Synthesis of indole
Fischer's synthesis
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
CH3
N
H
C - CH3
N
anhy
ZnCl2
(Acid)
N
H
+ NH3
CH3
acetonphenyl hydrazone
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Mechanism
H - CH2
N
H
H
CH2
CH2
C - CH3
N
H+
N
NH
H
H
C - CH3
CH2
C - CH3
-H+
NH2
N +
H
+
N
NH
H
H
C-H
CH
N NH 3
2
H
N
H
C - CH3
COOH
-NH3
[O]
N
H
CH3
-CO2
N
H
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Madelung synthesis
It is the cyclisation of O – acetamide toluene by an alkaline reagent
CH3 O
N
H
C - CH3
NaNH2
250 c0
-H2O
N
H
CH3
2 - methyl indole
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Indole itself is prepared from O – formamide toluene when heated
with potassium t-butoxide at 350 cº
CH3 O
N
H
C-H
K.T.butoxide
-H2O
N
H
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Lipp synthesis
This is carried out by heating O – aminochlorostyrene with sodium ethoxide
CH = CH - Cl
NH2
NaOEt
N
H
-HCl
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Reissert synthesis
This is a very good method and is carried out with onitrotoluene (or its derivative ) and ethyloxalate as follows .
CH2 - H
NO2
COOEt
+
COOEt
CH2
NaOEt
-EtOH
NO2
CH2
HCl
NO2
C=O
COOH
CH = C - OH
COOH
NH2
C=O
COOEt
CH2
Zn
CH3COOH
NH2
-H2O
C=O
COOH
CH
N C - COOH
H
- CO2
N
H
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Bischler's synthesis
H
x - CH - R
|
O = C - R'
O = C - R'
PhNH2
|
CH - R
-XH
N
H
PhNH2
N
C - R'
-H2O
α - aryl aminoketone
N
H
CH - R
R'
-PhNH2
N
H
R
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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
1
-
+
S
1a
+
S
+
S
1b
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1c
8
CH = CHCl
KOH
SH
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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NO2
HNO3
S
+2,4,6,7
nitro derivative
S
55 %
3 - nitro benzothiophene
Treatment of benzothiophene with halogene
Br
Br2
S
S
3 - bromo thiophene
H
Chloromethylation
S
CH2Cl
HCH O / H Cl
S
-H2O
3 - Chlor methyl benzothiophene
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Reduction :
The sulphur – containing ring can be opened in several ways the most useful
being desulphurization with Range nickel
Et
SH +
Na , EtOH
S
H
H
S
Raneg
Ni
H2
Et
+ H2S
2,3 - dihydrothionaphthene
Oxidation
Thianaphthene doesn't react with methyl iodide but with hydrogen
peroxide in refluxing acetic acid yield a 1,1 – dioxide or sulphone (2)
H2O2,ACOH
S
LiAlH4
S
O2
Zn/NaOH
100 c0
S
O2
(2)
1,1-dioxothianhthane 1,1 - dioxo
2,3 - dihydrothionaphthane
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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 cº
Sulphur dioxide is lost giving 3 , the structure of wich was proved by conversion
to 4
220c0
2
S
O2
(2)
-SO2
Diels - Alder
S
O2
(3)
a)Br2
b)Et3N
S
O2
(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
S
O2
+
S
O2
(5)
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Synthetic methods
General method for preparation of benzothiophene and benzofuran
XH
x = S or O
+ ClCH2COOH
H HO
-HCl
X
chloroacetic acid
O
-H2O
AlCl3
C=O
CH2
X
OH
X
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alkaline
X
14
CoCl
+ |
XH
CoCl
2-
-HCl
H Cl
X
C=O
C=O
oxalylechloride
O
-HCl
X
O
3 –Thianaphthene is possibly prepared from ethyl benzene in the vapour phase
CH2CH3
H2S
Cr2O3/Al2O3
S
H
H CH2 - CH
H
H
H
S
H
CH
CH + 3H2
S
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4 – I can also be prepared in 71% yield from thiophenol and acetylene at 600
– 650 cº
+ CH
CH
600 / 650 c0
SH
CH = CH2
SH
Cr2O3/Al2O3
-H2
S
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5CH(OMe)2
S[CH2CH(OMe)2]2
Li
di(dimethoxyethyl)sulphide
Polyphosphoricacid
CH2
S
-2MeOH
S
BrCH2CH(OMe)2
1,1-dimethoxybromo ethane
SH
thiophenol
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6 – Diels – Alder reaction
O
O
O
O
+
S
malic anhydride
H2C = H2C
O
O
decarboxylation
dehydrogenation
S
2 - vinyl thiophene
- CO2
-H2O
-H2
S
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