Note: Descriptions are shown in the official language in which they were submitted.
~9074
The present invention relates to optically active compounds
belonging to the class of the aminophosphines, and to their
use, together with suitable derivatives of transition metals,
in the asymmetrical hydrogenation of a broad range of
compounds, selected amongst prochiral and racemic olefins and
the compounds containing CO and/or CN groups.
The preparation on industrial basis of optically active
organic compounds having high optical purity, such as for
instance levorotatory amino acids, is still now almost exclu-
sively depending on processes of biochemical or microbiologicaltype.
Until some years ago no approaches of pure chemical nature
were known which, due to the process economy and to the optical
yield, were able to compete with the above mentioned methods.
However, the discovery of new homogeneous catalytic systems
having high stereospecificity, such as for example tris
(triphenyl-phosphine) chloro-rhodium, and the new developments
in the synthesis of asymmetrical phosphorus based phosphines
lead to the preparation of chiral complexes of transition
metals having high stereoselectivity in the hydrogenation of
prochiral olefins.
We found now a process permitting the preparation of a
wide range of active complexes for the asymmetrical hydrogen-
ation of unsaturated compounds, more particularly of olefins,
with high conversion and optical purity.
In fact, the object of the present invention is a complex
of a transition metal with an asymmetrical aminophosphine of
the general formula:
P Rx (NR R )3 x
wherein Rl is alkyl, aryl, alkylaryl, cycloalkyl, alcoxy,aryl-
oxy, alkylthio, arylthio , alkylphosphino , arylphosphino or
aminophosphino; x varies between 0 and 2;R2 and R3 are identical
f~ -- 2
`~i
~19~1~4
or different an~ each represents an alkyl, aryl,alkylaryl,aryl-
alky],cycloalkyl radical, at least one of the radicals R2 and
R containing one or more non racemic chiral centers.
The radical NR2R3 represents optically active ~uno groups deriving
from the amino compounds as hereinafter described, which consti-
tute a wide category of mono- and poly-~entate ligands~ capable
of coordinating transition metals, thus forming complexes sui~-
able for the asymme-trical hydrogenation, with high conversion
level~ of prochiral and racemic olefins~ to produce the corre-
sponding satura-ted compounds with a good opbica] purity. The
reparation ol the amino-pllosl)llo-org.lnic coml)owlds is carried
out starting from compounds having the formula
1~2
R3- N - X
_ _ n
wherein~ when n is 1~ X may represent hydrogen~ an alkali metal
or PR X; when n is 2~ X is a radical of the type -PR, R being
selec~ed amongst the above mentioned radicals and, when n is 3,
X represents P~ R and R3, identical or different from each
other~ may represent an alkyl~ alkylaryl, aryl-a:lkyl~ cycloalkyl
olle
radical~ at least/of the two radicals containing one or more non
racemic chiral centers. The said prep~ra~ion of the compounds
can be carried Ollt according to one o~ tlle following schemes :
1 ) R~NH + R2PCl + B ~_ R -NH-PR2 + . HCl
2 ) RR Nll + R2PCl + B --~RR N-l'R2 +- IICl
3 ) RR NNa + R2PCl -~D RR N - PR2 + NaCl
4) 2RR NH + RPC12 +2B _ (RR N)2PR + 2 B HCl
5) R NH2 + 2 R2PCl + 2 ~R N(PR2)2 + 2 B- IICl
6 ) (RRl~N)2PR + ROII ~ (RR N)PR(OR) + I~NII
7 ) 3 RR Nll + I'C13 + 3 13 --b- ( 1~ N ) 3P + 3 IS IlCl
wherein the groups R have the above meanings, B is an organic
base~ or the preparation can ~e carried out accordin~ to already
-- 3
. ~
~5~7~
known processes and related to the corresponding achiral
compounds.
Amongst the optically active amines (R*~H2) there can
be for instance cited alpha-methyl-benzylamine, bornylamine,
sec~-butylamine, menthylamine or any primary amine containing
one or more non racemic chiral centers; or secondary amines
(R RNH) wherein one or both the groups attached to the nitrogen
atom contain one or more non racemic chiral centers. For ex-
ample, unsubstituted N alpha-methylbenzylamine, pipecoline,
desoxyephedrine, 0-substituted ephedrine, N-monosubstituted
and N,N'-disubstituted ethylendiamine with at least a non racemic
chiral substituent, piperazines containing one or more non race-
mic chiral centers.
The ac1:ive catalytic complex is formed in the asymme-
trical hydrogenation by reacting one of the above described
ligands with a coordination compound of a metal of the transition
series, preferably Cr Mo W Fe Co Ni Ru Rh Pd Pt Os
Ir Cu Ag Au Ti V.
The ligands of the coordination compounds can be anionic
or neutral. Amongst the anionic ligands the halogens, the cya-
nide, nitrate, acetate, acetylacetonate, the sulfide and like
ions can be cited. Amongst the neutral ligands, water, ammonia,
amines, phosphines, carbon monoxide, olefins, diolefins and the
like can be cited.
Amongst the representative compounds rhodium (III) hydra-
ted chloride, ruthenium(III? chloride~ dichloro-tetrakis (tri-
phenylphosphine)ruthenium( ), rhodium (I) ~-dichloro-tetrakis
(ethylene)~ rhodium (I) Ju-dichloro-bis(norbornadiene), dichloro-
tetraamino-platinum (II),dibromo-tetrakis(triphenylphosphine) pal-
ladium can be indicated.
The molar ratio between the ligand and the complex of the
transition metal, as expressed as the ratio between the number of
4.
110907,4
phosphorus atoms of the ligand and the number of metal atoms
of the complex may vary between 1 and 15, the values of 2, 3,
4 being preferred.
The reaction solvents can be aromatic aliphatic hydro-
carbons~ alcohols, ethers, ketones~ esters~ amides and their
mixtures
The reaction of asymmetrical hydrogenation is carried
out at a molar ratio between the substrate and the catalyst
variable between 10,000 and 10. The reaction temperature can be
of between -70C and +200Co~ preferably of between O and 50C.
The hydrogen pressure is in the range of l and 100 atmospheres.
The following examples are illustrative of the characte-
ristics of the invention, but should not anyhow be construed as
a limitation
EXAMPLE
N~N'-bis(S(-)alphamethylbenzyl)ethylendiamine is separa-
ted starting from S(-)alphamethylbenzylamine and diethyl oxalate;
the reduction of the diamide is carried out with lithium aluminum
hydride in THF and the corresponding diamine is isolated as the
dihydrochloride, having melting point of 250C (yield : 80~).
After the dihydrochloride has been cleared by 10% NaOH,
0.050 moles of the diamine are treated with 0.100 moles of di-
phenylchlorophosphine in 300 mls of anhydrous benzene, in the pre-
sence of 0.200 moles of triethylamine.
The mixture is refluxed for 20 hours, the hydrochloride
of triethylammoniùm being then filtered and the benzene solution
is concentrated until N-N' bis (S(-)alpha-methylbenzyl) N-N' bis
(diphenylphosphino) ethylendiamine is separated~ mOpO 138-140C
(yields of 70% with respect to the starting diamine).
3 / ~ 725 = _ 91.5 ( c = 1~ CHC13)
The catalyst is prepared by treating 505mg of rhodium( )
Judichloro tetrakis(ethylene) (17.7 x 10-6 moles) with 22.5 mg of
ilO9074
N~N' bis(S(-)alpha-methylbenzyl) N-N' (diphenylphosphino)
ethylendiamine (35.4 x 10-6 moles)~ 6 mls of anhydrous benzene
being used as the solvent.
Atomic ratio P/Rh ~ 2
The solution is -transferred into a flask containing
2.8 g of alpha-acetamido cinnamic acid in 24 mls of anhydrous
methanolg the flask being connected to an hydrogenating appara-
tus operating at atmospheric pressure and thermostated at 25C,
by which a careful purge with hydrogen of the reaction environ-
ment is affected before the catalytic complex is addedO
The reaction pattern is monitored through the normal
gauging techniques.
The initial rate of hydrogen absorption is of about 4
mls/min., as measured under the operating conditions.
After 3 hours the conversion is about 85%. The reaction
is terminated and the reaction product is separated by evaporating
the solvent under reduced pressure .
The residue product is treated by a 0.5 N NaOH solution
and the insoluble catalyst is filtered.
The aqueous solution is made acidic to pH 2-3 with dilu-
ted HCl~ and the organic phase is extracted five times with ethyl
ether; the combined ethereal fractions are dried over Na2SO40
The ether is then evaporated. The residue product, examined by
N-
spectroscopic route (NMR, IR) consists of R(-)acetylphenyl ala-
nine / d 7 = -40 ( c = 1~ EtOH 95%) with an optical yield of
84%; the specific rotation for enantiomeric pure S(+) N-acetyl
phenyl alanine is / ~ 7 = + 4705 ( c = 1~ EtOH 95%)0
EXAMPLE 2
By repeating the process described in the Example 1 and
by using R(+) alpha methylbenzylamine, the N-N'(R(+)alphamethyl
benzyl) N-NI (diphenylphosphino) ethylendiamine is prepared~
having the two centers of chirality of opposite configuration
11()9074
with r-espect to -those of the diphosphine of the Example 1.
The ligand is reacted with the complex of rhodium(I)
and the catalytic complex is used in the hydrogenation of
alpha-acetaminocinnamic acid. The hydrogenated product~ after
isolation and examination as in the Example 1~ consists of S(+)
N-acetyl phenyl alanine~ having an observed rotation / CC 7
= + 38 9 (c = 1~ EtOH 95%) indicating an enantiomeric purity
of 82%.
EXAMPLE~ A3
2(S)~5(S) dimethylp.iperazine is prepared through the
cyclodimerization or S(-) alanine and reduction of the resulting
diketopiperazine by l.ithium aluminium hydride ~
Th.e subsequent reaction of the above mentioned piperazine
with diphenyl ch.lorophosphine in the presence of triethylamine
leads to the formation of 2(S),5(S) dimethyl N,N' diphenylphos-
phino (+) piperazine / ~_7 3 = + 78 ( c = 1~ THF). Yield 60%.
By operating according to the Example l~ the thus prepa-
red ligand (134 x 10-6 moles) is reacted with rhodium (I))udichloro
tetrakis ethylene (67 x 10-6 moles) and this catalytic complex
is used in the hydrogenation of alpha-acetamidocinnamic acid
(13 x 10 3 moles) at 25C and under atmospheric pressure. ~ .:
N acetyl (S) phenyl alanine is thus obtained with a yield of
80-85%~ / 0~ 7 = + 0.5 ( c = 1~ EtOH 95%). Optical purity : 1%.
~ D
EXAMPLE 4
The catalytic complex prepared according the technique
of the Example 1~ starting from 4709 mg of rhodium(I)~udichloro
tetrakis cyclooctene (66.8 x 10-6 moles) and 86 mg of N-N' (S(-)
methylbenzyl) N-N' (diphenylphosphino) ethylen-diamine (135 x 10-6
moles) is used in the catalytic hydrogenation of 3-acetoxy 4-
methoxy alpha-acetamido cinnamic acid ( 2 g) under atmospheric
pressure at 25Co By operating as described in the Example 1,
3-acetoxy 4-methoxy N acetyl (R) phenylalanine is isolated from
074
the reas~tion medium with a yield of 85-90%~ / d 7 = -16.9
c = 1, acetone).
The optical yield is 77%, and the enantiomeric pure
3-acetoxy 4-methoxy N-acetyl (R) phenyl alanine has / o~ 7
- 22 ( c = 1, acetone).
EXAI~IPLE 5
l-phenyl,295 S(-)alpha-methylbenzyl, l-phospha-2,5-
azacyclopentane ls prepared by reacting N~N'-(S(-)-alphamethyl-
benzyl) ethylendiamine with phenyl-dichlorophosphine in the pre-
sence of triethylamine 380 x 10 moles of the compound are
reacted with 95 x 10 6 moles of rhodium (I))udichloro tetrakis
(ethylene) ( P/Rh = 2)o
By opera-ting according to the Example 3 the catalyst is
used in the hydrogenation of acetamino acrylic acid~ under 15
atmospheres of hydrogen and at room temperature.
The enantiomeric pure N-acetyl S(-) alanine is obtained
with a yield of 85-90% and has / a~ 7D5 = ~ 5 ( c = l~ H20).
Optical yield 7.5
The enantiomeric pure N-acetyl R(-) alanine has / 0~ 7 5 ~
= 66.5 ( c = 2, H20). D
EXAMPLE 6
The catalytic complex prepared according to the Example
l~ starting from rhodium( )Judichloro tetrakis (ethylene) (73 x
10 moles) and N,N' (S(-)alpha-methylbenzyl) N~N' (diphenyl-
phosphine) ethylendiamine (146 x 10-6 moles) is used in the cata-
lytic hydrogenation of 3.4 methylendioxy) alpha-acetamido cinnamic
acid (6.98 x 10 3 moles) at 25C and under atmospheric pressure.
By operating as described in the Example 1~ 3~4 methylen-
dioxy, N acetyl (R) phenyl alanine is isolated with quantitative
yield~ 7 = - 40 ( c = 1.8, EtOH 95%). Optical yield: 75%.
~ D
The enantiomeric pure 3-4 methylendioxyg N acetyl (R)
phenylalanine has / ~ 7 = - 5304 ( c = 1.8, EtOH 95%).
1109~74
EXAMPLE 7
The catalytic complex as prepared according to the
techniq-ue of the Example 1, starting from rhodium(I) ~dichloro-
tetrakis (cyclooctene) (13~g x 10-6 moles) and N~NI~S(-)alpha-
methylbenzyl) N~N' (diphenyl-phosphino) ethylendiamine (27.5 x
10 6 moles) is uscd in the catalytic hydrogenation at 25C and
under atmospheric pressure o-E alpha-acetamido acrylic acid
(15.5 x 10 3 moles)~
The N acetyl (R) alanine which is isolated with quanti-
10 tative yïeld has / ~ 7 5 = 48.5. Optical yield : 73%.
EXAMPLE 8
The catalytic complex prepared as described in the
Example 1~ starting from rhodium ( ) ~dichloro tetrakis (cyclo-
octene) (146 x 10 6 moles) and N~N'(S(-)alpha-methylbenzyl) N~
N' (diphenylphosphino) ethylendiamine ( 278 x lo moles)~ is
used in the catalytic hydrogenation of the methyl ester of alpha-
acetamido cinnamiG acid ( 13.7 x lo 3 moles). The R(-) N acetyl-
phenyl alanine methyl ester~ which is isolated by chromatography
on silica gel~ has / o~ 7 5 = - lo (c = 1.9g MeOH).
Optical yield : 46 o5% .
The enantiomeric pure S(-) N acetyl phenylalanine methyl
ester has / 0~ 725 = ~ 21.4 ( c = 1.9, MeOH).
EXAMPLE 9
The catalytic complex as prepared according to the tech-
nique described in the Example 1~ starting from rhodium (I) ~dichloro-
tetrakis (ethylene) (77 x lo moles) and N~N' (S(-) alpha-methyl-
benzyl) N9N' (diphenylphosphino) ethylendiamine (154 x 10-6 moles),
is used in the catalytic hydrogenation of propan-2,3-dicarboxylic
acid (15 X lo 3 moles) at 15,5 atmospheres and 30c~
The propan 2~3 dicarboxylic (R) acid~ isolated with quanti-
tative yield, has / o~ 7 5 = - 1.5 ( c = lg H20). Optical yield :10%.
EXAMPLE 10
116~g~'74
The ~atalytic complex as prepared according to the
technique described in the Example 1~ starting from rhodium( )
~d:ichlo:ro tetrakis (ethylene) ( ~2 x 10 6 moles) and N~N~(S(-)
alpha-methylben~yl NgNI (diphenylphosphino) ethylendiamine
(146 x 10 moles)9 is used in the catalytic hydrogenation of
alpha-methyl cinnamic acid at 5 atmO a~d 25~C. The 2-benzyl
propion.ic (S) acid~ as quantitatively recovered according to the
disclosure of the Example 1, has / ~ 7 5 = - 1 ( c ~ l,benzene).
Optical y:ie].d : 4%q D
EXAMPLE 1].
. . . _
7 mls of anhydrous methanol and 5 g of acetophenone are
charged .in an autoclave under nitrogen atmosphere; a solution of
2 mls of ber-zene containing 1807 mg of rhodiumchl.oro-norbornadiene
~RhClNBD 7 dimer and 5603 mg of N-N' bis (S(-)alpha-methylbenzyl)-
-N-N' (diphenyl.phosphino) ethylendiamine (PNNP) is then added.
After establishing a vacuum condition~ the autoclave i.s charged
wi-th 112 at the pressure of 12 atmospheres. After 12 hours at
room temperature 4 atmospheres of hydrogen were absorbed with a
conversion of about 80%o The reaction is stopped at this time;
benzene and methanol are removed under reduced pressure and then,
by fractionated vacuum distillation, 3.9 g of a product are re-
co~ered whichS after analysis by spectroscopic route ~MR), con-
sists of R(~)l-methyl-phenyl-carbinol / ~ 7D = ~7-4 (pure
product). Optical purity : 17% ( / ~ 7 = ~ 44.2).
EXAMPLE 12
The catalyst is prepared from 45 mg of /RhClNBD 72 and
124 mg of (PN~P) in 3 mls of benzeneO Such a catalytic solution
is charged in an autoclave containing 5 g of cycl.ohexyl-methyl-
lc~o~o -in 7 mls of methanol. The autoclave is brought to 12
atmosphere pressure with hydrogen. After 48 hours at room
temperature about 3 atmO of H were absorbed; the reaction is
terminated; with a process like that of Example 1~ 3015 g of a
10~
11(~9~74
product are recovered~ which is R (-) l-cyclohexyl-ethanol
72 = _ 0 430 (pure compound) with optical yield of 8~.
~ D
( /-OC 7 20 5 5)
D
EXA~IPLI 13
A flask containing 2 mls of benzene is charged with
24.2 mg of /RhClNBD 72 and 66.8 mg of (PNNP), thereafter add-
ing 2.28 mls of diphenylsilane. The flask is cooled at 0C
C113
and 1.21 g of acetophenone-anil (0- N = C - 0) in 6 mls of ben-
zene are added dropwise . After 12 hours, still at 0C, 4 mls
of 10% HCl and acetone are added until a homogeneous solution is
obtained~ after filtration of the hydrolysis products~ After
removal of the acetone under reduced pressure~ 100 mls of 5%
HCl are added and the mixture is extracted six times with 25 mls
of Et20. The aqueous phase is made alkaline with 2N NaOH, and
the new organic phase~ as obtained by extracting four times with
20 mls of Et20, is dried over Na2S04; then the ether is removed.
The residue product is distilled under vacuum 700 mg being obtain-
ed, at the end, of a compound identified as R(-)N-phenyl-N-
methylbenzylamine, having / ~ 7 = - 3.29 ( c = 2.15~ EtOH).
Optical purity : 12.2% ( /~ 720 = 26.1).
EXAMPLE 14
By operating as described in the Example 3 and by using
a catalytic solution comprising 19 mg of j~hClNBD ~ and 55 mg of
(PNNP) in 2 mls of benzene~ 4.3 g of ethyl piruvate in 10 mls of
benzene are reacted with 5.79 g of Diphenyl silane in 5 mls of
benzeneO In this Example3 differently from the Example 3, the
silane is added dropwise to the solution of the other reactants
maintained at 0C. After 2 hours, still at 0C, the hydrolysis
is effected by means of 30 mls of MeOH containing 10 mg of p-toluen-
sulphonic acid~ After filtration and removal of the methanol,
llV9~74
3.5 g of D(~) ethyl lactate, / ~ 7 = + 3.25, arc isolatedby fractionated distillation,
Optical purity : 22.4% (/ o~7 = 14~5)~
