Note: Descriptions are shown in the official language in which they were submitted.
s
Background of the Invention
1) Field of the Invention
This invention relates to a novel process for the
preparation of indole and derivatives thereof by reacting
an aniline with an ethanolamine.
2) Description of the Prior Art
In the prior art, indole derivatives have long
been prepared by the well-known Fischer indole synthesis in
which phenylhydrazine is reacted with a compound having an
aldehyde group. If the aldehyde compound is other than
acetaldehyde, the aforesaid Fischer indole synthesis can be
.~ 9395
applied to obtain indole derivatives in good yield. How-
ever, if the aldehyde compound is acetaldehyde, no reaction
that yields indole has been believed to take place. In
order to overcome this disadvantage, there has recently
been proposed an improved process which comprises reacting
phenylhydrazine with acetaldehyde at an elevated temperature
of from 300 to 400C in the prçsence of an alumina catalyst
(Japanese Patent Laid-Open No. 76864/'73).
This process surely permits the reaction to
proceed and brings about the formation of indole, but fails
to give a satisfactory yield. Moreover, it is greatly
disadvantageous in that the catalyst has so short a life as
to become totally inactive after 0.5-1 hour's use.
Indole can also be prepared by another process
which comprises reacting o-toluidine with formic acid to form
o-methyl-N-formylaniline and then fusing it together with
potassium hydroxide. However, it is usually impossible to
selectively prepare o-toluidine that is used as the starting
material in this process. That is, the p-isomer is always
formed in an amount equal to or greater than that of the
o-isomer. Thus, treatment of the isomer formed as a by-
product poses a serious problem in the case of industrial
production. Moreover, the handling of solids as in alkali
fusion is troublesome. For these reasons, the aforesaid
process cannot be regarded as suitable for industrial
purposes.
Furthermore, a number of attempts have been made
to synthesize indole from N-~-hydroxyethylamine, but none
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of them are satisfactory from an industrial point of view.
For example, a process which comprises effecting the reaction
at 300C in the presence of an aluminosilicate catalyst
[Zhur. Obschue. Khim., Vol. 24, pp. 671-678 (1954)] gives
only a very low yield of indole. A process which comprises
heating the reactant together with a molten mixed salt
consisting mainly of zinc chloride (Japanese Patent Laid-
Open No. 57968/'73) can give a fairly high yield of indole.
However, this process has the disadvantage of requiring a
complicated procedure, which makes it unsuitable for indus-
trial purposes.
As described above, a number of processes for
the synthesis of indole and derivatives thereof have been
proposed. However, many of them are disadvantageous in
that large amounts of by-products are formed, expensive
compounds are used as the starting materials, and/or lengthy
and complicated procedures are required to obtain the
desired products.
Summary of the Invention
It is an object of the present invention to pro-
vide a one-step process for the highly selective preparation
of indole and derivatives tkereof by using inexpensive
compounds as the starting materials.
. ~...
An aspect of the invention is as follows:
A process for the preparation of indoles which
comprises contacting an aniline of the formula
NH2
~R
where R represents a hydrogen atom, halogen atom,
hydroxyl group, alkyl group or alkoxy group with an
ethanolamine selected from the group consisting of mono-
ethanolamine, diethanolamine and triethanolamine to react
with each other, thereby forming the corresponding indole.
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This reaction can be carried out both in the
liquid phase and in the vapor phase. By way of example,
the process of the present invention makes it possible to
obtain indole by reacting aniline with an ethanolamine and
to obtain 5-methylindole by reacting p-toluidine with an
ethanolamine.
Thus, the process of the present invention has a
number of advantages. First, the anilines and ethanolamines
which can be used as the starting materials are very in-
expensive. Secondly, the preparation of indole or a deriv-
ative thereof from the starting materials can be achieved
in a single step. Thirdly, by-products are scarcely formed
and a very high selectivity is attained, so that indole or
a derivative thereof can be obtained in highly pure form.
Detailed Description of the Invention
The aniline used in the process of the present
invention is a compound of the general formula
NH2
~ R (I)
where R represents a hydrogen atom, halogen atom, hydroxyl
group, alkyl group or alkoxy group. Specific examples
thereof are aniline, o-toluidine, m-toluidine, ~-toluidine,
o-haloanilines, p-haloanilines, _-haloanilines, o-aminophenol,
m-aminophenol, _-aminophenol, o-anisidine, _-anisidine and P-
anisidine.
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~ 3~ 5
The ethanolamine used in the process of the present
invention is a member selected from the gTOUp consisting of
monoethanolamine, diethanolamine and triethanolamine.
Although the process of the present invention can
be carTied out in the absence of catalyst, it is preferably
carried out in the presence of a solid acid catalyst, a
metallic catalyst or activated carbon to obtain the desiTed
product in good yield.
The solid acid catalysts which can be used in the
process of the present invention fall under the following
three categories:
(1) Catalysts containing an oxide OT hydTOXide
(hereinafter referred to as the catalytic substance (1)) of
at least one element selected from the group consisting of
Si, Al, B, Sb, Bi, Sn, Pb, Ga, Ti, ZT, Be, Mg, Y, Ag, Zn,
Cd and the lanthanides. Specific examples of the catalytic
substance (1) are CdO, ZnO-Sb20, PbO2, A1203-B203, SiO2-CdO,
2 2 3' 2 Mg0, Ti02-Sn02, TiO2-Zr0 CdO Bi
SiO2-Y203, SiO2, Bi203-BeO, SiO2-Ga203, SiO2-La203, SiO2-
Ce203, SiO2-ZnO-AgO, Si02-MgO-Cu0 and the like.
(2) Catalysts containing a sulfide or selenide
(hereinafteT refeTTed to as the catalytic substance (2)) of
at least one element selected from the group consisting of
Pd, Pt, CT, Fe, Ni, Co, Zn, Mo, Cd and W. Specific examples
of the catalytic substance (2) are PdS, PtS, CTS, FeS, NiS,
CoS, ZnS, MoS , CdS, WS2, ZnSe, CdSe and the like.
(3) Catalysts containing an inorganic acid salt
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(hereinafter referred to as the catalytic substance (3)) of
at least one element selected from the group consisting of
Fe, Tl, Ca, Mn, Bi, Sr, Y, Al, Zn, Cd, Ni, Mg, In, Be, Co,
Ga and the lanthanides. The useful inorganic acid salts
include halides, carbonates, nitrates, sulfates, phosphates,
pyrophosphates, phosphomolybdates and silicotungstates, and
specific examples of the cataly~ic substance (3) are ferric
sulfate, thallium sulfate, calcium sulfate, manganese sulfate,
bismuth sulfate, strontium sulfate, yttrium sulfate, cadmium
7/~ J7
; bromide, ~1~*~ sulfate, zinc sulfate, nickel sulfate,
cadmium chloride, magnesium sulfate, indium sulfate,
beryllium sulfate, cadmium nitrate, cobalt sulfate, zinc
aluminum sulfate, magnesium chloride, cadmium sulfate,
cadmium phosphate and the like.
The metallic catalysts which can be used in the
process of the present invention include catalysts containing
at least one element (hereinafter referred to as the catalytic
substance (4)) selected from the group consisting of Cu, Ag,
Pt, Pd, Ni, Co, Fe, Ir, Os, Ru and Rh.
f The solid acid catalysts and metallic catalysts
which are usable in the process of the present invention can
be prepared by any suitable methods that are known in this
field of art. More specifically, solid acid catalysts
falling under the category of the catalytic substance (l)
can be prepared, for example, by hydrolyzing a water-soluble
salt of the principal constituent element of the desired
catalyst to form its hydroxide and then drying and calcining
the resulting gel, or by pyrolyzing an easily decomposable
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salt of the principal constituent element of the desired
catalyst in air.
Solid acid catalysts falling under the category of
the catalytic substance (2) can be prepared, for example, by
adding sodium sulfide or potassium selenide to a water-soluble
salt of the principal constituent element of the desired
catalyst or by contacting the pPincipal constituent element
of the desired catalyst or a salt thereof with hydrogen
sulfide gas or hydrogen selenide gas.
Metallic catalysts falling under the category of
the catalytic substance (4) can be prepared, for example,
by reducing a salt, hydroxide or oxide of the principal
constituent element of the desired catalyst by means of a
reducing agent such as hydrogen, formalin, formic acid,
phosphorous acid, hydrazine or the like.
In the process of the present invention, the above-
described catalytic substances (1), ~2), (3) and (4) may be
used alone or in admixture. Moreover, these catalytic
substances and mixtures thereof may be used as such or in
the form of supported catalysts. Although any carriers that
are in common use for this purpose can be used, diatomaceous
earth, pumice, titania, silica-alumina, alumina, magnesia,
silica gel, activated carbon, activated clay, asbestos and
the like are used in typical cases. Supported catalysts can
be prepared by supporting the above-described catalytic
substances on these carriers according to any conventional
techniques. No particular limi-tation is placed on the amount
of catalytic substance supported on the carrier. Usually,
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depending on the type of carrier used, any suitable amount
(for example, from 1 to 50%) o-f catalytic substance may be
supported thereon.
In addition, various types of activated carbon
can be used in the process of the present invention. They
include, for example, products made from coconut shell,
wood, sawdust, lignin, coal, blpod charcoal, bone charcoal,
petroleum carbon and the like. They are commercially
available in powdered form, in crushed form, or in shaped
form (for example, in the shape of globules or cylinders).
However, no particular limitation is placed on the form of
activated carbon used.
Among the solid acid catalysts falling under the
category of the catalytic substance (3), the sulfates and
particularly cadmium sulfate are preferred for the purpose
of obtaining the desired product in good yield. Among the
solid acid catalysts falling under the category of the
catalytic substance (2), platinum sulfide and palladium
sulfide are particularly preferred. Among the metallic
catalysts falling under the category of the catalytic
substance (4), Ag is preferred.
Although the process of the present invention can
be carried out in the vapor phase, the liquid phase or a
mixed vapor-liquid phase, it is usually carried out in the
vapor phase. Where the process of the present invention is
carried out in the vapor phase, a fixed-bed, fluidized-bed
or moving-bed reactor can be used to effect the reaction by
heating the vapors of an aniline and an ethanolamine in the
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~9~9~
presence or absence of a catalyst. In this case, various
inert gaseous substances may coexist as diluents for the
vapors of the starting materials. The useful inert gaseous
substances include, for example, nitrogen gas, carbon dioxide
gas, water vapor, and the vapors of compounds that are inert
to this reaction. Moreover, hydrogen gas or a hydrogen-
containing gas may be used as a diluent.
The use of hydrogen gas or a hydrogen-containing
gas is especially suitable for the purpose of maintaining
the activity of the catalyst.
Similarly, owing to its ability to suppress the
decomposition of the ethanolamine over 'he catalyst, the use
of water vapor is suitable for the purpose of maintaining
the activity of the catalyst and enhancing the yield of the
desired product.
The amounts of aniline and ethanolamine fed to the
reactor should be such that from 0.01 to 5 moles and prefer-
ably from 0.05 to`2 moles of the l" -glycol is provided for
each mole of the aniline. If the amounts are outside this
range, a reduction in yield will be caused and/or large
amounts of by-products will be formed. These starting mate-
rials are fed, after being vaporized in advance or directly
in liquid form, to the reactor at a liquid space velocity
of from 0.01 to 5 liters/liter of the catalyst/hour.
The process of the present invention is carried out
at a reaction temperature in the range of from 200 to 600C
and preferably from 250 to 500C. If the reaction temper-
ature is lower than 200C, the reaction can hardly proceed,
~1~939S
while if it is higher than 600C, undesirably large amounts
of by-products will be formed.
The reaction pressure may be superatmospheric,
atmospheric or subatmospheric.
Where the process of the present invention is
carried out in the liquid phase or a mixed vapor-liquid phase,
the reaction is effected by heating a mixture of an aniline
and an ethanolamine in the presence of at least one member
selected from the above-described catalysts. In this case,
various inert gaseous substances and/or solvents may coexist
as diluents for the starting materials. The useful inert
gaseous substances include, for example, nitrogen gas, carbon
dioxide gas, water vapor and the vapors of compounds that
are inert to this reaction. The useful solvents include,
for example, benzene, toluene, xylene, methanol, ethanol,
isopropanol, dioxane, dimethylformamide, dimethyl sulfoxide,
pyridine, N-methylpyrrolidone, trimethylamine, diethylamine,
triethylamine, tripropylamine, tributylamine, diphenylamine,
triphenylamine and other organic solvents.
In the case of liquid-phase reaction, the process
of the present invention can be carried out in a fixed-bed,
fluidized-bed or moving-bed reactor or in a rotary or
continuous reactor for liquid-phase reactions. However, no
particular limitation is placed on the type of reactor used.
The amounts of aniline and ethanolamine used as
the starting materials for this reaction should be such that
from 0.05 to 5 moles and preferably from 0.1 to 2 moles of
the ethanolamine is provided for each mole of the aniline.
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395
No particular limitation is placed on the amount
of catalyst used for this reaction. However, the catalyst
is generally used in an amount of from 0.01 to 20 g and
preferably from 0.1 to 10 g of the active component thereof
per mole of the aniline used as one of the starting materials.
The reaction temperature should be in the range of
from 200 to 500C and preferably from 250 to 400C. If the
reaction temperature is lower than 200C, the reaction can
hardly proceed, while if it is higher than 500C, undesirably
large amounts of by-products will be formed.
The reaction pressure may be superatmospheric or
atmospheric.
¦ In various embodiments of the present invention,
indole or a derivative thereof can readily be ~btained in
pure form by isolating it from the reaction product according
to any conventional technique such as distillation.
The present invention is further illustrated by
the following examples.
Example 1
A 25-mm flow reactor made of Pyrex glass was
packed with 50 mQ of a palladium-carbon catalyst in cylin-
drical form (having a Pd content of 0.5%). The front end
of thi~s reactor was connected with a feed inlet pipe and
a gas inlet pipe to form a feed vaporization zone, while the
rear end thereof was connected with a receiver by way of an
air-cooling zone. In the reaction zone, the internal
temperature of the reactor was kept at 325C. After the
~, ~
I t~c./J,e ~r7~r/~ - 11 -
~ ~ ~9 39 5
catalyst was reduced by passing hydrogen gas through the
reactor -for about 1 hour, a mixture consisting of 9.3 g (0.1
mole) of aniline and 6.1 g (0.1 mole) of monoethanolamine
was introduced thereinto through the feed inlet pipe at a
liquid space velocity of 0.1 liter/liter of the catalyst/hour.
At the same time, nitrogen gas at atmospheric pressure was
passed therethrough in an amoun~ of 10 moles per mole of the
aniline used as one of the starting materials. The reaction
product withdrawn from the reactor, condensed and collected
in the receiver was analyzed by gas chromatography. This
revealed that 7.1 g of indole was obtained in a 60.5% yield
based on the aniline and accompanied with very small amounts
of by-products.
Example 2
Reaction was carried out in the same manner as
described in Example 1 except that various ethanolamines
were used in place of the monoethanolamine. The type and
amount of ethanolamines used and the results thus obtained
are summarized in Table 1.
,~ ~
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~9~5
,
.,
Table 1
.1
.. j Ethanolamine ! Yield of Indole
., Run I I AmountAmounti Percentage
ll No. j Type I ( ) I Based on
! ~ g mole g ! Aniline
ll , l
1' 1 Diethanolamine 9.3 0.1 ~ 7.5 63.4
l 2 Triethanolamine 7.5 0.05 4.2 42.4
! 3 Diethanolamine 5.3 0.05 6 5 55 6
Triethanolamine 4.5 0.03 .
, 4 Monoethanolaminel 6.1 0.1
. Diethanolamine 5.3 0.05 8.3 70.6
" Triethanolamine 4.5 0.03
.1
Example 3
.j
Reaction was carried out in the same manner as
described in Example 1 except that 6.1 g (0.1 mole) of
monoethanolamine or 9.3 g (0.1 mole) of diethanolamine was
ùsed in combination with a variety of catalysts. The types
of ethanolamines and catalysts used and the results thus
obtained are summarized in Table 2.
i Table 2
¦ Yield of Indole
No ~ amine* Catalyst Amount ¦ Based on
M Pd-CaC03 (with a Pd 5.7 49.1
content of 5%)
6 D Ditto 6.7 57.5
7 M Pt-C (with a Pt 5.8 ¦ 49.4
content of 0.5%)
~: 8 D Pt-silica gel (with a 6.1 52.3
, ~ Pt content of 5%)
',
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395
Table 2 (Cont'd)
_ Yield of Indole
RNuOn amine* Catalyst Amount Percentage
l (g) , Aniline
'I 9 j D ! Rh-alumina (with an Rh I 3.0 25.4
content of 5%) ~
I M Os-C (with an Os content¦ 3.8 32.8
of 5%)
l 11 ~ D Ditto l~ 4.6 1 39.6
i 12 ! D J Ir-asbestos (with an Ir 1 2.8 1 23.7
! i ~ content of 5%)
,~ l13 M I Ru-alumina (with an Ru 1~ 2.3 1 19.6
I content of 5%)
¦14 D ¦Ni-diatomaceous earth 3.4 ~ 29.3
(with an Ni content of I ¦
¦ DI Co-diatomaceous earth ~ 3.5 ~ 29.6
with a Co content of
~16 ¦ MFe-diatomaceous earth I 2.7 23.1
¦ (with an Fe content of I
50%)
¦17 I MCu-C (with a Cu content ~ 5.6 . 48.2
I I of 5%)
; ¦18 ~ D Ditto ~, 5.2 ~ 44.5
19 M ¦ CU-si2 (with a Cu ' 5.2 ; 44.3
content of 5%) ¦ ~ I
D Ditto ~ 5.1 , 43.6
. 21 ~ MAg-C (with an Ag content¦ 4.4 37.7 ¦ ,
of 1%) 1 ~ ;
22 D¦ Au-C ~with an Au content~ 4.0 34.0
. 23 I M ~ ZnC12(with a ZnC12 I 5.5 I 47.0
. ~ content of 20%) i
, 24 ~ D ~ Ditto l 6.1 52.5
ll
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I Table 2 (Cont'd)
i:
_ Yield of Indole
~un ~e ~ Catalyst Amount Based on
¦ M ~ ZnSO4-C ~with a ZnSO4 5.7 48.7
¦ content of 5%) ~
26 ¦ M ' Zinc phosphate ~ 5.5 46.8
27 I D I Ditto 6.0 51.7
28 ¦ M ¦ CdC12-CaC12 (with a , 6.1 51.9
I CdC12 content of 50%)
29 M ~ CdSO4 ' 6.8 58.0
D ! Ditto ¦ 7.1 60.3
31 D I CdSO4-C (with a CdSO4I 6.6 56.6
' content of 5%)
32 D ~ Cadmium phosphate~ 6.5 55.2
33 D ~ Magnesium pyrophosphate I 7.2 61.4
34 D MgO-C (with an MgO 7.7 65.5
_ content of 5%)
*M stands for ethanolamine and D for diethanolamine.
Example 4
Reaction was carried out in the same manner as
described in Example 1 except that granular activated carbon
~ was used in place of the Pd-C catalyst, 6.1 g (0.1 mole) of
I monoethanolamine or 9.3 g (0.1 mole) of diethanolamine was
used as the ethanolamine, and the reaction temperature was
raised to 400C. When monoethanolamine was used, 2.7 g of
indole was obtained in a 23.5% yield based on the aniline.
Similarly, when diethanolamine was used, 2.9 g of indole
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was obtained in a 24.5% yield based on the aniline.
Example 5
¦ Reaction was carried out in the same manner as
described in Example 1 except that a Pd-C catalyst (having
a Pd content of 5%) was used in place of the Pd-C catalyst
(having a Pd content of 0.5%), hydrogen gas was used in
place of the nitrogen gas, and 6.1 g (0.1 mole) of mono-
ethanolamine or 9.3 g (0.1 mole) of diethanolamine was used
as the ethanolamine. When monoethanolamine was used, 7.7 g
, of indole was obtained in a 66.0% yield based on the aniline.
Similarly, when 7.8 g of indole was obtained in a 66.7%
yield based on the aniline.
Example 6
Reaction was carried out in the same manner as
described in Example 1 except that various combinations of
anilines and ethanolamines were used. The types of aniline
and ethanolamines used and the results thus obtained are
summarized in Table 3.
,, ,
, I .
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. . .
~939S
Table 3
; l Yield of Product
;RuOn. Aniline* Ethanol-¦ Type of Amount Based on
. I ~g) Aniline
T M 5-Methylindole 1.6 12.4
36 T D Ditto 1.8 13.9
. 37 A M 5-Methoxyindole 1.7 11.9
38 A D Ditto 2.0 13.3
*T stands for 10.7 g ~0.1 mole) of ~-toluidine
and A for 12.3 g (0.1 mole) of ~-anisidine.
**M stands for 6.1 g (0.1 mole) of monoethanolamine
and D for 9.3 g (0.1 mole?.~of diethanolamine.
Example 7
Into a 200-mQ autoclave made of a titanium alloy
and fitted with a stirrer were charged 93.1 g (1 mole) of
aniline, 10.6 g (0.1 mole) of diethanolamine, and 1 g of
a palladium-carbon catalyst in powder form (having a Pd
content of 0.5%). After the autoclave was purged with
nitrogen gas and filled therewith at a pressure of 5 kg/cm ,
reaction was carried out at 300C for 30 minutes with
stirring. After completion of the reaction, the catalyst
was separated from the reaction mixture by filtration and
the resulting reaction product was analyzed by gas
chromatography. Furthermore, the reaction product was
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~ ~ ~9395
subjected to distillation and the formation of indole was
confirmed by IR and NMR spectroscopy. This revealed that
4.4 g of indole was formed in a 38.0% yield based on the
diethanolamine and accompanied with a small amount of
indoline formed as a by-product.
Example 8
Cadmium sulfide in powder form was compressed and
then crushed to particles. A 10-mm flow reactor made of
PyTex glass was packed with 5 mQ of the particles. The
front end of this reactor was connected with a feed inlet
pipe and a gas inlet pipe to form a feed vaporization zone,
while the rear end thereof was connected with a receiver
by way of an air-cooling zone. In the reaction zone, the
internal temperature of the reactor was kept at 325C.
Then, a mixture consisting of 1 mole of aniline and 0.2 mole
of monoethanolamine was introduced thereinto through the
feed inlet pipe at a liquid space velocity of 0.1 liter/liter
of the catalyst/hour. At the same time, nitrogen gas at
atmospheric pressuTe was passed therethrough in an amount of
10 moles per mole of the aniline used as one of the starting
materials. After the reaction was carried out for 3 hours,
the resulting reaction product was analyzed by gas
chromatography. This revealed that indole was obtained in
a 55% yield based on the monoethanolamine and accompanied
with very small amounts of by-products.
e ~ ~G~ rk
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~9~95
;
Example 9
~ Reaction was carried out in the same manner as
; described in Example 8 except that various catalysts were
used in place of the cadmium sulfide. The results thus
obtained are summarized in Table 4.
,,,
,~ Table 4
i
Run No. Type of Catalyst Yield of Indole (%)
39 ZnS 30
40 ZnSe 15
41 I CdSe I 52
. 42 ¦ SrSO4 ~ 12
43 NiSO4 6H2 1 20
44 r~gSO4 7H2O ~ 26
BeSO4 7 2 38
46 CoSO4 7H2O 40
47 MgC12 6 2 42
;
.Example 10
The procedure of Example 8 was repeated except
that 5 mQ of glass beads having a diameter of 2 mm was used
in place of the catalyst of Example 8. As a result, indole
was obtained in a 1% yield. Then, the same procedure was
repeated once more at a reaction temperature of 500C to
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.~4~3~35
I obtain indole in a 6% yield.
,
Example 11
Using the catalyst of Example 8, reaction was
carried out for 27 hours in the same manner as described in
Example 8. The reaction mixture collected between the start
of the reaction and 3 hours afte~ that (hereinafter referred
to as reaction mixture A) and the reaction mixture collected
between 24 hours and 27 hours after the start of the reaction
(hereinafter referred to as reaction mixture B) were analyzed.
Thls revealed that the yield of indole was 56% for reaction
ixture A and 19~ for reaction mixture B.
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