PROCESS FOR PRODUCING PYRIDINES SUBSTITUTED AROMATICALLY OR HETEROAROMATICALLY IN THE 3 POSITION

PROCEDE DE PRODUCTION DE PYRIDINES SUBSTITUEES AROMATIQUEMENT OU HETEROAROMATIQUEMENT EN POSITION 3

English Abstract

ABSTRACT OF THE DISCLOSURE
A process for the production of a pyridine which is
aromatically or heteroaromatically substituted in the 3-position
is disclosed wherein the process comprises reacting an aliphatic
oxo compound which contains an unsaturated carbon bond adjacent
to the oxo group with an aliphatic-aromatic or aliphatic-heteroaro-
matic aldehyde and with ammonia in the gas phase in the presence
of n dehydrating and dehydrogenating catalyst at a temperature in
the range of from 250 to 550°C. The pyridines can be produced
in high yields from readible available starting substances and
are important intermediate products for the production of
medicaments, plant protection agents and plastics.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the production of a pyridine which
is aromatically or heteroaromatically substituted in the 3-
position which corresponds to the following general formula:-
<IMG>
wherein Rl,R2, and R3, which may be the same or different,
represent hydrogen or lower alkyl groups R4 represents an aromatic
or heteroaromatic ring which may be substituted one or more times
by cyano groups or lower alkyl groups and n represents a number
of from 0 to 6, which comprises reacting an aliphatic oxo
compound which contains an unsaturated carbon bond adjacent to
the oxo group corresponding to the following general formula:-
<IMG> I
where R1, R2 and R3 are as above with an aliphatic-aromatic or
aliphatic-aromatic or aliphatic-heteroaromatic aldehyde
corresponding to the following general formula:-
0 = CH - CH2 - (CH2)n - R4
where R4 and n are as above and with ammonia in the gas phase in
the presence of a dehydrating and dehydrogenating catalyst at
a temperature in the range of from 250 to 550°C.
2. A process as claimed in Claim 1, wherein the
reaction is carried out at a temperature in the range of from
300 to 500°C.
3. A process as claimed in Claim 2, wherein the
reaction is carried out at a temperature in the range of from
350 to 450°C.
4. A process as claimed in Claim 1, 2 or 3, wherein
16

aluminium silicate is used as a catalyst.
5. A process as claimed in Claim 1, 2 or 3, wherein
compounds of the elements A1, F and O which additionally contain
at least one element of the Second, Third or Fourth Group of
the Periodic System and which have been pretreated at a tempera-
ture of from 550 to 1200°C are used as catalysts.
6. A process as claimed in Claim 1, 2 or 3, wherein
compounds of the elements Al, F and O which additionally con-
tain at least two elements of the Second, Fourth, Fifth or Sixth
Group of the Periodic System and which have been pretreated at
a temperature of from 550 to 1200°C are used as catalysts.
7. A process as claimed in Claim 1, 2 or 3, wherein
compounds of the elements Al, F and O which additionally con-
tain at least one element of the Second Main Group of the Peri-
odic System and which have been pretreated at a temperature of
from 550 to 1200°C are used as catalysts.
8. A process as claimed in Claim 1, 2 or 3, wherein
the oxo compound (I) is used in a quantity of from 1 to 5 moles
per mole of aldehyde (II).
9. A process as clalmed in Claim 1, 2 or 3, wherein
ammonia is used in a quantity of from 1 to 20 moles per mole of
aldehyde corresponding to the following general formula II.
10. A process as claimed in Claim 1, 2 or 3, wherein
at least one inert gas is introduced.
11. A process as claimed in Claim 1, 2 or 3, wherein
the reaction is carried out in a fluidised bed and the oxo
compound corresponding to the general formula I and the aldehyde
corresponding to the general formula II are introduced separately
from the ammonia.
12. A process as claimed in claim 1,in which the
17

oxo compound I has the general formula
<IMG>
wherein R1, R2 and R3 are hydrogen or an alkyl group having 1 to
6 carbon atoms at least one of R1, R2 and R3 being an alkyl group.
13. A process as claimed in claim 12 in which the alkyl
group has 1 or 2 carbon atoms.
14. A process as claimed in claim 12 or 13 in which
the aldehyde has the formula
o = CH - CH2 - (CH2)n R4
where R4 is an aromatic or heteroaromatic ring which may be
substituted by cyano groups or alkyl groups having 1 to 6 carbon
atoms and n is a number from 0 to 6.
15. A process as claimed in claim 12 or 13 in which the
aldehyde has the formula
O = CH - CH2 - (CH2)n R4
where R4 is an aromatic or heteroaromatic ring which may be
substituted by cyano groups or alkyl groups having 1 or 2 carbon
atoms and n is 0 or 1.
16. A process as claimed in claim 12 or 13 in which
the aldehyde has the fomula
<IMG>
where n is 0 to 6.
17. A process as claimed in claim 12 or 13 in which
the aldehyde has the formula
<IMG>
where n is 1 or 2.
18

Description

1~L2Z986
This invention relates to a process for the
production of pyridines which are aromatically or
heteroaromatically substituted in the 3-position.
These substituted pyridines are important intermediate
productæ for the production of medicaments, plant
protection agents and plastics.
It is known that 3-phenyl pyridine can be
produced from 4-phenyl isoquinoline by oxidising
the 4-phenyl isoquinoline and decarboxylating the
3-phenyl pyridine-4,5-dicarboxylic acid formed
(Ber. 93 (1960), 1740 to 1745). 3-Phenyl pyridine
can also be obtained from 3-bromopyridine and
cyclohexanone. The 3-bromopyridine is converted
with butyl lithium into 3-pyridyl lithium, and the 3_
pyridyl lithium thus obtained is reacted with
cyclohexanone to form 3-(1'-cyclohexenyl)-pyridine
which is then reduced (J.Org.Chem. 25 (1960), 366
to 371). It is also known that the reduction of
3-benzoyl pyridine with hydroidic acid gives 3-benzyl
pyridine (8er. 36 (1903), 2711 to 2712). 3-Benzyl
pyridine is also obtained by reacting pyridine with
lithium aluminium hydride to form lithium-tetrakis-
(N-dihydropyridyl)-aluminate and further reactin~
the aluminate thus obtained with benzyl chloride
(J.Am.Chem.Soc. 93 (1971),1294 to 1296). It is also

i 3
known that the reaction of nicotinoyl peroxide with
benzene gives 3-phenyl pyridine and, with toluene,
3-tolyl pyridine (J.Chem.Soc. 1958, 1294 to 1296).
3-Phenyl pyridine is also obtained by diazotising
3-aminopyridine in the presence of benzene. Where
substituted 3-~amonopyridines and/or substituted
benzenes are used, correspondingly substituted
3-phenyl pyridines are obtained (German Offenlegung_
sschrift No. 1,810,822). Finally, 3-phenyl pyridine
is obtained by coupling 3-halogen pyridine ~nth
phenyl magnesium halide in the presence of di-
chloro-bis-(triphenyl phosphine)-nickel (II) as a
catalyst. In this case, too, the use of substituted
starting substances gi~es the correspondingly
substituted 3-phenyl pyridines, such as 4-methyl-
3-phenyl pyridine and 4-methyl-3-benzyl pyridine
(J. Heterocycl.Chem. 12 (1975), 443 to 444).
The processes are not suitable for working
on a commercial scale. They are expensive and
difficult to handle and give unsatisfactory yields.
In addition, the starting substances required can
only be obtained with difficulty in several cases.
A process for the production of pyridines
which are aromatically or heteroaromatically
substituted in the 3-position has now been found,
wherein the process comprises reacting an

. l~LZ29~6
-- 4 --
aliphatic oxo compound which contains an unsaturated
carbon bond adjacent to the oxo group with
a~ aliphatic-aromatic or aliphatic-heteroaromatic
~ldehyde and with ammonia in the gas phase at a
temperature of f-rom 250 to 550C in the presence of
a dehydrating and dehydrogenating catalyst.
In this process, the pyridines which are aromatically
or heteroaromatically substituted in the 3-position
are produced from simple, readily available substances
in a one-step reaction. High yields are obtained. In
contrast to conventional processes, the process
according to the present invention is eminently
suitable for working on a commercial scale.
According to one embodiment of the present
invention, oxo compounds corresponding to the
following general formula:-
O = C - C = C~
Rl R2 R3
wherein Rl, R2, and R3, which may be the same or
different, represent hydrogen or optionally branched
lower alkyl groups preferably containing from 1 to 6,
more particularly 1 or 2 carbon atoms, either Rl or R2
or R3 representing an alkyl group of this type, are
reacted with aliphatic-aromatic or aliphatic-

---" llZ~86
- 5-
heteroaromatic aldehydes corresponding to the
following general formula:-
0 = CH - CH2 - (CH2)n - R4 II
wherein R4 represents an aromatic or heteroaromatic
ring optionally substituted one or more times by
cyano groups or lower al~yl groups preferably
containing from 1 to 6, more particularly, 1 or 2
carbon atoms and n represents a number of from n to 6,
particularly 0 or 1, and with ammonia to form pyridines
~hich are aromatically or heteroaromatically
substituted in the 3-position and which correspond
to the following general formula:-
. ,R3
R4 - (CH2)n - C "~ ~C - R2 III
HC C - R
N ~ ;
wherein Rl, R2, R3, R4 and n are defined as above.
Suitable oxo compounds are, for example, ethyl
vinyl ketone, 3-penten-2-one, preferably methacrolein,
crotonaldehyde, methyl vinyl ketone and, in particnlar,
acrolein.
.Suitable aliphatic-aromatic aldehydes are, for
example, pyridyl-2-acetaldehyde, pyridyl-3-
acetaldehyde, pyridyl-4-acetaldehyde, pyridyl-2-
~) or aliphatic-heteroaromatic

:~2Z~86
propionaldehyde, pyridyl-3-propionaldehyde, pyridyl-
4-propionaldehyde,thiophene-2-acetaldehyde,
thiophene-3-acetaldehyde, thiophene-2-propionaldehyde,
thiophene-3-propionaldehyde and particularly
phenylacetaldehyde and 3-phenyl propionaldehyde.
The reaction conditions, such as temperature
and pressure, the quantitative ratios between the
substances to be reacted and the residence times are
optionally interdependent to a certain extent and
are optionally governed by the type of substances
to be reacted and by the type of catalyst used.
In general, the reaction is carried out at a
temperature in the range of from about 250 to 550C.
In most cases, a temperature of from about 300 to
500C is preferred, a temperature in the range of
from 350 to 450C being particularly preferred. It
is advantageous to work under a pressure of from
about 1 to 4 bars, although the reaction may also
be carried out under lower or hi~her pressures.
To enable simple apparatus to be used, however, it
is best not to apply significantly deviating pressures
'rhe quantitative ratios between the o~o compound
(I) and the aldehyde (II) may be selected largely as
required, i.e. it is possible to use both stoichiometric,
substoichiometric and overstoichiometric quantitative

`` llZ;~986
. . .
ratios. In generRl, it is advantageous to use from
0.5 to 10 moles oi the oxo compound (I) per mole of
aldebyde (II). The oxo compound (I) is preferably
used in a quantity of from 1 to 5 moles and, more
particularly, in a quantity of from 1 to 3 moles per
mole of aldehyde (II).
The ammonia may be present in sub-stoichiometric
to overstoichiometric quantities during the reaction.
In most cases, it is best for at least about 0.5
mole of ammonia and at most about 100 moles of ammonia
to be present per mole of aldehyde (II). It is
advantageous to use from 1 to 20 moles of ammonia,
preferably from 2 to 15 moles of ammonia and, more
particularly, from 3 to 12 moles of ammonia per mole
of aldehyde (II).
The reaction is carried out in the gas phase.
It can be ad~antageous to dilute the gases of the oxo
compound (I), the aldehyde (II) and the ammonia
with inert gases. Suitable inert gases are, for
example, steam, air and, in particular, nitrogen. In
general, it is best to use no more than about 20
moles of inert gas per mole of aldehyde (II). It
is preferred to use from 0.5 to 10 moles and, more
particularly, from 1 to 5 moles of inert gas per
mole of aldehyde (II~.

112Z~86
-- 8 --
Suitable catalysts are substances having a
dehydrating and dehydrogenating effect. Substances
such as these are, for example, the catalysts based
on aluminium compounds, such as aluminium oxide and
aluminium silicate, optionally with the addition of
other metal o~ides and fluorides, which are
described in Yydrocarbon Processing 47 (1968), 103
to 107. It i~ advantageous to use catalysts
produced by the process according to German
Offenlegungsschrift No. 2,151,417, German
Offenlegungsschrift No. 2,224,160 and German
Offenlegungsschrift No. 2,239,801. These catalysts
- Co~ J~ai~
A are compounds ~ the elements Al~ ~ and O which
additionally contain at least one element of the
Second, Third or Fourth Group of the Periodic
System or at least two elements of the Second, Fourth,
Fifth or Sixth Group of the Peribdic System or at
least one element of the Second ~Sain Group of the
Periodic System and which have been pretreated at a
20 temperature in the range of from 550 to 1200C. These
catalysts are used in the form of a Iixed bed or
fluidised bed. It is particularly advantageous to
adopt the procedure according to German Offenlegung-
sschrift No. 2,449,~40 where the oxo compound (I)
2~ and the aldehyde (II) are introduced into the reactor

2Z986
_ g _
separately from the ammonia. In general, the
residence times amount to from 0.2 to 5.0 seconds.
The product mixture may be worked up in the
usual way by washing the gas mixture with a liquid
and, optionally, by further ~eparation by
extraction and distillation.
It is particularly advantageous to adopt the
procedure according to German Offenlegungsschrift
No. 2,554,946 where the gas mixtures are not washed,
but are cooled and partly condensed in such a way
that any excess ammonia remains in the residual gas
and is directly recycled therewith.
The process of the present invention is
illustrated by the following Examples.
EXLMPLE 1
. ~. .. .
An apparatus of the type described in German
Oifenlegungsschrift No. 2,449,340, as illustrated
in the accompanying drawing, was used. The reactor
10 and the regenerator 20 consisted of 70 mm wide
tubes which, at their lower ends, had a 200 mm tall
empty space, 12 and 22, surmounted at intervals of
50 mm by forty 5 mm mesh wire gauzes, 11 and 21,
and which at their upper ends had an empty space,
13 and 23, which was 60o mm tall and up to 160 mm wide.
A gas mixture of 1500 normal litres/hour of

11~2986
-- 10 --
.
nitrogen ~nd 2150 normal lit-re~/hour of ammonia was
delivered to the reactor 10 from below 14 in a uniform
stream. A gas mixture of 2130 g/hour of acrolein
ar~d 325 normal litres/hour of nitrogen was prepared
in one evaporator and a gas mixture of 1342 g/hour
of 3-phenyl propionaldehyde and 325 normal litres/hour
o~ nitrogen in another evaporator. These gas mixtures
were combined and introduced into the fluidised bed
at a temperature of 250C from the side 15 130 mm abo~e
the base of the reactor.
~ he reactor contained 2.0 kg of catalyst which
had been produced in accordance with German
Offenlegungsschrift No. 2,224,160 from aluminium
o~ide, magnesium nitrate and titanium tetra~luoride
and which had an atomic ratio of aluminium to
magnesium to titanium to fluorine of 1000:25:25:100.
The catalyst had a grain size of from 0.4 to 1.0 mm.
The temperature in the reactor was kept at 440C.
The reaction mixture 16, which was free from acrolein
and 3-phenyl propionaldehyde, was introduced at
a temperature of 250C into a gas scrubber in wllich
3-benzyl pyridine and the accompanying pyridineand
3-methyl pyridine were washed out with methanol. The
residual gas of ammonia and nitrogen was recycled
to the reactor.

llZ;~86
The regenerator 20 contained another 2.0 kg
of the catalyst. 3000 normal litres/hour of air
were introduced into the regenerator from below through
line 29 exiting through line 30.
The temperature in the regenerator was kept at 440C.
1.4 kg/hour of the catalyst were transferred from
the reactor to the regenerator through line 25 in a steady
stream and 1.4 kg/hour returned from the regenerator to
the reactor through line 27.
The conversion of 3-phenyl propionaldehyde
amounted to 100 ~. 904 g/h of 3-benzyl pyridine,
214 g/h of pyridine and 446 g/h of 3-methyl pyridine
were obtained. This corresponded to a 53 ~ yield of
3-benzyl pyridine, based on the 3-phenyl propion-
aldehyde used and to yields of pyridine and 3-methyl
pyridine of 14 % and 25 %, respectively, based on
the acrolein used. The 3-benzyl pyridine had a boiling
point of from 114 to 118C under a pressure of ~ mbar.
The procedure adopted in the following Examples
was the same as described in Example 1:
EXAMPLE 2
Starting substances: 3-phenyl propionaldehyde,
methacrolein and ammonia in a
molar ratio of 1:1:3
Catalyst: as in Example 1
Reaction temperature: 425C

112Z9B6
- 12 -
Con~ersion: 100 % of the 3-phenyl
propionaldehyde used
Product: . 3-benzyl-5-methyl pyridine
b.p. 123 to 125C/l mbar
5 Yield: 46 ~, based on the 3-phenyl
propionaldehyde used.
EXAMPLE 3
Starting substances: 3-phenyl propionaldehyde,
methyl vinyl ketone and
ammonia in a molar ratio
of 1.0:1.1:3.0
Catalyst: produced in accordance with
German Offenlegungsschrift
No. 2,151,417 from aluminium
oxide, magnesium nitrate
and fluorosilicic acid, atomic
ratio of aluminium to
magnesium to silicon to
fluorine 1000:24:25:156
20 Reaction temperature: 440C
Con~ersion: 100 ~ of the 3-phenyl
propionaldehyde
Product: 3-benzyl-6-methyl pyridine,
b.p. 120 to 124C/l mbar
25 Yield: 42 %, based on the 3-phenyl
propionaldehyde used.

- 13 -
EXAMPLE 4
-
Starting substances- phenyl acetaldehyde, acrolein
and ammonia in a molar ratio
of 1:2:6
5 Catalyst: produced in accordance with
German Offenlegungsschrift
No. 2,239,801 from aluminium
oxide, magnesium nitrate and
ammonium hydrogen fluoride,
atomic ratio of aluminium
to magnesium to fluorine
1000:25:50
Reaction temperature: 460C
Product: 3-phenyl pyridine, b.p. 116
to 118C/7 mbar
Yield: 65 ~, based on the phenyl
acetaldehyde used
Secondary products: 11 % of pyridine and 23 %
of 3-methyl pyridine, based
on the acrolein used.
EXAMPLE 5
Starting substances: 3-phenyl propionaldehyde,
crotonaldehyde and ammonia
in a molar ratio of 1.0:1.2:3.0
25 Catalyst: as in Example 1

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_ 14 -
Reaction temperature: 430C
Conversion: 100 ~ of the 3-phenyl
propionaldehyde
Product: 3-benzyl-4-methyl pyridine,
b.p. 127 to 129C/2 mbar
Yield: 37 ~, based on the 3-phenyl
. propionaldehyde used.
EXAMPLE 6
Starting substances: phenyl acetaldehyde,
crotonaldehyde and ammonia
in a molar ratio of 1.0:1.2:3.0
Catalyst: as in B ample 1
.Reaction temperature: 420C
Conversion: 100 ~ of the phenyl acet-
aldehyde
Product: 3-phenyl-4-methyl pyridine,
b.p. 109 to 112C/2 mbar
Yield: 39 ~, based on the phenyl
acetaldehyde used.
EX~LE ?
Starting substances: phellyl acetaldehyde,
methacrolein and ammonia
in a molar ratio of
1.0:1 .1:~.0
25 Catalyst: as in E~ample 4

112Z986
_ 15 --
Reaction temperature: 420C
Conversion: 100 % of the phenyl
acetaldehyde
Product: 3-phenyl-5-methyl pyridine,
b.p. 158 to 160C/18 mbar
Yield: 62 %, based on the phenyl
. acetaldehyde used.
EXAMPLE 8
Starting substances: phenyl acetaldehyde, methyl
vinyl ketone and ammonia in a
ratio of 1.0:1.1:3.0
Catalyst: as in Example 4
Reaction temperature: 420C
Conversion: 100 % of the phenyl
acetaldehyde
Product: 3-phenyl-6-methyl pyridine,
b.p. 142 to 145~C/17 mbar
Yield: 44 %, based on the phenyl
acetaldehyde used.