NO771419L - NEW AMINOPHOSPHINES AND PROCEDURES FOR THEIR PREPARATION - Google Patents

Description

New aminophosphines and method

for their production.

The present invention relates to the synthesis of new optically active compounds belonging to the class of aminophosphines, and their use together with suitable derivatives of transition metals,

by asymmetric hydrogenation of a wide variety of compounds,

selected from prochiral and racemic olefins and the compounds containing Co and/or CN groups.

Production of optically active organic compounds with hby optical purity on an industrial basis, such as e.g. left-handed amino acids, are still almost exclusively dependent on processes of a biochemical or microbiological type.

Until a few years ago, no attempt of a purely chemical type was known which, due to process economy and optical yield, was able to compete with the above-mentioned methods.

The discovery of new homogeneous catalytic systems with hby stereo-specific action, such as e.g. tris(triphenyl-phosphine)chloro-rhodium, and new advances in the synthesis of asymmetric phosphorus-based phosphines for the preparation of chiral complexes of transition metals with high stereoselectivity by hydrogenation of prochiral olefins.

A new class of optically active compounds has now been found which can be easily obtained and which allows the preparation of a wide range of active complexes for the asymmetric hydrogenation of unsaturated compounds, more particularly olefins, with high conversion and optical purity.

The object of the present invention is a new class of

12 3 1 amine derivatives of phosphorus of the type PR (NR R )_ , in which R is alkyl, aryl-thio, alkyl-phosphino, aryl-phosphino, amino-phosphino and the like, 2 3 x varies from 0 to 2, NR R represents optically active amino groups derived from the amino compounds described below, which constitute a broad category of mono- and poly-dentate ligands, capable of coordinating transition metals, such that complexes suitable for asymmetric hydrogenation, with a high degree of conversion, of prochirals are formed. and racemic olefins, for the production of the corresponding saturated compounds with a good optical purity. The production of the amino-phospho-organic compounds is carried out by starting from compounds of the formula

wherein, when n is 1, X represents hydrogen, an alkali metal or PR^X, and when n is 2, X is a radical of the type -Pr\where R'*' is selected from among the above-mentioned radicals, and when n is 3, X stands for P, R 2 and R 3 are the same or different from each other and stand for an alkyl, alkylaryl, aryl-alkyl or cycloalkyl radical, at least one of the two radicals containing one or more non-racemic chiral centers. The aforementioned preparation of the compounds can be carried out according to one of the following forms:

in which the groups R have the above meanings, B is an organic base, or the preparation can be carried out according to previously known processes and in accordance with the corresponding achiral compounds.

Among the optically active amines (R*NH2) can e.g. mention is made of alpha-methyl-benzylamine, bornylamine, sec-butylamine, menthylamine or any primary amine containing one or more non-racemic chiral centers, or secondary amines (R<*>RNH) in which one or both groups attached to the nitrogen atom contains one or more non-racemic chiral centers. E.g. unsubstituted N alpha-methylbenzylamine, pipecoline, desoxyephedrine, o-substituted ephedrine, N-monosubstituted and N,N<1->disubstituted ethylenediamine with at least one non-racemic chiral substituent, ipip^azines containing one or more non-racemic chiral centers.

The active catalytic complex is formed by the asymmetric hydrogenation by reacting one or more 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 in the coordination compounds can be anionic or neutral. Among the anionic ligands, halogen, cyanide, nitrate, acetate, acetylacetonate, sulfide and similar ions can be mentioned. Among the neutral ligands, mention may be made of water, ammonia, amines, phosphines, carbon monoxide, olefins, diolefins and the like.

Among representative compounds can be mentioned rhodium (III) hydrated chloride, ruthenium (III / chloride, dichloro-tetrakis (tri-phenylphosphine) ruthenium (II), rhodium (I hj.-dichloro-tetrakis (ethylene), rhodium (I ha-dichloro -bis(norbornadiene), dichlorotetraamino-platinum (II), dibromo-tetrakis(triphenylphosphine) palladium.

The molar ratio between the ligand and the complex of the transition metal, expressed as the ratio between the number of phosphorus atoms in the ligand and the number of metal atoms in the complex can vary between 1 and 15, the values 2, 3 and 4 being preferred.

The reaction solvents may be aromatic or aliphatic hydrocarbons, alcohols, ethers, ketones, esters, amides and their mixtures.

The reaction with asymmetric hydrogenation is carried out at a molar ratio between substrate and catalyst varying between 10,000 and 10. The reaction temperature can be between -70°C and +200°C, preferably between 0 and 50°C. The hydrogen pressure is in the range of 1 to 100 atmospheres.

The following examples illustrate the invention.

Example 1.

N,N'-bis(S(-)alphamethylbenzyl)ethylenediamine is separated by 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 with a melting point of 250°C (yield: 80%).

After the dihydrochloride has been clarified with 10% NaOH, 0.050 mole of the diamine is treated with 0.100 mole of diphenylchlorophosphine in 300 ml of anhydrous benzene, in the presence of 0.200 mole of triethylamine.

The mixture is refluxed for 20 hours, the triethylammonium hydrochloride is filtered off and the benzene solution is concentrated until N-N• bis (S(-)alphamethylbenzyl) N-N' bis(diphenylphosphino) ethylenediamine is separated, melting point 138-140°C (yield 70% in relation to starting the diamine.).

/a7<25>= - 91.5° (c = 1 in CHC1,)

D

f (I) The catalyst is prepared by treating 5.5 mg of rhodium p-— 6

dichlorotetrakis(ethylene) (17.7 -.10 mol) with 22.5 mg N-N' bis (S(-)alpha-methylbenzyl) N-N * (diphenylphosphino)ethylenediamine

— 6

(35.4 • 10 mol), 6 ml of anhydrous benzene being used as solvent.

Atomic ratio P/Rh = 2

The solution is transferred to a flask containing 2.8 g of alpha-acetamido-cinnamic acid in 24 ml of anhydrous methanol, the flask being connected _ to a hydrogenation apparatus operating at atmospheric pressure and ^ / which is thermostatically set to 25°C, and with which a careful flushing is carried out with hydrogen of the reaction environment for / the catalytic complex is added.

The course of the reaction is controlled by standard measuring techniques.

The initial rate of hydrogen absorption is approximately 4 ml/min., measured under working conditions. \

/ After 3 hours the conversion is approximately 85%. The reaction ends //

and the reaction product is separated by evaporation of the solvent under reduced pressure. ^

The residual product is treated with a 0.5 N NaOH solution and it

) insoluble catalyst is filtered off. //

The aqueous solution is made acidic to pH 2-3 with dilute HCl, and the organic phase is extracted five times with ethyl ether. The combined ether fractions are dried over Na 2 SO 4 . The ether is then evaporated. The residual product, examined by spectroscopy (NMR, IR) consists of

R(-)N-acetylphenyl-alanine /q?<20>= -40 ( c = 1, EtOH 95%) with a ) J optical yield . on. 84%^ The specific rotation for enantiomeric <<>C Irent S( + ) N-acetylphenyl-alanine is /a7d° = + 47'5 ( c = 1, EtoH95%). ,

Example 2.

By repeating the procedure described in example 1 and using R(+) alpha-methylbenzylamine, N-N'(R(+) alphamethylbenzyl) N-N• (diphenylphosphino) ethylenediamine is prepared, with two chirality centers with the opposite configuration in relation to them in the diphosphine of Example 1.

The ligand is reacted with the complex rhodium (I) and the catalytic complex is used in the hydrogenation of alpha-acetaminocinnamic acid. The hydrogenated product, after isolation and examination as in example 1, consists of S-£f) N-acetylphenyl-alanine, with an observed

— 20

rotation /a7 d + 38'9 (c = 1, EtOH 95%) indicating a

Example 3.

2(S),5(S) dimethylpiperazine is prepared by cyclodimerization of S(-) alanine and reduction of the resulting diketopiperazine with 1ithium aluminum hydride.

The subsequent reaction of the above-mentioned piperazine with diphenylchlorophosphine in the presence of triethylamine leads to the formation of 2(S),

— 23

5(S) dimethylN,N" diphenylphosphino (+) piperazine / a7 D = 78 (c = 1, THF). Yield: 60%.

By working according to example 1, the thus prepared ligand (134 • 10~^ mol) is reacted with ^rhodium (I)^- diklcxotetra-,kjLsj|tyJLej^(6^^ this catalytic complex is used c in the hydrogenation of alpha -acetamidocinnamic acid (13 • 10~^ mol) at 2 5°C and while mo sfæ retryKk^^ N^ a.cetyl ,(Sj_fÆnylj-ajLani n is obtained

in the same way with a yield of 80-85%, / oc7 ^ - + 0.5 (c = 1, EtOH 95%). Optimum unit: 1%. ~~~~-«-—

Example 4.

The catalytic complex prepared according to the procedure in Example 1, starting from 47.9 mg of rhodium (I) ^i-dichlorotetrakiscyclotone (66.8<*>IO"<6>mol) and "86 mg of N-N (S(-) methylbenzyl) N-N<*>(diphenylphosphino)ethylenediamine (135 • 10" -6 mol) is used

by the catalytic hydrogenation of 3-acetoxy 4-methoxy alpha-acetamidocinnamic acid (2g) under atmospheric pressure at 25°C. By working as described in the example, 3-acetoxy 4-methoxy N-acety]^Rj_j^ejiyJL.alam is isolated at^ 85-90%, /«7<22>= -16.9 (c = 1, acetone).

The optical yield is 77%, and the enantiometrically pure 3-acetoxy 4-methoxy N-acetyl (R)phenylalanine has /op ^<2>-22 c

acetone)..

Example 5.

1-Phenyl,2,5 S(-)alpha-methylbenzyl,1-phospha-2,5-azacyclopentane is prepared by reacting N-N(S(-)-alphamethylbenzyl)ethylenediamine with phenyl-dichlorophosphine in the presence of triethylamine. 380 • 10~^ mol of the compound is reacted with 95 • 10~ —6 mol of rhodium (I)^i-dichloro-tetrakis"(ethylene) ( P/Rh =2).

By proceeding in accordance with example 3, the ka ta lysator is used for the hydrogenation of acetaminoacrylic acid, under 15 atmospheres of hydrogen and at room temperature.

The enantiomerically pure N-acetyl S(-)-alanine is obtained with a yield of 85-90% and has /a/ 25 = -5 ( c = 1, H 2 O).

"s-°>c^t=—~ ~ ' • • —- ->

Optical yield^: 7.5

25

The enantiomerically pure N-acetyl R(-)-alanine has /a7 D = rr66;>5

(c = 2, H 2 O). ~~ ——____—_—_

Example 6.

The catalytic complex prepared according to Example 1,

starting from rhodium (I)^i-dichlorotetrakis (éylene) (73 * 10~—6

mol) and N,N' (S(-)-alpha-methylbenzyi) N,N<*>(diphenylphosphine) ethylene-diamine (146 • 10~ —6 mol) are used in the catalytic hydrogenation of 3,4 methylenedioxy, alpha- acetamidocinnamic acid (6.98 • 10 _3 mol)

at 25°C and under atmospheric pressure.

By working as described in example 1, 3,4 methylenedioxy, N-acetyl (R) phenylalanine is isolated with quantitative yield.

//«7 ^ 8 ="40 ('c = 1/8, EtOH 95%). Optical yield : 75%. N

The enanjy^merjur ene-S.^^me^ylendipksy/ N-a ce ty 1 (R) f enyl-alanine ^har^a7 *8 = -53.4 ( c = 1.8, EtOH 95%).

Example 7.

The catalytic complex prepared according to the procedure in example 1, starting from rhodium (I) ^i-dichlorotetrakis (cyclooctene) (13.9 • IO"<6>mol) and N,N<1>(S. (-)-alpha-methylbenzyl) N,N• (diphenyl-phosphino) ethylenediamine (27.5 -10 mol) is used ^"In the catalytic hydrogenation at 25°Cag under atmospheric pressure of alpha-acetamidoacrylic acid"(15.5 . 10~<3>mol).

The N-acetyl (R)-alanine that is isolated in quantitative yield has /a7 £5 = 48.5. Optical yield: 73%.

Example 8.

The catalytic complex prepared as described in example 1, starting from rhodium (I)^i-dichlorotetrakis (cyclooctene)

(146 • 10~<6>mol) and N,N<«>(S(-)-alphamethylbenzyl)N,N• (diphenyl-phosphino)ethylenediamine (278 • IO<-6>mol), are used in the /^catalytic hydrogenation of the methyl ester of alpha-acetamidocinnamic^-—3 / acid (13.7 • 10 mol). The R(-) N-acetylphenyl^alanine methyl ester, — 25 I which is isolated by chromatograph is ing on silica gel, has /cc7 D<=>-10 (c = 1.9, MeOH).

Optical yield: 46.5%

The enantiomerically pure S(-) N-acetylphenyl-alanine methyl ester has<25>%+21.4 c 1.9, MeOH).

Example 9.

The catalytic complex prepared according to the method described in example 1, starting from rhodium (I) yu-dichlorotetrakis (ethylene) 77 •10 mol) and N,N• (S(-) alphamethylbenzyl) N,N< 1>(diphenylphosphino)ethylenediamine (154 • 10~<6>mol), is used in the catalytic hydrogenation of propane-2,3-dicarboxylic acid (15 • 10~<3>mol) at 15.5 atmospheres and 30°C.

r The propane 2,3-dicarboxylic acid (R) isolated in quantitative yield,] /a7 q<5>= 2* 1, 5 ( c = 1, H2O). Optical yield: 10%. j

Example 10.

The catalytic complex prepared according to the procedure described in Example 1, starting from rhodium (I) u-dichlorotetrakis(ethylene) (72 • 10"<6>mol) and N,N'(S(-) alpha -methylbenzyl N, N1 (diphenylphosphino)ethylenediamine (146 • 10 mol)

used in the catalytic hydrogenation of alpha-methylcinnamic acid I^^ B^^^ S^ S^^^ S^^^' 2-benzylpropionic acid (S) quantitatively

gj enwonnet in he2jhoj.d„tilMfr.emgangsmoden^deskrøyet 1,

has / a7 c benzene).

Optical yield : 4%.</>

Example 11.

7 ml of anhydrous methanol and 5 g of acetophenone are introduced into an autoclave under a nitrogen atmosphere. A solution of 2 ml of benzene containing 18.7 mg of rhodium chloro-norbornadiene /RhClNBD72dimer<q>g 56.3 mg of N-N<1>bis (S(-)alpha-methylbenzyl)-N-N' (diphenylphosphino)ethylenediamine (PNNP) is then added . After vacuum conditions have been created, the autoclave is filled with H2 at a pressure of 12 atmospheres. After 12 hours at room temperature, 4 atmospheres of hydrogen had been absorbed with a conversion of approximately 80%. R^ ksionji__aybrytes on_dejfcbe^j;4gBa&kt. Benzene_and^metaho 1 is removed under reduced pressure and then recovered by fractional vacuum distillation 3.9 g of a product which, according to spectroscopic analysis (NMR), consists of R(+)l-methyl-phenyl-carbinol /a/ D 47, , 4 regj^pjrodu kt). Optical purity : 17%

(/a7 1° = +44.2)':" — '

Example 12.

The catalyst prepared from 45 mg /R^C1NBD72 and 124 mg (PNNP)

in 3 ml of benzene. Such a catalytic solution is introduced into an autoclave containing 5 g of cyclohexyl methyl ketone in 7 ml of methanol. The autoclave is brought to 12 atmospheres pressure with hydrogen. After 48 hours at room temperature, about 3 atmospheres of H2 had been absorbed. The reaction is interrupted. With a method similar to that in example 1, 3.15 g of a product which is recovered

Claims (12)

R (-) 1-cyclohexyl-ethanol / a? D 20 = -0.430 (pure compound) with optical yield 8%. (/ W 1° = - 5, 5). Example 13. A flask containing 2 ml of benzene is charged with 24.2 mg /RhC21NBD72 °9 66.8 mg (PNNP), then 2.28 ml of diphenylsilane is added. The flask. is cooled at 0°C and 1.21 g of acetophenone-anil ^ ' ^3 in 6 ml (6- N = C - 6) benzene is added dropwise. After 12 hours, still at 0°C, 4 ml of 10% HC1 and acetone are added until a homogeneous solution is obtained, after filtering the hydrolysis products. After removal of acetone under reduced pressure, 100 ml of 5% HC1 are added and the solvent is extracted 6 times with 25 ml of Et2 0. The aqueous phase is made alkaline with 2N NaOH and the new organic phase, obtained by extracting four times with 20 ml of Et2 0, is dried over Na2 SO^ . The ether is then removed. The residual product is destilled under vacuum and finally 700 mg of a compound identified as R (-)N-phenyl-N-methylbenzylamine with /ct7 ~ 20 = -3.29 ( c = 2.15, EtOH). Optical purity : 12.2% (/«7 £ = 26>1>)- Example 14. By proceeding as described in example 3 and by using a catalytic solution comprising 19 mg of /RhClNBD7o and 55 mg of (PNNP) in 2 ml of benzene, 4.3 g of ethyl pyruvate in 10 ml of benzene are reacted with 5.79 g of diphenylsilane in 5 ml of benzene. In this example, in contrast to example 3, the silane is added dropwise to the solution of the other reaction components kept at 0°C. After two hours, still at 0°C, the hydrolysis is carried out using 30 ml of MeOH containing 10 mg of p-toluenesulfonic acid. After filtration and removal of methanol, 3.5 g of D(+) ethyl lactate, / aj D 20 = 3.25, is isolated by fractional distillation. Optical purity: 22.4% (/«7 <20> = 14.5). PATENT CLAIMS. 1. Asymmetric aminophosphines, characterized in that they have the formula 12 3 PR (NR R )_ where R is alkyl, aryl, alkylaryl, cycloalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylphosphino, arylphosphino, 2 3 aminophosphino, x varies between 0 and 2, R and R are the same or different and are selected from the above-mentioned radicals, at least one of which contains one or more non-racemic chiral centers. 2. Process for the production of the asymmetric amino-phosphines specified in claim 1, characterized in that the reaction is carried out starting from compounds of formula (R 3 R 2N) X, in which n when n is equal to 1, X is hydrogen, an alkal ime number or PR01, and when n is 2, X is a radical of the type -PR 1 , wherein R 1 is selected from among the above-mentioned radicals and, when n is 3, X is P, R 2 and R 3 are the same or different and is selected from among the above-mentioned radicals, wherein at least one of them contains a or multiple non-racemic chiral centers. 3. Process for the preparation of a complex with catalytic activity for the asymmetric hydrogenation of prochiral and racemic olefins, characterized by converting a asymmetric aminophosphine as set forth in claim 1, with a coordination compound of a transition metal. 4. Procedure as stated in claim 3, characterized in that the reaction is carried out with a molar ratio between aminophosphines and the complex of the transition metal, expressed as the ratio between phosphorus atoms and metal atoms, of between 1 and 15. 5. Procedure as specified in claims 3 and 4, characterized in that the reaction is carried out in the presence of a solvent selected from aromatic and aliphatic hydrocarbons, alcohols, ethers, ketones, esters, amides or mixtures thereof. 6. Use of complexes of a transition metal and an asymmetric aminophosphine as stated in claim 1, for the asymmetric hydrogenation of substrates selected from prochiral olefins and compounds containing CO and/or CN groups by bringing the olefin in question into contact with the said complex. 7. Application as stated in claim 6, characterized in that the asymmetric aminophosphine is selected from among aminophosphines of formula PR <1> (NR2R3)- ^ x 3-x wherein R<1> is alkyl, aryl, alkylaryl, cycloalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylphosphino, arylphosphino, aminophosphino, x varies between 0 and 2, R 2 and R 3 are the same or different and are alkyl, aryl, alkylaryl, arylalkyl, cycloalkyl, at least one of which contains one or more non-racemic chiral centers. 8. Application as stated in claims 6 and 7, characterized in that the reaction is carried out at a molar ratio between olefin and the complex varying between 10,000 and 10. 9. Asymmetric hydrogenation as stated in claims 6-8/characterized in that the reaction is carried out at a temperature varying between -70°C and +200°C, preferably between 0 and 50°C. 10. Asymmetric hydrogenation according to claims 6 - 9, characterized in that the reaction is carried out at a hydrogen pressure varying between 1 and 100 atmospheres. 11. A complex of a transition metal and an asymmetric aminophosphine, characterized in that it is produced by the method according to claims 3-5.