alder reaction

malic anhydride

OO

O +S

H2C = H2C

OO

O

S

decarboxylationdehydrogenation

2 - vinyl thiophene

-CO 2-H 2O-H 2 S