Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~WO 95/21151 PCT/EP95/00221
f
-1-
Process for the hydrogenation of imines
The present invention relates to a process for the hydrogenation of imines
with hydrogen
under elevated pressure in the presence of iridium catalysts and a halide,
wherein the
reaction mixture contains an inorganic or organic acid.
US-A-4. 994 615 describes a process for the asymmetric hydrogenation of
prochiral
N-arylketimines wherein iridium catalysts having chiral diphosphine ligands
are used.
US-A-5 011995 describes a process for the asymmetric hydrogenation of
prochiral
N-alkylketimines using the same catalysts. US-A-5 112 999 discloses
polynuclear iridium
compounds and a complex salt of iridium, which contain diphosphine ligands, as
catalysts
for the hydrogenation of imines.
Those homogeneous catalysis processes have proved valuable, although it is
evident,
especially in the case of relatively large batches or on an industrial scale,
that the catalysts
frequently tend to become deactivated to a greater or lesser extent depending
on the
catalyst precursor, the substrate and the diphosphine ligands that are used.
In many cases,
especially at elevated temperatures - for example at temperatures
>25°C, which are
necessary for a short reaction time - it is not possible to achieve complete
conversion. For
industrial applications of the hydrogenation process, therefore, the catalyst
productivity is
too low from the point of view of economic viability.
It has now been found, surprisingly, that the catalyst activity can be
increased by a factor
of 10 or more if the reaction mixture essentially contains a halide and also
contains an
acid. It has also unexpectedly been found that at the same time the
deactivation of the
catalysts can be considerably reduced or completely eliminated. It has also
been found,
surprisingly, that the enantioselectivity under the chosen conditions is high,
and high
optical yields of, for example, up to 80 % can be achieved, even at reaction
temperatures
of more than 50°C.
The invention relates to a process for the hydrogenation of imines with
hydrogen under
elevated pressure in the presence of iridium catalysts and with or without an
inert solvent,
wherein the reaction mixture contains an ammonium chloride, bromide or iodide,
or a
metal chloride, bromide or iodide that is soluble in the reaction mixture, the
metal prefer-
ably being an alkali metal, and additionally contains an acid.
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According to another aspect of the present
invention, there is provided a process for the preparation
of a compound of the formula
~3
C1CH2C0~ *H-Rp4
N
~a Roy
/ ( I'' ) ,
wherein Roz, Roz and Ro3 are each independently of the other
Cl-C4alkyl, and Ro4 is C1-C4alkyl or C1-C4alkoxymethyl or
C1-CQalkoxyethyl, by (1) hydrogenation of an imine of the
formula
R03 ~ ~ R04
C
N
Ro ~
/ I (~)
\
with hydrogen in the presence of an iridium catalyst and
with or without an inert solvent to form an amine of the
formula
~3
H\ ,CH-R~4
N
(VI)
and (2) reaction thereof with the compound of formula
C1CHZC0-C1 (VII) ,
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wherein in the hydrogenation the reaction mixture contains
an ammonium chloride, bromide or iodide, or a metal
chloride, bromide or iodide that is soluble in the reaction
mixture, and additionally contains an acid.
According to still another aspect of the present.
invention, there is provided a process as described in the
previous paragraph, wherein the imine used is a compound of
the formula
CH3~ CH20CH3 CH3~ CH20CH3
I I
N N
CH3 CH3 C2H5 CH3
(Vb) .
(Va) or
WO 95/21151 PCT/EP95/00221
-2-
Suitable imines are especially those that contain at least one jC-N- group. If
the
groups are substituted asymmetrically and are thus compounds having a
prochiral
ketimine group, it is possible in the process according to the invention for
mixtures of
optical isomers or pure optical isomers to be formed if enantioselective or
diastereo- '
selective iridium catalysts are used. The imines may contain further chiral
carbon atoms.
The free bonds in the above formulae may be saturated with hydrogen or organic
radicals
having from 1 to 22 carbon atoms or organic hetero radicals having from I to
20 carbon
atoms and at least one hetero atom from the group O, S, N and P. The nitrogen
atom of the
group jC-N- may also be saturated with NH2 or a primary amino group having
from 1 to 22 carbon atoms or a secondary amino group having from 2 to 40
carbon atoms.
The organic radicals may be substituted, for example, by F, Cl, Br, Cl-
C4haloalkyl
wherein halogen is preferably F or Cl, -CN, -N02, -C02H, -CONH2, -S03H, -
P03H2, or
Cl-Cl2alkyl esters or amides, or by phenyl esters or benzyl esters of the
groups -C02H,
-S03H and -P03H2. Aldimine and ketimine groups are especially reactive, with
the result
that using the process according to the invention it is possible selectively
to hydrogenate
j~N-groups in addition to the j~C~ andlor ~O---O groups. Aldimine and
ketimine groups are also to be understood to include j~N° N- hydrazone
groups.
The process according to the invention is suitable especially for the
hydrogenation of
aldimines, ketimines and hydrazones with the formation of corresponding amines
and
hydrazines, respectively. The ketimines are preferably N-substituted. It is
preferable to use
chiral iridium catalysts and to hydrogenate enantiomerically pure, chiral or
prochiral
ketimines to prepare optical isomers, the optical yields Lnanttomeric excess,
ee) being,
for example, higher than 30 %, preferably higher than 50 %, and yields of more
than 90 %
being achievable. The optical yield indicates the ratio of the two
stereoisomers formed,
which ratio may be, for example, greater than 2: l and preferably greater than
4:1.
The imines are preferably imines of formula I
R1
~~N R3
(n~
R2
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30041-65
-3-
which are hydrogenated to form amines of formula II
Rt
\ CH - NH- R3 ~R)
R2
wherein
R3 is preferably a substituent and wherein
R3 is linear or branched Cl-Ct2alkyl, cycloalkyl having from 3 to 8 ring
carbon atoms;
heterocycloalkyl bonded via a carbon atom and having from 3 to 8 ring atoms
and 1 or 2
hetero atoms from the group O, S and NR6; a C~-Ct6aralkyl bonded via an alkyl
carbon
atom or Cl-Ct2alkyl substituted by the mentioned cycloalkyl or
heterocycloalkyl or
heteroaryl;
or wherein
R3 is C6-Ct2aryl, or C4-Cltheteroaryl bonded via a ring carbon atom and having
1 or 2
hetero atoms in the ring; R3 being unsubstituted or substituted by -CN, -N02,
F, Cl,
Ct-Ct2alkyl, Ct-Ct2allcoxy, Cl-Ct2alkylthio, Cl-C6haloalkyl, -OH, C6-Ct2-aryl
or
-aryloxy or -arylthio, C~-C16-aralkyl or -aralkoxy or -aralkylthio, secondary
amino having
from 2 to 24 carbon atoms, -CONR4R5 or by -COORø, and the aryl radicals and
the aryl
groups in the aralkyl, aralkoxy and aralkylthio in turn being unsubstituted or
substituted by
-CN, -N02, F, Cl, Cl-C4-alkyl, -allcoxy or -alkylthio, -OH, -CONR4R5 or by -
COOR4;
R4 and RS are each independently of the other hydrogen, Ct-Ct2alkyl, phenyl or
benzyl, or
R4 and RS together are tetra- or penta-methylene or 3-oxapentylene;
R6 has independently the same meaning as given for R4;
Rt and R2 are each independently of the other a hydrogen atom, Cl-Cl2alkyl or
cycloalkyl
having from 3 to 8 ring carbon atoms, each of which is unsubstituted or
substituted by
-OH, Cl-Cl2allcoxy, phenoxy, benzyloxy, secondary amino having from 2 to 24
carbon
atoms, -CONR4R5 or by -COOR4; C6-C12ary1 or C~-Ct6aralkyl that is
unsubstituted or
substituted as R3, or -CONR4R5 or -COOR4, wherein R4 and RS are as defined
hereinbefore; or
R3 is as defined hereinbefore and Rl and RZ together are alkylene having from
2 to 5
carbon atoms that is optionally interrupted by 1 or 2 -O-, -S- or -NR6-
radicals, and/or
unsubstituted or substituted by =O as defined for R, and Rz above, and/or said
alkylene
condensed with benzene, pyridine, pyrimidine, furan, thiophene or pyrrole; or
WO 95/21151 _ PCT/EP95/00221
..
:1 ~ ~ ~~
-4-
R2 is as defined hereinbefore and R1 and R3 together are alkylene having from
2 to 5
carbon atoms that is optionally interrupted by 1 or 2 -O-, -S- or -NR6-
radicals, and/or
unsubstituted or substituted by =O or as Rl and R2 above in the meaning of
alkyl, and/or
condensed with benzene, pyridine, pyrimidine, furan, thiophene or pyrrole.
The radicals Rl, R2 and R3 may contain one or more chirality centres.
Rl, R2 and R3 can be substituted in any desired positions by identical or
different radicals,
for example by from 1 to 5, preferably from 1 to 3, substituents.
Suitable substituents for Rl and R2 and R3 are: Ci-C12-, preferably Cl-C6-,
and especially
Cl-C4-alkyl, -alkoxy or -alkylthio, e.g. methyl, ethyl, propyl, n-, iso- and
tert-butyl, the
isomers of pentyl, hexyl, octyl, nonyl, decyl, undecyl and dodecyl, and
corresponding
alkoxy and alkylthio radicals;
Cl-C6-, preferably Cl-C4-haloalkyl having preferably F and Cl as halogen, e.g.
trifluoro-
or trichloro-methyl, difluorochloromethyl, ffuorodichloromethyl, 1,1-
difluoroeth-1-yl,
1,1-dichloroeth-1-yl, 1,1,1-trichloro- or 1,1,1-trifluoroeth-2-yl,
pentachloroethyl, penta-
fluoroethyl, 1,1,1-trifluoro-2,2-dichloroethyl, n-perfluoropropyl, iso-
perfluoropropyl,
n-perfluorobutyl, fluoro- or chloro-methyl, difluoro- or dichloro-methyl, 1-
fluoro- or
1-chloro-eth-2-yl or -eth-1-yl, 1-, 2- or 3-fluoro- or 1-, 2- or 3-chloro-prop-
1-yl or
-prop-2-yl or -prop-3-yl, 1-fluoro- or 1-chloro-but-1-yl, -but-2-yl, -but-3-yl
or -but-4-yl,
2,3-dichloro-prop-1-yl, 1-chloro-2-fluoro-prop-3-yl, 2,3-dichlorobut-1-yl;
C6-C12-aryl, -aryloxy or -arylthio, in which aryl is preferably naphthyl and
especially
phenyl, C~-C16-aralkyl, -aralkoxy and -aralkylthio, in which the aryl radical
is preferably
naphthyl and especially phenyl and the alkylene radical is linear or branched
and contains
from 1 to 10, preferably from 1 to 6 and especially from 1 to 3, carbon atoms,
for example
benzyl, naphthylinethyl, 1- or 2-phenyl-eth-1-yl or -eth-2-yl, 1-, 2- or 3-
phenyl-prop-1-yl,
-prop-2-yl or -prop-3-yl, with benzyl being especially preferred;
the radicals containing the aryl groups mentioned above may in turn be mono-
or poly-
substituted, for example by Cl-C4-alkyl, -alkoxy or -alkylthio, halogen, -OH, -
CONR,4R5
or by -COORS, wherein R4 and RS are as defined; examples are methyl, ethyl, n-
and iso-
propyl, butyl, corresponding alkoxy and alkylthio radicals, F, Cl, Br,
dimethyl-, methyl-
ethyl- and diethyl-carbamoyl and methoxy-, ethoxy-, phenoxy- and benzyloxy-
carbonyl;
halogen, preferably F and Cl;
WO 95121151 PCT/EP95/00221
-5-
secondary amino having from 2 to 24, preferably from 2 to 12 and especially
from 2 to 6
carbon atoms, the secondary amino preferably containing 2 alkyl groups, for
example
dimethyl-, methylethyl-, diethyl-, methylpropyl-, methyl-n-butyl-, di-n-propyl-
,
di-n-butyl-, di-n-hexyl-amino;
-CONR4R5, wherein R4 and RS are each independently of the other Cl-Ct2-,
preferably
Cl-C6-, and especially Ci-C4-alkyl, or R4 and RS together are tetra- or penta-
methylene or
3-oxapentylene, the alkyl being linear or branched, e.g. dimethyl-,
methylethyl-, diethyl-,
methyl-n-propyl-, ethyl-n-propyl-, di-n-propyl-, methyl-n-butyl-, ethyl-n-
butyl-, n-propyl-
n-butyl- and di-n-butyl-carbamoyl;
-COOR4, wherein R,t is Ci-C12-, preferably Cl-C6-alkyl, which may be linear or
branched,
e.g. methyl, ethyl, n- and iso-propyl, n-, iso- and tert-butyl, and the
isomers of pentyl,
hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.
Rl, R2 and R3 may contain especially functional groups, such as keto groups, -
CN, -N02,
carbon double bonds, N-O-, aromatic halogen groups and amide groups.
Rl and R2 as heteroaryl are preferably a 5- or 6-membered ring having 1 or 2
identical or
different hetero atoms, especially O, S or N, which contains preferably 4 or 5
carbon
atoms and can be condensed with benzene. Examples of heteroaromatics from
which Rl
can be derived are furan, pyrrole, thiophene, pyridine, pyrimidine, indole and
quinoline.
Ri and R2 as heteroaryl-substituted alkyl are derived preferably from a 5- or
6-membered
ring having 1 or 2 identical or different hetero atoms, especially O, S or N,
which contains
preferably 4 or 5 carbon atoms and can be condensed with benzene. Examples of
hetero-
aromatics are furan, pyrrole, thiophene, pyridine, pyrimidine, indole and
quinoline.
Ri and R2 as heterocycloalkyl or as heterocycloalkyl-substituted alkyl contain
preferably
from 4 to 6 ring atoms and 1 or 2 identical or different hetero atoms from the
group O, S
and NR6. It can be condensed with benzene. It may be derived, for example,
from pyrrol-
idine, tetrahydrofuran, tetrahydrothiophene, indane, pyrazolidine,
oxazolidine, piperidine,
piperazine or morpholine.
Ri, R2 and R3 as alkyl are preferably unsubstituted or substituted Cl-C6-,
especially
... .,
WO 95!21151 ' ' PCT/EP95/00221
-6-
C1-C4-alkyl, which may be linear or branched. Examples are methyl, ethyl, iso-
and
n-propyl, iso-, n- and tert-butyl, the isomers of pentyl, hexyl, heptyl,
octyl, nonyl, decyl,
undecyl and dodecyl.
Rl, R2 and R3 as unsubstituted or substituted cycloalkyl contain preferably
from 3 to 6,
especially 5 or 6, ring carbon atoms. Examples are cyclopropyl, cyclobutyl,
cyclopentyl,
cyclohexyl, cycloheptyl and cyclooctyl.
Rl, R2 and R3 as aryl are preferably unsubstituted or substituted naphthyl and
especially
phenyl. Rl, R2 and R3 as aralkyl are preferably unsubstituted or substituted
phenylalkyl
having from 1 to 10, preferably from 1 to 6 and especially from 1 to 4 carbon
atoms in the
alkylene, the alkylene being linear or branched. Examples are especially
benzyl, and
1-phenyleth-1-yl, 2-phenyleth-1-yl, 1-phenylprop-1-yl, 1-phenylprop-2-yl, 1-
phenyl-
prop-3-yl, 2-phenylprop-1-yl, 2-phenylprop-2-yl and 1-phenylbut-4-yl.
In R2 and R3 as -CONR,~RS and -COOR4, R4 and RS are preferably Cl-C6-,
especially
Cl-C4-alkyl, or I~ and RS together are tetramethylene, pentamethylene or 3-
oxapentylene.
Examples of alkyl are mentioned hereinbefore.
Rl and R2 together or Rl and R3 together as alkylene are preferably
interrupted by 1-O-,
-S- or -NR6-, preferably -O-. Rl and R2 together or Rl and R3 together form,
with the
carbon atom or with the -N=C group to which they are bonded, respectively,
preferably a
5- or 6-membered ring. For the substituents the preferences mentioned
hereinbefore apply.
As condensed alkylene, Rl and R2 together or Rl and R3 together are preferably
alkylene
condensed with benzene or pyridine. Examples of alkylene are: ethylene, 1,2-
or
1,3-propylene, 1,2-, 1,3- or 1,4-butylene, 1,5-pentylene and I,6-hexylene.
Examples of
interrupted or =O-substituted alkylene are 2-oxa-1,3-propylene, 2-oxa-1,4-
butylene,
2-oxa- or 3-oxa-1,5-pentylene, 3-this-1,5-pentylene, 2-this-1,4-butylene, 2-
thia-
1,3-propylene, 2-methylimino-1,3-propylene, 2-ethylimino-1,4-butylene, 2- or 3-
methyl-
imino-1,5-pentylene, 1-oxo-2-oxa-1,3-propylene, 1-oxo-2-oxa-1,4-butylene, 2-
oxo-3-oxa-
1,4-butylene, 1-oxa-2-oxo-1,5-pentylene. Examples of condensed alkylene are:
CH2 CH2 CHI
~ I H2
\N O/ 'CH2
WO 95/21151 PCT/EP95/0~221
_?_
Examples of condensed and interrupted and unsubstituted or =O-substituted
alkylene are:
CH2~0 ~ O'CH2 ~ S~CH2 ~ O~CO
R4 and RS are preferably each independently of the other hydrogen, C1-C4alkyl,
phenyl or
benzyl. R6 is preferably hydrogen or Cl-C4alkyl.
A further preferred group is formed by prochiral imines in which in formula I
Rl, R2 and
R3 are each different from the others and are not hydrogen.
In an especially preferred group, in formula I R3 is 2,6-di-Cl-C4alkylphen-1-
yl and
especially 2,6-dimethylphen-1-yl or 2-methyl-6-ethylphen-1-yl, Rl is Cl-
C4alkyl and
especially ethyl or methyl, and R2 is Cl-C4alkyl, Ci-C4alkoxymethyl or Cl-
C4alkoxyethyl,
and especially methoxymethyl.
Of those compounds, imines of formulae
CH3 \ ,CH20CH3 CH3 ' ,CH20CH3
C C
N
N
CH3 CH3 Via) arid C2H5 CH3 (Vb) are especially
\ ) \
important, as is the imine of the formula
CH3 N - C - CH20CH3
I
CH3 (Vc).
S CHa
Imines of formula I are known or they can be prepared in accordance with known
processes from aldehydes or ketones and primary amines.
The iridium catalysts are preferably homogeneous catalysts that are
substantially soluble
WO 95/21151 PCT/EP95/00221
_ g._.
in the reaction medium. The term "catalyst" also includes catalyst precursors
that are
converted into an active catalyst species at the beginning of a hydrogenation.
The
catalysts preferably correspond to the formulae III, IIIa, IIIb, ITIc and
IIId,
[XIrYZ] ~). [~'1']~Ae ~a)~
[~'Za]~M~ (~)~ [Z'B'~2 (~c)~
[Z'~'~]2 (~d)~
wherein X is two olefin ligands or a diene ligand, Y is a ditertiary
diphosphine
(a) the phosphine groups of which are bonded to different carbon atoms of a
carbon chain
having from 2 to 4 carbon atoms, or
(b) the phosphine groups of which are either bonded directly or via a bridge
group
-CRaRb- in the ortho positions of a cyclopentadienyl ring or are each bonded
to a cyclo-
pentadienyl ring of a ferrocenyl, or
(c) one phosphine group of which is bonded to a carbon chain having 2 or 3
carbon atoms
and the other phosphine group of which is bonded to an oxygen atom or a
nitrogen atom
bonded terminally to that carbon chain, or
(d) the phosphine groups of which are bonded to the two oxygen atoms or
nitrogen atoms
bonded terminally to a C2-carbon chain;
with the result that in the cases of (a), (b), (c) and (d) a 5-, 6- or 7-
membered ring is
formed together with the Ir atom, the radicals Z are each independently of the
others) Cl,
Br or I, A~ is the anion of an oxy or complex acid, and M~ is an alkali metal
cation or
quaternary ammonium, and Ra and Rb are each independently of the other
hydrogen,
Cl-C8alkyl, Cl-C4fluoroalkyl, phenyl or benzyl or are phenyl or benzyl having
from 1 to 3
Cl-C4alkyl or Cl-C4alkoxy substituents. Rb is preferably hydrogen. Ra is
preferably
Ci-C4alkyl and especially methyl.
The diphosphine Y contains preferably at least one chiral carbon atom and is
especially an
optically pure stereoisomer (enantiomer or diastereoisomer), or a pair of
diastereoisomers,
since the use of catalysts containing those ligands leads to optical induction
in asymmetric
hydrogenation reactions.
X as an olefin ligand may be a branched or, preferably, linear C2-Cl2alkylene,
especially
C2-C6alkylene. Some examples are dodecylene, decylene, octylene, 1-, 2- or 3-
hexene, 1-,
WO 95/21151 ~~~ ~ ' PCT/EP95/00221
-9-
2- or 3-pentene, 1- or 2-butene, propene and ethene. X as a diene ligand may
be open-
chain or cyclic dimes having from 4 to 12, preferably from 5 to 8, carbon
atoms, the dime
groups preferably being separated by one or two saturated carbon atoms. Some
examples
are butadiene, pentadiene, hexadiene, heptadiene, octadiene, decadiene,
dodecadiene,
cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene and bridged
cyclo-
dienes such as norbornadiene and bicyclo-2,2,2-octadiene. Hexadiene,
cyclooctadiene and
norbornadiene are preferred.
The phosphine groups contain preferably two identical or different, preferably
identical,
unsubstituted or substituted hydrocarbon radicals having from 1 to 20,
especially from 1 to
12 carbon atoms. Preference is given to diphosphines wherein the secondary
phosphine
groups contain two identical or different radicals from the following group:
linear or
branched Cl-Cl2alkyl; unsubstituted or Cl-C6alkyl- or Cl-C6alkoxy-substituted
CS-Cl2-
cycloalkyl, CS-Cl2cycloalkyl-CH2-, phenyl or benzyl; and phenyl or benzyl
substituted by
halogen (e.g. F, Cl or Br), Cl-C6haloalkyl, (Cl-Cl2alkyl)3Si, (C6H5)3Si, Cl-
C6haloalkoxy
(e.g. trifluoromethoxy), -NH2, phenyl2N-, benzyl2N-, morpholinyl, piperidinyl,
pyrrolidin-
yl, (Cl-Cl2alkyl)ZN-, -ammonium-Xle, -S03M1, -C02M1, -P03M1 or by -COO-Cl-C6-
alkyl (e.g. -COOCH3), wherein Ml is an alkali metal or hydrogen and Xle is the
anion of
a monobasic acid. Ml is preferably H, Li, Na or K. Ale , as the anion of a
monobasic
acid, is preferably Cle, Bre or the anion of a carboxylic acid, for example
formate,
acetate, trichloroacetate or trifluoroacetate.
A secondary phosphine group may also be a radical of the formula
p ~ ~ , wherein
m and n are each independently of the other an integer from 2 to 10, and the
sum of m+n is
from 4 to 12, especially from 5 to 8. Examples thereof are [3.3.1]- and
(4.2.1]-phobyl of
the formulae
p and p
WO 95/21151 ~ ~~ PCT/EP95/00221
- 10-
Examples of alkyl that preferably contains from 1 to 6 carbon atoms are
methyl, ethyl,
n-propyl, isopropyl, n-, iso- and tert-butyl and the isomers of pentyl and
hexyl. Examples
of unsubstituted or alkyl-substituted cycloalkyl are cyclopentyl, cyclohexyl,
methyl- or
ethyl-cyclohexyl and dimethylcyclohexyl. Examples of alkyl-, allcoxy- or
haloalkoxy-
substituted phenyl and benzyl are methylphenyl, dimethylphenyl,
trimethylphenyl, ethyl-
phenyl, methylbenzyl, methoxyphenyl, dimethoxyphenyl, trifluolnmethylphenyl,
bis-tri-
fluoromethylphenyl, tris-trifluoromethylphenyl, trifluoromethoxyphenyl and bis-
trifluoro-
methoxyphenyl. Preferred phosphine groups are those that contain identical or
different,
preferably identical, radicals from the group Cl-C6alkyl; cyclopentyl and
cyclohexyl that
are unsubstituted or have from 1 to 3 Cl-C4alkyl or Cl-C4alkoxy substituents,
benzyl and,
especially, phenyl that is unsubstituted or has from 1 to 3 Cl-C~allcyl, Ci-
C4alkoxy, F, Cl,
Cl-C4fluoroalkyl or Cl-C4fluoroalkoxy substituents.
Y as a diphosphine is preferably of formula IV, IVa, IVb, IVc or xVd,
R~RgP-R~-PRipRll (IV),
R~R8P-O-R12-PR1oR11 (Iya),
R~R8P-NR~-R12-PR1oR11 (IVb),
R~RgP-O-R13-O-PR1aR11 (IVc),
R~RBP-N~-Rls-~-PR1oR11 (Nd)~
wherein
R~, Rg, Rlo and Rll are each independently of the others a hydrocarbon radical
having
from 1 to 20 carbon atoms that is unsubstituted or substituted by Cl-C6alkyl,
Cl-C6alkoxy,
halogen, Cl-C6haloalkyl, (Cl-Cl2alkyl)3Si, (C6H5)3Si, Cl-C6haloalkoxy, -NH2,
phenyl2N-,
benzyl2N-, morpholinyl, piperidinyl, pyrrolidinyl, (Ci-Cl2alkyl)2N-, -ammonium-
Xl~,
-S03M1, -C02M1, -P03M1 or by -COO-Cl-Cbalkyl, wherein Ml is an alkali metal or
hydrogen and Xle is the anion of a monobasic acid;
Rg is linear CZ-C4alkylene that is unsubstituted or substituted by Cl-C6alkyl,
CS- or
C6-cycloalkyl, phenyl, naphthyl or by benzyl; 1,2- or 1,3-cycloalkylene or -
cycloalkenyl-
~WO 95121151 PCT/EP95/00221
-11-
ene, -bicycloalkylene or -bicycloalkenylene having from 4 to 10 carbon atoms,
each of
which is unsubstituted or substituted by Cl-C6alkyl, phenyl or by benzyl; 1,2-
or
1,3-cycloalkylene or -cycloalkenylene, -bicycloalkylene or -bicycloalkenylene
having
from 4 to 10 carbon atoms, each of which is unsubstituted or substituted by Cl-
C6alkyl,
phenyl or by benzyl, and in the 1- and/or 2-positions or in the 3-position of
which methyl-
ene or CZ-C4alkylidene is bonded; 1,4-butylene substituted in the 2,3-
positions by
O-
R21R~C\ and unsubstituted or substituted in the 1,4-positions by C1-C6allcyl,
O-
phenyl or by benzyl, wherein R21 and R~ are each independently of the other
hydrogen,
Cl-C6alhyl, phenyl or benzyl; 3,4- or 2,4-pyrrolidinylene or 2-methylene-
pyrrolidin-4-yl
the nitrogen atom of which is substituted by hydrogen, Cl-Cl2allcyl, phenyl,
benzyl,
Cl-Cl2alkoxycarbonyl, Cl-C8acy1 or by Cl-Cl2alkylaminocarbonyl; or 1,2-
phenylene,
2-benzylene, 1,2-xylylene, 1,8-naphthylene, 2,2'-dinaphthylene or 2,2'-
diphenylene, each
of which is unsubstituted or substituted by Cl-C4alhyl;
or R9 is a radical of the formula
X14- ~14-
Fe
Fe ~ CFiRl4-
Fe ~ Fe ~
Ru
v
WO 95/21151 PCT/EP95/00221
~~ ' ~ -12-
X14- ~R14-
Fe or Fe
~14-
wherein R14 is hydrogen, C1-Cgalkyl, C1-C4fluoroalkyl, phenyl or phenyl having
from
1 to 3 Cl-C4a.lkyl or Cl-C4alkoxy substituents;
R12 is linear C2- or C3-alkylene that is unsubstituted or substituted by Cl-
C6alkyl, CS- or
C6-cycloallcyl, phenyl, naphthyl or by benzyl; 1,2- or 1,3-cycloalkylene or -
cycloalkenyl-
ene, -bicycloallcylene or -bicycloalkenylene having from 4 to 10 carbon atoms,
each of
which is unsubstituted or substituted by Cl-C6alkyl, phenyl or by benzyl; or
1,2- or 1,3-
cycloalkylene or -cycloalkenylene, -bicycloalkylene or -bicycloalkenylene
having from 4
to 10 carbon atoms, each of which is unsubstituted or substituted by Cl-
C6allcyl, phenyl or
by benzyl, and in the 1- and/or 2-positions or in the 3-position of which
methylene or
C2-C4alkylidene is bonded; 3,4- or 2,4-pyrrolidinylene or 3-methylene-
pyrrolidin-4-yl the
nitrogen atom of which is substituted by hydrogen, Cl-Cl2alkyl, phenyl,
benzyl,
Cl-Cl2alkoxycarbonyl, Cl-Cgacyl or by Cl-Cl2alkylaminocarbonyl; or 1,2-
phenylene,
2-benzylene, 1,2-, 2,3- or 1,8-naphthylene, each of which is unsubstituted or
substituted by
Cl-C4~Y1~ and
R13 is linear C2alkylene that is unsubstituted or substituted by Cl-C6alkyl,
CS- or
C6-cycloallcyl, phenyl, naphthyl or by benzyl; 1,2-cycloallcylene or -
cycloalkenylene,
-bicycloalkylene or -bicycloalkenylene having from 4 to 10 carbon atoms, each
of which
is unsubstituted or substituted by Cl-C6alkyl, phenyl or by benzyl; 3,4-
pyrrolidinylene the
nitrogen atom of which is substituted by hydrogen, Cl-Cl2alkyl, phenyl,
benzyl,
Cl-Cl2alkoxycarbonyl, Cl-C8acy1 or by Cl-Cl2alkylaminocarbonyl; or 1,2-
phenylene that
is unsubstituted or substituted by Cl-C4alkyl, or is a radical, less two
hydroxy groups in
the ortho positions, of a mono- or di-saccharide, and
R~ is hydrogen, Cl-C4allcyl, phenyl or benzyl.
R~, R8, Rlo and Rll are preferably identical or different, preferably
identical, radicals from
the following group: Cl-C6alkyl; cyclopentyl and cyclohexyl that are
unsubstituted or
~WO 95/21151 ~ PCT/EP95/00221
- 13 -.
have from 1 to 3 Cl-C4alkyl or Ci-C4alkoxy substituents, benzyl and,
especially, phenyl
that is unsubstituted or has from 1 to 3 Cl-C4alkyl, Cl-C4alkoxy, F, Cl, Cl-
C4fluoroalkyl
or Cl-C4fluoroalkoxy substituents.
A preferred subgroup of diphosphines Y is formed by those of the formulae
Rls
Ris Rls ~~_A
\C A A
CH2
/CH-A /C-A
A A
R16 R16 /
Ri6
A
A-HRt5C
A ~ /Rts
C CHR -A
O/ \R ~ N~ t5
p A_HRtsC is I
Rte
CHRtS-A CHRts-A
CHRts-A O OCgHs
O
(C 2) n '
I CHRts-A HsCs O-A
Rt7 O-A
A A
Rts
Rt5 -A
Rt5 \ A
I
Rte Rts
WO 95/21151 ' PCT/hP95/00221
- 14-
CHR14-A
and Fe ~ A
wherein
Rls and R16 are each independently of the other hydrogen, Cl-C4alkyl, phenyl,
benzyl, or
phenyl or benzyl having from 1 to 3 Cl-C4alkyl or Cl-C4alkoxy substituents,
R14 1S hydrogen, Cl-C4aIkyl, phenyl, benzyl, or phenyl or benzyl having from 1
to 3
Cl-C4alkyl or Cl-C4alkoxy substituents,
Rl~ is hydrogen, Cl-C4alkyl, phenyl, benzyl, Cl-C6alkoxy-CO-, Cl-C6alkyl-CO-,
phenyl-CO-, naphthyl-CO- or Cl-C4a11cy1NH-CO-,
A may be identical or different groups -PR2, wherein R is Ci-C6alkyi,
cyclohexyl, phenyl,
benzyl, or phenyl or benzyl having from 1 to 3 Cl-C4alkyl, Cl-C4alkoxy, -CF3
or partially
or fully fluorinated Cl-C4alkoxy substituents, and
n is 0, 1 or 2.
Of those diphosphines, chirally substituted compounds are especially
preferred.
Some preferred examples of diphosphines Y are as follows (Ph is phenyl):
HsC CH-PPh2
HsC~ CH-PPh2
-PPh2
CH2-PPh2 ,
/CH-PPh2 CH-PPh
Ra = methyl, ~- 2
cyclohexyl,
phenyl Rb = H, methyl
Ph2PH2C
~ C/ Rc
PPh2 PPh2 /
Ph2PH2C ~ \ Rd
PPh2 PPh2 Rc = H, methyl, phenyl
Rd = H, methyl, phenyl
WO 95/21151 ,~ PCT/EP95/00221
'~~~9
-ls-
Ph2P
CH3
Ph2PHC O /CH3 ~ CH2-PPh2
C N
Ph2PHC O \CH3 Re
Re = -C02-tert-butyl, -CO-tert-butyl, H,
CH3 -CO-phen 1, -CO-NH-C -C 1
y 1 4~'
Ph2P PPh2
CH2-PPh2
N~ ~CH2)n
CH2-PPh2
Rf
n=0, 1 or2
Rf=Ci-Cq.~YI. benzyl
CHRi4 -P(RgyZ
O OCg~"y Fe ~ PPh2
O
H5C6 O ~ ~O-PPh2
O-PPh2 R14 = Ci-C4alkyl, especially methyl,
Rg = phenyl or cyclohezyl that is
unsubstituted or has from i
to 3 methyl, -CF3 or methozy
substituents
Suitable diphosphines and diphosphinites have been described, for example, by
H.B. Kagan in Chiral Ligands for Asymmetric Catalysis, Asymmetric Synthesis,
Volume s, pp. 13-23, Academic Press, Inc., N.Y. (198s). The preparation of
ferrocenyl
diphosphine ligands is described, for example, in EP-A-0 s64 406 and by T.
Hayashi et al.
in Bull. Chem. Soc. Jpn., 53, pages 1136-llsl.
A~ in formula BIa can be derived from inorganic or organic oxy acids. Examples
of such
acids are H2S04, HC104, HC103, HBr04, HI04, HN03, H3P03, H3P04, CF3S03H,
C6HSS03H, CF3COOH and CC13COOH. Complex acids from which A~ can be derived
WO 95!21151 ~ ' PCT/EP95/00221
3
S
- 16-
are, for example, the halo complex acids of the elements B, P, As, Sb and Bi.
Preferred
examples of A~ in formula IIIa are C104e, CF3S03~, BF4~, B(phenyl)4e, PF6~,
SbCl6~, AsF6~ and SbF6~.
When M~ in formula IIIb is an alkali metal cation, it may be, for example, a
Li, Na, K,
Rb or Cs cation. When M~ is quaternary ammonium, it may contain a total of
from 4
to 40, preferably from 4 to 24, carbon atoms. M~ may correspond to the formula
phenyl-
N~(Cl'C6~'1)3~ benzylN~(Cl-C6alkyl)3 or (Cl-C6alkyl)4N~. M~ in formula IIIb is
preferably Li~, Na~ or K~ or (Cl-C6alkyl)4N~.
Z in formula III is preferably Br or Cl and especially Cl. Z in formula IIb is
preferably Br
or I and Z in formulae ITIc and Illd is preferably I.
Especially suitable diphosphine ligands which can preferably be used in
catalysts of
formula (III) are, for example:
{(R)-1-[(S)-2-diphenylphosphino)ferrocenyl] }ethyl-di(3,5-dimethyl-4-N,N-
dipropyl-
aminophenyl)phosphine
{ (R)-1-[(S)-2-diphenylphosphino)ferrocenyl] }ethyl-di(3,5-dusopmpyl-4-N,N-
dimethyl-
aminophenyl)phosphine
{ (R)-1-[(S)-2-diphenylphosphino)ferrocenyl] } ethyl-di(3,5-diisopropyl-4-N,N-
dibenzylyl-
aminophenyl)phosphine
{ (R)-1-[(S)-2-diphenylphosphino)ferrocenylJ }ethyl-di(3,5-dimethyl-4-N,N-
dibenzylyl-
aminophenyl)phosphine
{ (R)-1-[(S)-2-diphenylphosphino)ferrocenylJ }ethyl-di(3,5-dimethyl-4-(1'-
pyrrolo)-
phenyl)phosphine
{ (R)-1-[(S)-2-diphenylphosphino)ferrocenyl] }ethyl-di(3,5-dimethyl-4-N,N-
dipentyl-
aminophenyl)phosphine
{ (R)-1-[(S)-2-diphenylphosphino)ferrocenyl} }ethyl-di(3,5-dimethyl-4-N,N-
dimethyl-
aminophenyl)phosphine
1,4-bis(diphenylphosphino)butane
{ (R)-1-[(S)-2-di(4-methoxyphenyl)phosphino)ferrocenyl} }ethyl-di(3,5-dimethyl-
4-N,N-
dimethylaminophenyl)phosphine and preferably
{ (R)-1-[(S)-2-diphenylphosphino)ferrocenyl] }ethyl-di(3,5-dimethyl-
phenyl)phosphine.
The preparation of the catalysts is known per se and is described, for
example, in
US-A-4 994 615, US-A-5 011 995, US-A-5 112 999 and EP-A-0 564 406. The
preparation
~WO 95!21151 PCT/EP95/00221
-17-
of the catalysts of formula III can be carried out, for example, by reacting a
diiridium
complex of the formula [IrXZ]2 with a diphosphine Y. The iridium catalysts can
be added
to the reaction mixture as isolated compounds. It has proved advantageous,
however, to
produce the catalyst in situ with or without a solvent prior to the reaction
and to add
optionally a portion or all of the acid and of an ammonium or alkali metal
halide.
The iridium catalysts are preferably used in amounts of from 0.0001 to 10 mol
%,
especially from O.OOI to 10 mol %, and more especially from 0.01 to 5 mol %,
based on
the imine.
The molar ratio of the imine to the iridium catalyst may be, for example, from
5 000 000
to 10, especially from 2 000 000 to 20, more preferably from 1000 000 to 20,
and more
especially from 500 000 to 100.
The process is carried out preferably at a temperature of from -20 to
100°C, especially
from 0 to 80°C and more especially from 10 to 70°C, and
preferably at a hydrogen
pressure of 2 x 105 to L5 x 10~ Pa (5 to 150 bar), especially 106 to 10~ Pa
(10 to 100 bar).
The chorides, bromides and iodides employed are preferably used in
concentrations of
from 0.01 to 500 mmol/1, especially from 0.01 to 50 mmol/1, based on the
volume of the
reaction mixture.
The process according to the invention comprises the additional concomitant
use of an
ammonium or metal chloride, bromide or iodide. The chlorides, bromides and
iodides are
used preferably in amounts of from 0.01 to 20(? mol %, especially from 0.05 to
100 mol %
and more especially from 0.5 to 50 mol %, based on the iridium catalyst. The
iodides are
preferred. Ammonium is preferably tetraalkylammonium having from 1 to 6 carbon
atoms
in the alkyl groups, and the metal is preferably sodium, lithium or potassium.
Special
preference is given to tetrabutylammonium iodide and sodium.
Provided that they are soluble in the reaction mixture and provided that
oxidation
reactions with other reactants can be ruled out, virtually any metal
chlorides, bromides and
iodides, that is to say those of the main groups and sub-groups of the
Periodic Table of the
Elements, can be used in the process according to the invention.
The reaction can be carried out in the absence or in the presence of solvents.
Suitable
WO 95/21151 PCTIEP95/00221
,,.
-18-
solvents, which can be used alone or as a mixture of solvents, are especially
aprotic
solvents. Examples are:
aliphatic and aromatic hydrocarbons, such as pentane, hexane, cyclohexane,
methylcyclo-
hexane, benzene, toluene and xylene; ethers, such as diethyl ether, diethylene
glycol
dimethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons, such as
methyl-
ene chloride, chloroform, 1,1,2,2-tetrachloroethane and chlorobenzene; esters
and
lactones, such as ethyl acetate, butyrolactone and valerolactone; acid amides
and lactams,
such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone, and
ketones,
such as acetone, dibutyl ketone, methyl isobutyl ketone and methoxyacetone.
The process according to the invention further comprises the additional
concomitant use
of an acid. It may be an inorganic or, preferably, an organic acid. The acid
is preferably
used in at least the same molar amount as the iridium catalyst (equivalent to
catalytic
amounts) and can also be used in excess. The excess may even consist in the
use of the
acid as solvent. Preferably from 0.001 to 50, in particular from 0.1 to 50 %
by weight of
acid is used, based on the amine. In many cases it can be advantageous to use
anhydrous
acids.
Some examples of inorganic acids are H2S04, highly concentrated sulfuric acid
(oleum),
H3P04, orthophosphoric acid, HF, HCI, HBr, HI, HC104, HBF4, HPF6, HAsF6,
HSbCl6,
HSbF6 and HB(phenyl)4. H2S04 is particularly preferred.
Examples of organic acids are aliphatic or aromatic, optionally halogenated
(fluorinated or
chlorinated) carboxylic acids, sulfonic acids, phosphorus( acids (for example
phosphon-
ic acids, phosphonous acids) having preferably from 1 to 20, especially from 1
to 12 and
more especially from 1 to 6, carbon atoms. Examples are formic acid, acetic
acid, propion-
ic acid, butyric acid, benzoic acid, phenylacetic acid, cyclohexanecarboxylic
acid, chloro-
or fluoro-acetic acid, dichloro- or difluoro-acetic acid, trichloro- or
trifluoro-acetic acid,
chlorobenzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic
acid,
p-toluenesulfonic acid, chlorobenzenesulfonic acid, trifluoromethanesulfonic
acid, methyl-
phosphonic acid and phenylphosphonic acid. Preferred acids are acetic acid,
propionic
acid, trifluoroacetic acid, methanesulfonic acid and chloroacetic acid.
It is also possible for acidic ion exchangers of an inorganic or organic
nature to be used as
the acids.
,iWO 95/21151 ~ PCT/EP95/00221
- 19-
In detail, the process according to the invention can be carried out by first
preparing the
catalyst by dissolving, for example, (Ir-dieneCl)2 in a solvent or an acid or
both, adding a
diphosphine and then an alkali metal or ammonium halide and stirring the
mixture.
(Ir-dieneCl)2 can also be used in solid form. A solution of imines is added to
that catalyst
solution (or vice versa) and, in an autoclave, hydrogen pressure is applied,
thus removing
the protective gas that is advantageously used It is advantageous to ensure
that the
catalyst solution stands for only a short time, and to carry out the
hydrogenation of the
imines as soon as possible after the preparation of the catalyst. The reaction
mixture is
heated, if desired, and then hydrogenated. Where appropriate, when the
reaction has
ceased the reaction mixture is cooled and the autoclave is depressurised. The
reaction
mixture can be removed from the autoclave under pressure with nitrogen and the
hydro-
genated organic compound can be isolated and purified in a manner known per
se, for
example by precipitation, extraction or distillation.
In the case of the hydrogenation of aldimines and ketimines, the aldimines and
ketimines
can also be formed in situ before or during the hydrogenation. In a preferred
form, an
amine and an aldehyde or a ketone are mixed together and added. to the
catalyst solution
and the aldimine or ketimine formed in situ is hydrogenated It is also
possible, however,
to use an amine, a ketone or an aldehyde together with the catalyst as the
initial batch and
to add the ketone or the aldehyde or the amine thereto, either all at once or
in metered
amounts.
The hydrogenation can be carried out continuously or batchwise in various
types of
reactor. Preference is given to those reactors which allow comparatively good
intermixing
and good removal of heat, such as, for example, loop reactors. That type of
reactor has
proved to be especially satisfactory when small amounts of catalyst are used.
The process according to the invention yields the corresponding amines in
short reaction
times while having chemically a high degree of conversion, with surprisingly
good optical
yields (ee) of 70 % or more being obtained even at relatively high
temperatures of more
than 50°C, and even with high molar ratios of imine to catalyst.
The hydrogenated organic compounds that can be prepared in accordance with the
invention, for example the amines, are biologically active substances or are
intermediates
for the preparation of such substances, especially in the field of the
preparation of pharma-
WO 95/21151 PCT/EP95/00221 ~~
-20-
ceuticals and agrochemicals. For example, o,o-dialkylarylketamine derivatives,
especially
those having alkyl and/or alkoxyalkyl groups, are effective as fungicides,
especially as
herbicides. The derivatives may be amine salts, acid amides, for example of
chloroacetic
acid, tertiary amines and ammonium salts (see, for example, EP-A-0 077 755 and
EP-A-0 115 470).
Especially important in this connection are the optically active amines of
formula
'R' 03
H' ,CH- Roa
N
Ro2 Roi
which can be prepared from the imines of formula (V) using the processes
according to
the invention, wherein Rol, R~ and Ro3 are each independently of the others Cl-
C4alkyl,
and Rte. is Cl-C4alkyl or Cl-C4alkoxymethyl or Cl-C4alkoxyethyl, and
especially the
amines of the formulae
CH3 CH3
H~N/CH-OCH3 H'N j H-OCH3
CH3 CH3 Via) ~d CH3 C2H5
/I
which can be prepared from the imines of the formulae (Va) and (Vb) and which
can be
converted in accordance with methods that are customary per se with
chloroacetic acid
into the desired herbicides of the chloroacetanilide type.
The Examples that follow illustrate the invention in more detail. The chemical
conversion
is determined by gas chromatography [DB 17/30 W column (15 m), manufacturer:
JCW
Scientific Inc. USA, temperature programme: from 60°C/1 min to
220°C, OT:
10° x min'lJ. The optical yields (enantiomeric excess, ee) are
detexxnined either by gas
chromatography [Chirasil-Val column, 50 m, manufacturer: Alltech, USA, T =
150°C,
isothermic], by HPLC (Chiracel OD column) or by 1H-NMR spectroscopy (using
shift
reagents).
Example I: Preparation of N-(2'-methyl-6'-ethyl-phen-1'-yl)-N-(1-
methoxymethyl)ethyl-
WO 95/21151 ' PCTlEP95/00221
-21
amine.
17.2 mg (0.027 mmol) of {(R)-1-[(S)-2-diphenylphosphino)ferrocenyl]}ethyl-
di(3,5-di-
methylphenyl)phosphine and 40 mg (0.108 mmol) of tetrabutylammonium iodide are
introduced in succession into a solution of 8.8 mg (0.013 mmol) of [Ir(1,5-
cycloocta-
diene)Cl]2 in 10 ml of acetic acid (degassed) and stirred for 15 minutes.
Separately, 412 g
(2 mol) of N-(2'-methyl-6'-ethyl-phen-1'-yl)-N-(1-methoxymethyl)eth-1-
ylideneamine
are dissolved in 70 ml of acetic acid (degassed). The imine solution and the
catalyst
solution are transferred in succession to a 1000 ml steel autoclave which is
under an inert
gas. In four cycles (10 bar, normal pressure) the inert gas is displaced by
hydrogen. Then a
pressure of 80 bar of hydrogen is applied and the autoclave heated to
50°C. After a
reaction time of 18 hours, the reaction is discontinued and the reaction
solution is cooled
to room temperature. The hydrogen is depressurised and the reaction solution
is expelled
under pressure from the autoclave. The conversion is 100 %. 100 ml of toluene
are added
and then toluene and acetic acid are removed in a rotary evaporator. The
residue is
distilled under a high vacuum (0.1 mbar), yielding 401 g (yield of 97 %) of
pure
N-(2'-methyl-6'-ethyl-phen-1'-yl)-N-(1-methoxymethyl)ethylamine. A sample (2
g) is
purified by means of flash chromatography [silica gel 0.040-0.063 mm, eluant
hexane/-
ethyl acetate 10:1)] in order to determine the enantiomeric purity. The
optical yield is
75.6 % (S).
Examyle 2: Preparation of N-(2'-methyl-6'-ethyl-phen-1'-yl)-N-(1-
methoxymethyl)ethyl-
amine
10.4 mg (0.0155 mmol) of [Ir(1,5-cyclooctadiene)Cl]2, 21.4 mg (0.0335 mmol) of
{ (R)-1-[(S)-2-diphenylphosphino)ferrocenyl] }ethyl-di(3,5-
dimethylphenyl)phosphine and
50 mg (0.136 mmol) of tetrabutylammonium iodide are dissolved in 2.5 ml of
degassed
acetic acid and stirred for 15 minutes. Separately, 17 g (0.083 mol) of 2-
methyl-6-ethyl-
aniline are dissolved in 9 g of anhydrous methoxyacetone. The methoxyacetone
solution
and the catalyst solution are transferred in succession to a 50 ml steel
autoclave which is
under an inert gas. In four cycles (10 bar, normal pressure) the inert gas is
displaced by
hydrogen. Then a pressure of 40 bar of hydrogen is applied and the autoclave
is heated to
50°C. After a reaction time of 18 hours, the reaction is discontinued
and the reaction
solution is cooled to room temperature. Working up is effected in accordance
with
Example 1. The conversion is 97 % (based on 2-methyl-6-ethylaniline) and the
optical
yield is 75.6 % (S).
Example 3: Preparation of N-(2'-methyl-6'-ethyl-phen-1'-yl)-N-(1-
methoxymethyl)ethyl-
WO 95/21151 PCT/EP95/00221
.
-22-
amine
14.0 mg (0.032 mmol) of (ZS,4S)-bis(diphenylphosphino)pentane (BDPP), 70 mg
(0.19 mmol) of tetrabutylammonium iodide and 0.3 ml of methanesulfonic acid
are intro-
duced in succession into a solution of 10.2 mg (0.015 mmol) of [Ir(1,5-
cyclooctadiene)-
Cl]2 in 3.5 ml of toluene (degassed) and stirred for 5 minutes. Separately,
3.12 g
(15.2 mmol) of N-(2'-methyl-6'-ethyl-phen-1'-yl)-N-(1-methoxyrnethyl)eth-1-
ylidene-
amine are dissolved in 3.2 ml of toluene (degassed). With the aid of a steel
capillary the
imine solution and the catalyst solution are transferred in succession to a 50
ml steel auto-
clave which is under an inert gas. In four cycles (10 bar, normal pressure)
the inert gas is
displaced by hydrogen. Then a pressure of 30 bars of hydrogen is applied.
After a reaction
period of 2.5 hours at 25°C the reaction is discontinued. Working up is
effected in accord-
ance with Example 1. Conversion is 100 % and the optical yield is 53.5 % (R).
Example 4: Preparation of N-(2'-methyl-6'-ethyl-phen-1'-yl)-N-(1-
methoxymethyl)elhyl-
amine
The process is carried out analogously to Example 3 and the reaction
conditions are
modified as follows:
0.35 ml of trifluoroacetic acid (instead of methanesulfonic acid). The
reaction time is
2 hours, the conversion is 95 % and the optical yield is 52.6 % (R).
Example 5: Preparation of N-(2'-methyl-6'-ethyl-phen-1'-yl)-N-(1-
methoxymethyl)ethyl-
amine
The process is carried out analogously to Example 3 and the reaction
conditions are
modified as follows:
0.4 g of onho-phosphoric acid (instead of methanesulfonic acid) and 6.6 ml of
tetrahydro-
furan as solvent. The reaction time is 2.5 hours, the conversion is 98 % and
the optical
yield is 53.4 % (R).
Example 6: Preparation of N-(2',4'-dimethylthiophen-3'-yl)-N-(1-
methoxymethyl)ethyl-
amine
8.6 mg (0.0125 mmol) of [Ir(1,5-cyclooctadiene)Cl]2, 17.2 mg (0.0268 mmol) of
{ (R)-1-[(S)-2-diphenylphosphino)ferrocenyl] }ethyl-di(3,5-
dimethylphenyl)phosphine
(Iigand) and 30 mg (0.08 mmol) of tetrabutylammonium iodide are introduced in
succession into a 10 ml Schlenk flask which is under an argon atmosphere. 1 g
(5 mmol)
of N-(2',4'-dimethylihiophen-3'-yl)-N-(1-methoxymethyl)ethylideneamine, 5 ml
of
toluene and 2 mI of acetic acid are added thereto. That solution is
transferred by means of
~WO 95/21151 PCT/EP95/00221
...
_ 23 . _ .
a steel capillary to a 50 ml steel autoclave which is under argon. Then a
pressure of 30 bar
of hydrogen is applied as described in Example 1 and then the reaction
solution is stirred
for 20 minutes at room temperature. The reaction is discontinued, the hydrogen
is
depressurised and the reaction solution is expelled under pressure from the
autoclave.
Conversion is 100 %. The solvent (toluene) and acid additive (acetic acid) are
removed in
a rotary evaporator, yielding 1.2 g of oily crude product, which is then
purified by flash
chromatography (silica gel 0.040 - 0.063 mm, eluant hexane%thyl acetate
(3:1)). The
enantiomeric purity of the isolated product is 76.1 %.
Example 7: Preparation of N-(2',4'-dimethylthiophen-3'-yl)-N-(1-
methoxymethyl)ethyl-
amine
The process is carried out as in Example 6, but the reaction conditions are
modified as
follows:
Iigand: 12.3 mg (0.028 mmol) of (2S,4S)-bis(diphenylphosphino)pentane, 55 mg
(0.149 mmol) of tetrabutylammonium iodide. The reaction time is 1.4 hours. The
conversion is complete, the ee is 47.5%.
Example 8: Preparation of N-benzyl-N-(1-phenylethyl)amine
The process is carried out as in Example 6, but the reaction conditions are
modified as
follows: 0.636 g (3 mmol) of N-benzyl-N-(1-phenylethylidene)amine, 10.2 mg
(0.0152 mmol) of [Ir(1,5-cyclooctadiene)CI]2, 21.4 mg (0.0333 mmol) of {(R)-1-
((S)-2-di-
phenylphosphino)ferrocenyl]}ethyl-di(3,5-dimethylphenyl)phosphine (ligand) and
15 mg
(0.04 mmol) of tetrabutylammonium iodide, 2 ml of acetic acid, 15 ml of
toluene, 30 bar
of hydrogen, reaction temperature: 25°C. The reaction time is 20
minutes. The conversion
is complete, the ee 31°l0.
Example 9: Preparation of N-(2'-methyl-6'-ethyl-phen-1'-yl)-N-(1-
methoxymethyl)ethyl-
amine
2.7 mg (0.004 mmol) of [Ir(1,5-cyclooctadiene)Cl]2 and 5.8 mg (0.009 mmol) of
{ (R)-1-[(S)-2-diphenylphosphino)ferrocenyl] }ethyl-di(3,5-
dimethylphenyl)phosphine are
weighed into a Schlenk flask, and then the Schlenk flask is placed under an
argon atmos-
phere. Using a syringe, 2 ml of degassed tetrahydrofuran are then added and
the orange
solution is stirred for 30 minutes. 210 g (2 mol) of high-purity MEA-imine
(>99%) of
formula (Vb), 300 mg (0.8 mmol) of tetrabutylammonium iodide and 200 ml of
acetic acid
are introduced into a 1 litre laboratory autoclave. Then, using a syringe, 0.5
ml of the
above catalyst solution is added. The ratio of imine/Ir is 1000 000. The
autoclave is
WO 95/21151 i PCT/EP95/00221
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closed and flushed first with nitrogen, then with hydrogen. Then a pressure of
80 bar of '
hydrogen is applied and the reaction solution is stirred for 65 hours at a
temperature of
50°C internal temperature. When the absorption of hydrogen is complete,
the hydrogen is
depressurised and then the reaction solution is analysed. The conversion is
100 %, the
enantioselectivity 75% ee (S).
Examples 10 - 22: Preparation of N-(2'-methyl-6'-ethyl-phen-1'-yl)-N-(1-
methoxy-
methyl)ethylamine
In Examples 10 to 22, the process is carried out analogously to Example 6, but
with the
following modified reaction conditions: 105 g (0.5 mol) of N-(2'-methyl-6'-
ethyl-phen-
1'-yl)-N-(1-methoxymethyl)ethylideneamine, 1.7 mg (0.0025 mmol) of [Ir(1,5-
cycloocta-
diene)Cl]2, 3.8 mg (0.0059 mmol) of {(R)-1-[(S)-2-
diphenylphosphino)feirocenyl] }ethyl-
di(3,5-dimethylphenyl)phosphine, 70 mg (0.189 mmol) of tetrabutylammonium
iodide,
80 bar of hydrogen and 50°C. The acids used and the results of the
respective tests are
shown in Table 1.
Table 1:
Example acid time conversion ee
(g) [hrs] [%] [%]
CH3COOH (1 g) 16 100 70 (S)
11 CI2CHCOOH (1 g) *) 1.5 100 75 (S)
12 C13CCOOH (1 g) *) 1.75 100 76 (S)
13 CH3COOH (10 g) 2 100 76 (S)
14 CH3(CH2)3COOH (10 g) 3 I0(? 76 (S)
CH3(CH2)4COOH (10 g) 16 100 76 (S)
16 (CH3)2CHCH2COOH (10 g) 25 100 76 (S)
17 C6H5CH2COOH (10 g) 8 95 76 (S)
I8 C6H5COOH (10 g) 19 90 75 (S) ,
19 CH3S03H (1 g) 2.5 100 76 (S)
CH3P(O)(OH)2 (1 g) 2 100 76 (S)
21 HOOC(CH2)2COOH (10 g)**) 20 90 74 (S)
22 HOOC(CHOH)2COOH (10 g)**) 22 91 72 (S)
~WO 95!21151 PCT/EP95/00221
-25-
*) dissolved in 2 ml of isopropanol
**) suspension in 10 ml of isopropanol
Example 23: Preparation of N-(2'-methyl-6'-ethyl-phen-1'-yl)-N-(1-
methoxymethyl)-
ethylamine
The process is carried out analogously to Example 13, but using the following
Iigand:
4.3 mg (0.0059 mmol) of {(R)-1-[(S)-2-Biphenylphosphino)ferrocenyl]}ethyl-
di(3,5-di-
methyl-4-N,N-dipropylaminophenyl)phosphine. The reaction time is 3.5 hours,
the
conversion: 100%, the enantiomeric purity 83% (S).
Example 24: Preparation of N-(2'-methyl-6'-ethyl-phen-1'-yl)-N-(1-
methoxymethyl)-
ethylamine
The process is carried out analogously to Example 13, but using the following
ligand:
4.2 mg (0.0059 mmol) of { (R)-1-[(S)-2-diphenylphosphino)ferrocenyl] }ethyl-
di(3,5-diiso-
propyl-4-N,N-dimethylaminophenyl)phosphine. The reaction time is 24 hours, the
conversion: 98%, the enantiomeric purity 66% (S).
Example 25: Preparation of N-(2'-methyl-6'-ethyl-phen-1'-yl)-N-(1-
methoxymethyl)-
ethylamine
The process is carried out analogously to Example 13, but using the following
ligand:
5.0 mg (0.0059 mmol) of {(R)-1-[(S)-2-diphenylphosphino)ferrocenyl] }ethyl-
di(3,5-diiso-
propyl-4-N,N-dibenzylylaminophenyl)phosphine. The reaction time is 22 hours,
the
conversion: 99.5%, the enantiomeric purity 63% (S).
Example 26: Preparation of N-(2'-methyl-6'-ethyl-phen-1'-yl)-N-(1-
methoxymethyl)-
ethylamine
The process is carried out analogously to Example 13, but using the following
ligand:
4.8 mg (0.0059 mmol) of {(R)-1-[(S)-2-Biphenylphosphino)ferrocenyl]}ethyl-
di(3,5-di-
methyl-4-N,N-dibenzylylaminophenyl)phosphine. The reaction time is 24 hours,
the
conversion: 85%, the enantiomeric purity 76% (S).
Example 27: Preparation of N-(2'-methyl-6'-ethyl-phen-1'-yl)-N-(1-
methoxymethyl)-
ethylamine
The process is carried out analogously to Example 13, but using the following
ligand:
4.1 mg (0.0059 mmol) of {(R)-1-[(S)-2-Biphenylphosphino)ferrocenyl]}ethyl-
di(3,5-di-
methyl-4-(1'-pyrrolo)phenyl)phosphine. The reaction time is 3 hours, the
conversion:
WO 95/21151 PCT/EP95/00221
-26-.
100%, the enantiomeric purity 69% (S).
Example 28: Preparation of N-(2'-methyl-6'-ethyl-phen-1'-yl)-N-(1-
methoxymethyl)-
ethylamine
The process is carned out analogously to Example 13, but using the following
ligand:
4.6 mg (0.0059 mmol) of { (R)-1-[(S)-2-diphenylphosphino)ferrocenyl] } ethyl-
di(3,5-di-
methyl-4-N,N-dipentylaminophenyl)phosphine. The reaction time is 21 hours, the
.
conversion: 90%, the enantiomeric purity 82.5% (S).
Example 29: Preparation of N-(2'-methyl-6'-ethyl-phen-1'-yl)-N-(1-
methoxymethyl)-
ethylamine
The process is carried out analogously to Example 13, but using the following
ligands:
4.0 mg (0.0059 mmol) of {(R)-1-[(S)-2-diphenylphosphino)ferrocenyl]}ethyl-
di(3,5-di-
methyl-4-N,N-dimethylaminophenyl)phosphine. The reaction time is 1 hour, the
conversion: 100%, the enantiomeric purity 80% (S).
Example 30: Preparation of N-benzyl-N-(1-phenylethyl)amine
The process is carned out as in Example 8 but the reaction conditions are
modified as
follows: 0.636 g (4.8 mmol) of N-benzyl-N-(1-phenylethylidene)amine, 3.2 mg
(0.0048 mmol) of [Ir(I,5-cyclooctadiene)Cl]2, 4.5 mg (0.01 mmol) of 1,4-
bis(diphenyl-
phosphino)butane (ligand) and 30 mg (0.08 mmol) of tetrabutylammonium iodide,
2 ml of
acetic acid, 5 ml of toluene, 40 bar of hydrogen, reaction temperature:
25°C. The reaction
time is 2 hours, the conversion is complete.
Example 31: Preparation of N-(2'-methyl-6'-ethyl-phen-1'-yl)-N-(1-
methoxymethyl)-
ethylamine
The process is carried out analogously to Example 13, but using the following
ligand:
4.1 mg (0.0059 mmol) of { (R)-1-[(S)-2-di(4-
methoxyphenyl)phosphino)ferrocenyl] }-
ethyl-di(3,5-dimethyl-4-N,N-dimethylaminophenyl)phosphine. The reaction time
is
3.5 hours, the conversion: 100%, the enantiomeric purity 76% (S).
Example 32: Preparation of N-(2'-methyl-6'-ethyl-phen-1'-yl)-N-(1-
methoxymethyl)-
ethylamine
The process is carried out analogously to Example 13, but using the following
catalyst
precursors instead of the in sisu catalyst: 10.4 mg (0.01 mmol) of [Ir(1,5-
cyclooctadiene)-
( { (R)-1-[(S)-2-diphenylphosphino)ferrocenyl] } ethyl-di(3,5-
dimethylphenyl)phosphine)]-
,~WO 95/21151 J .~ PCT/EP95100221
-27-
BF4, 135 mg (0.365 mmol) of tetrabutylammonium iodide; 0.3 litre steel
autoclave. The
reaction time is 45 min, the conversion: 100%, the enantiomeric purity 78%
(S).
Example 33: Preparation of N-(2'-methyl-6'-ethyl-phen-1'-yl)-N-(1-
methoxymethyl)-
ethylamine
The process is carried out analogously to Example 13, but using the following
catalyst
precursors instead of the in situ catalyst: 9.9 mg (0.01 mmol) of [Ir(1,5-
cyclooctadiene)-
( { (R)-1-[(S)-2-diphenylphosphino)ferrocenyl] } ethyl-di(3,5-
dimethylphenyl)phosphine)-
Cl], 135 mg (0.365 mmol) of tetrabutylammonium iodide; 0.3 litre steel
autoclave. The
reaction time is 35 min, the conversion: 100%, the enantiomeric purity 77.8%
(S).
Example 34: Preparation of N-(2',6'-dimethylphen-1'-yl)-N-(1-
methoxymethyl)ethylamine
The process is carried out as in Example 6 but the reaction conditions are
modified. as
follows: 514 g (2.6 mol) of N-(2',6'-dimethylphen-1'-yl)-N-(1-
methoxymethyl)ethylamine,
77 mg (0.115 mmol) of [Ir(1,5-cyclooctadiene)Cl]2, 2I4 mg (0.27 mmol) of {(R)-
1-
[(S)-2-diphenylphosphino)ferrocenyl] }ethyl-di(3,5-dimethyl-4-N,N-
dipropylamino-
phenyl)phosphine, 3.5 g (9.5 mmol) of tetrabutylammonium iodide, 50 ml of
acetic acid,
80 bar of hydrogen, temperature: 50-60°C. The reaction time is 2.5
hours, the conversion:
100 %, the enantiomeric purity 78.9 % (S).
Example 35: Preparation of N-(2',6'-dimethylphen-1'-yl)-N-(1-
methoxymethyl)ethylamine
The process is carried out as in Example 33 but the reaction conditions are
modified as
follows:
ml (0.024 mol) of N-(2',6'-dimethylphen-1'-yl)-N-(1-methoxymethyl)ethylamine,
10.2 mg (0.015 mmol) of [Ir(1,5-cyclooctadiene)Cl]2, 21.5 mg (0.033 mmol) of
{(R)-
1[(S)-2-diphenylphosphino)ferrocenyl) }ethyl-di(3,5-dimethylphenyl)phosphine,
50 mg
(0.135 mmol) of tetrabutylammonium iodide, 2 ml of acetic acid, 80 bar of
hydrogen,
temperature: 50-60°C, 50 ml small autoclave. The reaction time is 1
hour, the conversion:
100 %, the enantiomeric purity 56.2 % (S).
Example 36:
The procedure followed is analogous to Example 6 but with the following
modified
reaction conditions.
31 kg (148.3 mol) of N-(2'-methyl-6'-ethyl-phen-1'-yl)-N-(1-
methoxymethyl)ethylidene-
amine are placed in a 50 litre steel autoclave, followed by the addition of
500 mg
(0.744 mmol) of [Ir(1,5-cyclooctadiene)Cl]2, 1.15 g (1.8 mmol) of { (R)-1-[(S)-
2-diphenyl-
WO 95/21151 PCT/EP95/00221 ~,
-28-
phosphino)ferrocenyl]}ethyl-di(3,5-dimethylphenyl)phosphine, 22.5 g (61 mmol)
of tetra-
butylammonium iodide and 3 litres of acetic acid. The hydrogen pressure is 75
bar, the
reaction temperature 50°C. After a reaction time of 13 hours the
conversion is complete.
The ee is 75 % (S).
Example 37: Preparation of S-2-chloro-N-(2,6-dimethylphenyl)-N-(2-methoxy-1-
methyl-
ethyl)-acetamide
With stirring and while passing nitrogen through the mixture, 433 g (5.48 mol)
of pyridine
are added dropwise at 15-20°C in the course of 25 minutes to a solution
of 883 g
(4.57 mol) of S-2,6-dimethyl-N-(2-methoxy-1-methylethyl)-aniline (ee 78.2 %)
in
1.8 litres of toluene. Then, with ice-cooling at 15-20°C, 547 g (4.84
mol) of chloroacetyl
chloride are added dropwise thereto in the course of 1.5 hours. When the
dropwise
addition is complete, the suspension so obtained is stirred for a further 1.5
hours at room
temperature. For working-up, the reaction mixture is poured onto 2 litres of
water and
extracted twice using 200 ml of toluene each time. The organic phases are
combined,
washed once with 300 ml of 2N hydrochloric acid, twice using 300 ml of
saturated sodium
chloride solution each time and once with 600 ml of saturated sodium hydrogen
carbonate
solution, dried over sodium sulfate and filtered, and the solvent is removed
in vacuo. For
purification, the crude product so obtained is subjected to fractional
distillation.
B~P~o.3 138-140°C; ee 78.1 %.
Exam~Ie 38: Preparation of S-2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-
1-
methylethyl)-acetamide
10.52 kg (50.7 mol) of S-2-ethyl-N-(2-methoxy-1-methylethyl)-6-methylaniline
(ee
80.9 %; ja]D~: 16.43 c: 2.6112 in hexane) are placed in 20 litres of toluene,
and at 10°C
4812 g (60.8 mol) of pyridine are added. With ice-cooling at 10-20°C,
6073 g (53.7 mol)
of chloroacetyl chloride are then added dropwise in the course of 2.5 hours to
the reaction
solution so obtained. When the addition is complete, the resulting suspension
is stirred at
room temperature for 16 hours. For working-up, the reaction mixture is poured
onto
20 litres of water and the resulting emulsion is stirred vigorously for 10
minutes. After
removal of the organic phase, the aqueous phase is extracted once with 10
litres of hexane.
The combined organic phases are washed once with 10 litres of water, once with
5 litres of
2N hydrochloric acid and once with 10 litres of water, dried over sodium
sulfate and
filtered, and concentrated in a rotary evaporator. For purification, the crude
product so
obtained is subjected to fractional distillation. B.p. p.i 135-140°C;
c~.,e 81.0 %;
[a]D2°- -6.53 c: 2.2364 in hexane.
~WO 95/21151 PCT/EP95/00221
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Example 39:
40 kg (194 mol) of MEA-imine of formula (Vb) are drawn into an inert container
towards
a closed vacuum and the residual vacuum is broken with nitrogen. The contents
of the
container are then introduced under pressure into an inert 50 litre loop
reactor (loop
reactor manufactured by Buss). After a mixture of
0.14 g (2.08 10'~ mol) of [Ir { COD } Cl]2
0.27 g (4.23 10~ mol) of ligand {(R)-1-[(S)-2-diphenylphosphino)ferrocenyl]
)ethyl-
di(3,5-dimethyl-phenyl)phosphine and
6.20 g (1.66 10'2 mol) of TBAI (tetrabutylammonium iodide),
has been introduced into the reactor via a solids sluice, rinsing is carried
out with 4.1 kg
(68 mol) of acetic acid (anhydrous) and the reactor is depressurised. The
reactor is then
twice pressurised with hydrogen to 5 bar and depressurised. The accompanying
heating of
the reactor is set to Ta = 50°C. The loop reactor is then pressurised
to 80 bar with
hydrogen and the circulating pump is switched on. A rapid absorption of
hydrogen is
observed which achieves the theoretical hydrogen consumption after about 1-2
hours.
When no further absorption of hydrogen can be detected, the reactor contents
are cooled to
room temperature and depressurised. The reactor is then rendered inert with
nitrogen and
the contents are removed. The hydrogenated solution is worked up by
distillation and the
product is isolated in a yield of 98 %.
Example 40:
The process is carried out as in Example 6, but the reaction conditions are
modified as
follows: in a 11-reaction vessel 413 g (2,004 mmol) of the imine, 2,8 mg of
the iridium
compound, 6,4 mg of the diphosphine ligand and 124,2 mg of the iodide are
used. Instead
of 2 ml of acetic acid 0,1 g of H2S04 are used.
The conversion is 100 %. After isolation and purification according to Example
6 one
obtains 99 % of the desired product, the optical yield being 76,0 %(S).
