PREPARATION OF STEREOISOMERIC N-ARALKYL-2,6-DIMETHYL-MORPHOLINE

PREPARATION DE N-ARALKYL-2 6-DIMETHYL-MORPHOLINE STEREOISOMERE

English Abstract

O.Z. 0050/033,283
Abstract of the Disclosure: A process for the preparation
of stereoisomeric N-aralkyl-2,6-dimethylmorpholines by
reacting aralkanals with stereoisomeric 2,6-dimethyl-
morpholines.

Claims

The embodiments of the invention in which an
exclusive property or privilege is claimed are defines as
follows:
1. A process for the preparation of a stereoisomeric
N-aralkyl-2,6-dimethylmorpholine of the formula
<IMG>
where R1 is hydrogen, an aliphatic radical of 1 to 10
carbon atoms or alkoxy of 1 to 6 carbon atoms and R2, R3 and
R4 are hydrogen or an aliphatic radical of 1 to 4 carbon
atoms, or of a defined mixture of such compounds, by reacting
a stereoisomeric 2,6-dimethylmorpholine of the formula
<IMG>
or a defined mixture of such compounds with a compound of
the formula
<IMG>
where R1, R2, R3 and R4 have the above meanings, wherein the
reaction is carried out in the presence of hydrogen and of
a hydrogenation catalyst which contains palladium mixed with
silver on an inert carrier.

2. A process as claimed in claim 1, characterized
in that the hydrogenation catalyst contains from 1 to 30% by
weight of palladium, based on the silver.
3. A process as claimed in claim 1, characterized
in that the hydrogenation catalyst additionally contains up
to 50% by weight, based on the silver, of manganese oxide.
4. A process as claimed in claim 1, characterized
in that the inert carrier is silicon dioxide or aluminium
dioxide.
5. A process as claimed in claim 1, characterized
in that the hydrogenation catalyst contains 0.36% by weight
of palladium, 4.8% by weight of silver and 1.05% by weight of
manganese in the form of manganese oxide, the inert carrier
being silicon dioxide.
6. A process as claimed in claim 1, characterized
in that the reaction is carried out at a temperature from
100°C to 190°C under a hydrogen pressure of from 5 to
300 bars.
7. A process as claimed in claim 5, characterized
in that the reaction is carried out at a temperature from
100°C to 190°C under a hydrogen pressure of from 5 to
300 bars.
8. A process as claimed in claim 1, characterized
in that the hydrogenation catalyst contains from 1 to 30%
by weight of palladium, based on the silver and additionally
contains up to 50% by weight, based on the silver, of manganese
dioxide.

9. A process as claimed in claim 8, characterized
in that the inert carrier is silicon dioxide or aluminium
dioxide.
10. A process as claimed in claim 9, characterized
in that the reaction is carried out at a temperature from
100°C to 190°C under a hydrogen pressure of from 5 to
300 bara.
11. A process for the preparation of a stereoiso-
meric N-aralkyl-2,6-dimethylmorpholine of the formula
<IMG>
where R1 is hydrogen, alkyl of 1 to 6 carbon atoms or
methoxy or of a defined mixture of such compounds, by
reacting a stereoisomeric 2,6-dimethylmorpholine of the
formula
<IMG>
or a defined mixture of such compounds with a compound of
the formula
<IMG>
where R1 has the above meaning, wherein the reaction is
carried out in the presence of hydrogen and of a hydrogena-
tion catalyst which contains palladium mixed silver or an
inert carrier.

12. A process as claimed in claim 11, characterized
in that the hydrogenation catalyst contains from 1 to 30% by
weight of palladium, based on the silver.
13. A process as claimed in claim 11, characterized
in that the hydrogenation catalyst additionally contains up
to 50% by weight, based on the silver, of manganese oxide.
14. A process as claimed in claim 11, characterized
in that the inert carrier is silicon dioxide or aluminium
dioxide.
15. A process as claimed in claim 11, characterized
in that the hydrogenation catalyst contains 0.36% by weight
of palladium, 4.8% by weight of silver and 1.05% by weight of
manganese, the inert carrier being silicon dioxide.
16. A process as claimed in claim 11, characterized
in that the reaction is carried out at a temperature from
100°C to 190°C under a hydrogen pressure of from 5 to 300
bars.
17. A process as claimed in claim 15, characterized
in that the reaction is carried out at a temperature from
100°C to 190°C under a hydrogen pressure of from 5 to 300
bars.
18. A process as claimed in claim 11, characterized
in that the hydrogenation catalyst contains from 1 to 30% by
weight of palladium, based on the silver and additionally
contains up to 50% by weight on the silver,of manganese
dioxide.
11

19. A process as claimed in claim 18, characterized
in that the inert carrier is silicon dioxide or aluminium
dioxide.
20. A process as claimed in claim 19, characterized
in that the reaction is carried out at a temperature from
100°C to 190°C under a hydrogen pressure of from 5 to 300
bars.
12

Description

~lZ2~8~
- 1 O.Z. 0050~0332
Preparation of stereoisomeric
N-aralkyl-2,6-dimethylmorpholines
The present invention relates to a process for the
preparation of stereoisomeric N-aralkyl-2,6-dimethylmorpho-
lines by reacting aralkanals with stereoisomeric 2,6-
dimethyl-morpholines.
The preparation of tertiary amines ~y reacting
secondary amines with carbonyl compounds in the presence of
hydrogen and of a hydrogenation catalyst is kIlown (Houben-
Weyl "Methoden der organischen Chemie!', 4/2, page 328).
German Laid-Open Application DOS 2,118,283 describes ~he
preparation of tertiary aliphatic or cycioaliphatic am~res
by reaction of aliphatic or cycloaliphatic carbonyl cc,~;pounds
with secondary aliphatic or cycloaliphatic amines in ~ e
presence of hydrogen and of a palladium-silver catalyst.
The advantage of this catalyst is that it enables the reduc-
tive alkylation of secondary aliphatic or cyc'oaliphati~
amines to be carried out with high yield and substantia'ly
without formation of by-products. The side-reaction fre-
quently observed on reductive alkylation of amines, ramely
hydrogenation of the carbonyl compounds, with formatiorl of
the corresponding alcohols, is avoided when usin~ the above
catalyst. Further, Germar Patent 1,179,947 discloses that
if the synthesis of N-alkylated aromatic amines is car~ied
out by reductive alk~rlation of aromatic amines over a
palladium-silver catalyst, the arom2tic system remains
unaffected.
We have found that stereoisomeric N-aral~yl-2,6-

llZZ~
dimethylmorpholines of the formula I
1 ~ CH-CH-CH-N ~ I
where R1 is hydrogen, an aliphatic radical of 1 to 10 carbon
atoms or alkoxy of 1 to 6 carbon atoms and R2, R3 and R4
are hydrogen or an aliphatic radical of 1 to 4 carbon atoms,
or defined mixtures of these compounds, may be obtained in
a simple manner by reacting stereoisomeric 2,6-dimethyl-
morpholines of the formula II
CH3
/--< II
HN~f
CH3with compounds of the formula III
Rl ~ 12 13 1 4 III
where Rl, R2, R3 and R4 have the above meanings, if the
reaction is carried out in the presence of hydrogen and of
a hydrogenation catalyst which contains palladium mixed wi~h
silver on an inert carrier.
In particular, the present invention provides a
process for the preparation of a stereoisomeric N-aralkyl
2,6-dimethylmorpholine of the formula
C~3 ~f H3
Rl~CH2-C~I-CH2 N~
CH3
where Rl is hydrogen, alkyl of 1 to 6 carbon atoms or methoxy
or of a defined mixture of such compounds, by reacting a
stereoisomeric 2,6-dimethylmorpholine of the formula
~ 2 --
,,
. ~ .,

112Z9~l
, ~ CH3
H~ 'o
CH3
or a defined mixture of such compounds with a compound of
the formula
fH3
1~ C~H2-cH--f=O
H
where Rl, has the above meaning, wherein the reaction is
carried out in the presence of hydrogen and of a hydrogenation
catalyst which contains palladium mixed with silver on an
inert carrier.
The reaction is advantageously carried out at from
100 to 190C under pressures of from 5 to 300 bar.
The advantaye of the proce~s according to the inven-
tion is that no isomerization reactions occur on the above
hydrogenation catalyst under the stated conditions~ so that,
for example,,on reacting pure cis-2,6-dimethylm~rphol_ne.,of ,,,

9~
- 3 - O.Z. 0050/0~28
the formula II with carbonyl compounds of the formula III,
the pure cis-isomers of the end products I are obtained,
free from their stereoisomers.
It is known that isomeriza~ions can be carried out
over hydrogenation catalysts and that on using such cata-
lysts for reductive alkylations of amines or for hydrogena-
tions, isomerizations must always be expected to occur as
side-reactions (Houben-Weyl "Methoden der organischen Chemie",
4/2, pages 276 - 283).
In the process according to the invention, the amine
component may be employed in the stoichiometric amount or in
up to 10-fold molar excess.
The following carbonyl compounds are examples of
suitable starting materials of the formula ITI: 3-phenyl-3-
methyl-propanal, 3-phenyl-2-methyl-propanal, 4-phenyl-butan-
2-one, 3-(4'-methylphenyl)-2-methylpropanal, 3-(4'-isopropyl-
phenyl)-2-methyl-propanal, 3-(4'-tertiary butylphenyl)-2-
methyl-propanal, 3-phenyl-2-ethyl-propanal, 3-phe~yl-2-iso-
propyl-propanal, 3-(4'-isopropylph.enyl)-3-methyl-propanal,
2b 3-(4'-tertiary butylphenyl)-3-methyl-propanal, 3-(4'-tertiary
butylphenyl)-butan-4-one, 3-(4'-methoxyphenyl)-2-methvl-
propanal and 3-(4'-.isopropoxyphenyl)-2-methyl-propanal.
The starting materials III are prepared from the
corresponding substituted benzaldehydes and aliphatic a.lde-
hydes or ketones by an aldol condensation followed by partial
hydrogenation of the resulting carbon-carbon double bond
(U,S. Patent 2,976,321). Some of the compounds C~l also
be prepared by hydroformylation of substituted styrenes.
The reaction is advantageously carried cut at fr~

1~ 2Z98~
- 4 - O.Z. 0050/033283
100 -to 190C under a hydrogen pressure of from 5 to 300 bar
It may be carried out without a solvent or in the presence
of solvents which are inert under the reaction conditions.
Examples of suitable solvents are cyclohexane,
hexane, hept&ne, toluene, o-, m and p-xylene, ethylbenzene,
di-n-butyl ether, cyclohexylmethyl ether, anisole, methanol,
ethanol, isopropanol, tebrahydrofuran and dioxane. The
reaction can be carried out either continuously or batchwise.
The preparation of the catalyst, comprising silver and
palladium on an inert carrier, is disclosed in German Patent
1,179,947 and Germa~ Laid-Open Application DOS 2,118,283.
The catalytically active metals are advantageously employed
in a ratio corresponding to from 1 to 30, especially from
3 to 15, per cent by weight of palladium, based on silver.
Sometimes, ~he activity of the catalyst can be further
improved by adding up to 50 per cent by weight, in particular
up to 25 per cent by weight, based on silver, of manganese
or vanadium oxide. Examples of suitable carriers are
silica, or alumina which has been heated at a high tempera-
ture and then cooled. The weight ratio of carrier tometal is, for example, 93 : 7. The catalyst may for
example be used in the form of extrudates of 5 mm diameter
and 1~ mm length.
The compounds prepared by the process of the inven-
tion may be used as active ingredients in crop protection
agents (~erman Laid-Open Application DOS 2,556,747).
In the Examples which follow, parts are by weight and
bear the same relation to parts by volume as that of the
kilo~am to the liter.

- ~5 ~ o.z.0050,/03328
EXA~SPLE 1
.~ c~tal~st consisting of 0036~ ~y ~.~ight of Pd, 4.8~ by weight of
~5 and 1.5~ b~ we~ght ~ Mn in the form of man~anese oxide on SiO2 as the
carrier is filled into a cylindrical reaction tube having a
volume of 500 parts, and is heated to 150C. Per hour,
120 parts of a mixture consisting of 204 parts of 3-(p-
tertiary butylphenyl)-2-methyl-propanal and 115 parts of cis-
2,6-dimethylmorpholine are passed over this catalyst bed.
At the same time, 10,000 parts by volume of hydrogen under
a pressure of 200 bar are passed, in co-current, through the
reaction tube. The reaction product issuing from the
reaction tube is cooled under pressure, after which the
pressure is let down. This gives about 120 parts per
hour of crude product, which is purified by distillation.
Distillation of 120 parts of crude product gi~res107 parts of
N-[3'-(p-tertiary butylphenyl)-2'-methyl-propyl]-cis-2,6-
dimethylmorpholine, boiling point = 206C/l~ mm Hg~
This corresponds to a yield of 94% of theory
EXAMPLE 2
3-(p-Tertiary butylphenyl)-2-methyl-propanal is
r~acted with a mixture of 75~0 by weight of cis-2,6-dimethyl-
morpholine and 25~o by weight of trans-2,6-dimethylmorpholine
in the same apparatus, under the same conditions, and in the
same ratio, as those described in Example 1. The end
product obtained is a mixture of 75,~ by weight of N-[~ t _ (p_
tertiary butylphenyl)-2'-methyl-propyl]-cis-2,6-dirnethyl-
morpholine and 25% by weight of N-C3'-(p-tertiary butyl-
phenyl)-2'-methyl-propyl]-trans-2,6-dimethylmorpholine,
boiling point = 206 - 210C/18 mm Hg The yield is 94%
~;~

~12'~9~1
- 6 ~ O.Z. 0050/0~3283
of theory.
EXAMPLE 3
A shaking autoclave having a volume of 250 parts is
filled with 50 parts of 3-(p-isopropylphenyl)-3-methyl-
propanal, 100 parts of trans-2,6-dimethylmorpholine and 10
parts of the catalyst mentioned in Example 1. The auto~
clave is then heated to 140C and hydrogen is forced in
until the pressure reaches 200 bar. As soon as the
hydrogen absorption has ended and a constant pressure has
been reached, the autoclave is cooled.
The catalyst is then removed from the reaction pro-
duct by filtration and the filtrate is purified by distilla-
tion. 69 parts of N-[3'-(p-isopropylphenyl)-3'-meth~
propyl]-trans-2,6-dimethylmorpholine, boiling point = 1,2C/
O.01 mm Hg,are obtained. The yield is 91~6 of theory.
EXAMPLE 4
The shaking autoclave mentioned in Example 3 is
filled Wit}l 50 parts by volume of 3-phenyl-3-~ethyl-propanal,
100 parts of cis-2,6-dimethylmorpholine and 10 parts of the
catalyst mentioned in Example 1. The autoclave is then
heated to 160C and hydrogen is forced in until the pro~sure
reaches 200 bar As soon as the hydrogen absorption has
ended and a constant pressure has been reached, the autoclave
is cooled. The catalyst is then removed from the reac-
tion product by filtration and the filtrate is purified by
distillation. 77.5 parts of N-(3'-phenyl-3'-methyl-
propyl)-cis-2,6-dimethylmorpholine, boiling point = lC3C/
0.1 mm Hg,are obtained. The yield is 93/0 of theory.
, . . . . . _ .. .

llZZ9~1
- 7 - O.Z. 0050~033283
EXAMPLE 5
The procedure followed is as described in Example 4,
but the starting materials used are 3-(p-methoxyphenyl)-2-
methyl-propanal and cis-2,6-dimethylmorpholine. Working
up the reaction product by distillation in this case gives
N-[3'-(p-methoxyphenyl)-2'-methyl-propyl]-cis-2,6-dimethyl-
morpholine, boiling point = 128C/0.1 mm Hg. The yield
is 93% of theory,
EXAMPLE 6
The procedure followed is as described in Example 4,
but the starting materials used are 4-(p-tertiary butyl-
phenyl)-butan-2-one as the carbonyl component and a mixture
of 75% by weight of cis- and 25% by weight of trans-2,6-
dimethylmorpholine as the amine component. Working up
by distillation gives a mixture of 75% by weight of N-[4~-
(p-tertiary butylphenyl)-but-2'-yl]-cis-2,6-dimethyl-
morpholine and 25% by weight of N-[4'-(p-tertiary butyl-
phenyl)-but-2'-yl]-trans-2,6-dimethylmorpholine, boiling
point = 143C/0.01 mm Hg, The yield is 86% of theory.
EXAMPLE 7
The procedure follo~ed is as described in Example 4,
but the catalyst used consists of 0.3% by weight of Pd and
4.5~ by weight of Ag on SiO2, the carbonyl component is 3-
(p-tertiary butylphenyl)-2-methyl-propanal and the amine
component is cis-2,6-dimethylmorpholine.
Working up the reaction product by distillation
gives N-[3'-(p-tertiary butylphenyl)-2'-methyl-propyl~-cis-
2,6-dimethylmorpholine in a yield of 92% of theory.
.
. .