EP0673381A1 - Homogeneous bimetallic hydroformylation catalysts and processes utilizing these catalysts for conducting hydroformylation reactions - Google Patents

Homogeneous bimetallic hydroformylation catalysts and processes utilizing these catalysts for conducting hydroformylation reactions

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Publication number
EP0673381A1
EP0673381A1 EP94907166A EP94907166A EP0673381A1 EP 0673381 A1 EP0673381 A1 EP 0673381A1 EP 94907166 A EP94907166 A EP 94907166A EP 94907166 A EP94907166 A EP 94907166A EP 0673381 A1 EP0673381 A1 EP 0673381A1
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group
metal
die
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same
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EP0673381A4 (en
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George G. Stanley
Wei-Jun Peng
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Louisiana State University and Agricultural and Mechanical College
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Louisiana State University and Agricultural and Mechanical College
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Definitions

  • This invention relates to novel homogeneous hydroformylation catalysts, and processes for the use of such catalysts in conducting hydroformylation reactions.
  • it relates to novel bimetallic catalyst complexes which selectively convert alkenes to linear aldehydes when a feed constituted of alkenes, hydrogen, and carbon monoxide is reacted in the presence of said catalyst complexes.
  • This invention also relates to asymmetric syntheses in which a prochiral or chiral compound is contacted in the presence of an optically pure metal-ligand complex catalyst, in enantiomeric form, to produce an optically active product.
  • Hydroformylation is an established process used by the chemical industry for converting alkenes to aldehydes, and sometimes alcohols, by reaction with hydrogen and carbon monoxide.
  • a feed stream constituted of alkenes, hydrogen and carbon monoxide is reacted over soluble rhodium- or cobalt-based transition metal catalyst at relatively low temperatures and pressures.
  • Rhodium catalysts the catalysts of choice for hydroformylation reactions, has long been recognized as more active than cobalt for promoting the "oxo" reaction, especially at low temperatures and pressures, even when the catalyst is used in relatively low concentrations.
  • Rhodium catalysts which produce primarily aldehydes, have also provided generally good selectivities in the production of linear aldehydes. Rhodium catalysts, however, require, inter alia, the use of an excess of a phosphine ligand in the reaction to stabilize the catalyst against the formation of decomposition products, and to maintain acceptably high product selectivities.
  • R, R' and R" can be the same or different and each is selected from the group consisting of hydrogen, F, Cl, Br, and I, C, to C ⁇ , alkyl, to C JO alkoxy, to Cg cycloalkyl, C 3 to cycloalkoxy, phenyl, phenyl substituted with F, Cl, Br, and I, phenyl substituted with C, to C JO alkyl, phenyl substituted with G, to cycloalkyl, phenyl substituted with C,to Cjo alkoxy, oxyphenyl, oxyphenyl substituted with C 3 to cycloalkyl, oxyphenyl substituted with F, Cl, Br, and I, oxyphenyl substituted with C 3 to Cg cycloalkoxy;
  • Q and Q' can be the same or different and each is selected from the group consisting of P, As and Sb, and X is an integer ranging from 1 to 5.
  • OBJECTS It is, accordingly, a primary objective of this invention to provide novel catalyst compositions of high activity and selectivity in carrying out hydroformylation reactions.
  • a further, and more specific object is to provide novel homogeneous bimetallic hydroformylation catalyst compositions, particularly rhodium- and ruthenium-based hydroformylation catalyst compositions, and process using these catalysts in conducting hydroformylation reactions to produce products rich in both linear and branched aldehydes; but particularly selective in producing products rich in linear aldehydes.
  • STATEMENT OF INVENTION These objects and others are achieved in accordance with this invention embodying catalyst compositions, and processes using these compositions in conducting hydroformylation reactions, characterized structurally by formula (I) as follows:
  • M and M' can be the same or different and is a Group VDI metal of the Periodic Table of the Elements (E.H. Sargent & Co. Scientific Laboratory Equipment, Copyright 1962), preferably a metal selected from the group consisting of rhodium, ruthenium, cobalt, iron, and palladium, or a Group IB metal, preferably copper
  • X is selected from the group consisting of methylene, substituted methylene CR'R 2 (sometimes referred to herein as CSS where R 1 and R 2 can be the same or different and each consists of a hydrocarbon moiety which can be saturated or unsaturated and which contains up to 20 carbon atoms and is a to C s alkyl (e.g., methyl, ethyl, n-butyl), to C 5 alkyenyl (e.g., vinyl, allyl, 1-butenyl), C, to C 5 alkoxy (e.g., methoxy, ethyoxy, butoxy),
  • the ligands L and V attached to each of the metal atoms, M and M' can be the same or different and can be H, CO, alkenes, alkyls, or other related ligands present either initially in the catalyst precursor or as formed in situ during the hydroformylation reaction.
  • bimetallic hydroformylation catalyst composition embodied by formula (I) can be written in a more simplified form as (IA):
  • the catalyst embodied by formula I or IA is formed by reaction between the polyphosphine ligand characterized by formula II, hereinafter LTTP,
  • LTTP ⁇ R , P-Y-P(R)-X-P(R)-Y-PR' ⁇ (LTTP) (II) as follows: LTTP and two molecules of a metal complex capable of complexing with the LTTP ligand form a generalized bimetallic complex characterized by formula in, as follows:
  • M and M' can be the same or different, L and L' can be the same or different and are ancillary ligands such as hydrogen, halogen, carbonyl, norbomadiene, or the like.
  • the charge on complex m will depend on the oxidation state of the metal centers and the charges and respective numbers of the ligands L and L' designated by w, x, y and z.
  • the values of the numbers w, x, y and z for the ligands L and L' are related to the exact nature of the metal centers and are set to give 14, 16 or 18 electron metal valence electron counts. For example, in the case of:
  • LTTP the ligand represented by formula II, acts as a template for building the bimetallic metal complex and has the ability to both bridge and chelate two metal centers, each of which will lie near the geometric center of the complex in general proximity to one another.
  • LTTP is thus preferably a binucleating tetratertiaryphosphine ligand having a bridging-chelating framework open at its center at which reaction with two metal centers can occur to produce bischelated bimetallic complexes represented by formula HI.
  • a prefered LTTP is one wherein the internal phosphorus atoms are linked through a methylene bridge, Y is an ethyl linkage, R is phenyl or a low molecular weight alkyl, and R' is a low molecular weight alkyl, such as ethyl (Et), as represented by the following structural formulae: rae-eLTTP
  • a tetratertiaryphosphine of this type is chiral at the two internal phosphorus atoms resulting in both racemic (R,R; S,S) and meso (R,S) diastereomers, a potentially desirable feature in promoting potential stereo- and enantio-selective reactions.
  • the catalyst of this invention is highly active and can convert alkenes, notably alpha olefins, via hydroformylation to linear and branched aldehydes at fast rates with remarkably high selectivities ( «30:1 linear to branched). Unlike present commerically used catalysts, there is no need to add excess phosphines to the reaction mixture to maintain the stability of the catalyst. The reason the catalysts of this invention produce a product having a high linea ⁇ branched aldehyde product ratio, it is believed, is due to the geometric configuration of the M 2 (LTTP) moiety. When, for example, an alkene coordinates to Rh 2 H 2 (CO) 2 (LTTP) it can only add to one of the outside axial rhodium coordination sites.
  • LTTP geometric configuration of the M 2
  • Rh 2 LTTP
  • Rh 2 can not attain this geometry because the other half of the complex is present and limits the extent of ligand motion toward trigonal bipyramidal or square pyramidal.
  • Rh(acyl)(CO)(u-LTTP)RhH(CO) a species similar to Rh(acyl)(CO)(u-LTTP)RhH(CO) would be a key intermediate in the catalytic cycle and that this type of system could readily access a "closed-mode" conformation in which an intramolecular hydride transfer could occur.
  • Such a proposed intermediate species is shown below.
  • RhjOL-l P unit essentially acts as a conventional monometallic hydroformylation catalyst until it reaches the acyl intermediate. Then, the rotational flexibility of the LTTP ligand comes into play and bimetallic cooperativity takes place to transfer a hydride to the acyl-bound rhodium. Reductive elimination of aldehyde product, it is believed, will then generate a Rh-Rh bonded complex which can react with Hj to regenerate the starting catalyst.
  • Rh(norb)(depmpe) + is, perhaps, the most analogous monometallic complex to our bimetallic Rh 2 (norb) 2 (LTTP) 2+ system and is a very poor hydroformylation catalyst (see Table A). It has an initial turnover frequency of about 5/hr with a product aldehyde selectivity of only 2:1 linear to branched with large amounts of alkene isomerization observed. Our bimetallic LTTP-based catalyst system is, therefore, at least 70 times faster than this "electronically correct" monometallic analog and markedly more selective and effective as a hydroformylation catalyst system.
  • Rh ⁇ no ⁇ TTP-pr Rh ⁇ no ⁇ TTP-pr * 80 30 30 30 1.9 10.0 4 94
  • Bimetallic model systems have also been prepared which have "spacer" groups replacing the central methylene bridge to probe the importance of having two metal centers present and near one another.
  • Bimetallic rhodium norbomadiene complexes based on p-xylene and pro pylene bridged tetraphosphine ligands (LTTP-p-xyl and LTTP-pr) shown below have been prepared and studied as hydroformylation catalysts.
  • Bimetallic Rh-norbomadiene complexes based on these spaced binucleating tetraphosphine ligands produce very poor hydroformylation catalysts giving results that essentially mirror those seen for the monometallic model systems.
  • the hydroformylation catalytic results for the mono- and bi-metallic complexes discussed here are also summarized in Table A.
  • Molecular modelling studies of the Rh 2 H 2 (CO) 2 (LTTP-p-xylene) and Rh 2 H 2 (CO) 2 (LTTP-pro pyl) catalyst systems clearly indicate that it will be very difficult, if not impossible for the metal centers in these systems to approach one another to do an intramolecular hydride transfer.
  • the presence of the single atom bridge in LTTP which constrains the two square planar rhodium centers to adopt a rotationally flexible face-to-face orientation may well be the key design feature in the Rh 2 (LTTP) complex. This, once again, allows facile intramolecular hydride transfer between the metal centers greatly enhancing the rate and efficency of the hydroformylation reaction.
  • the ethylene-linked terminal phosphines in LTTP simplify the synthetic procedure and gives higher yields of the final tetraphosphine (88-92%) based on Ph(H)PCH 2 P(H)Ph, or 39-43% yields based on the starting PhPH 2 .
  • the presence of the phenyl groups on the central P-CH 2 -P bridge allows more facile crystallizations of bimetallic complexes.
  • the electron-rich alkylated terminal and mostly alkylated internl phosphines coordinate strongly with metal centers and provide a very effective means for inhibiting ligand dissociation and bimetallic fragmentation.
  • the meso and racemic diastereomers of LTTP are both highly reactive binucleating ligands that can bridge and chelate two metal centers, albeit each can form complexes that have different overall geometrical orientations of the phosphines about the two metal centers.
  • the reaction of a metal compound as described by reference to formula HI will produce a large amount of the hydroformylation catalyst composition of the general geometrical configuration described by reference to formula I.
  • the catalyst or catalyst precursor is introduced into the autoclave or reaction vessel dissolved in a liquid medium, or slurried, or otherwise dispersed in a liquid medium to eventually provide a homogeneous reaction phase.
  • Suitable solvents are, e.g., alcohols, ethers, ketones, parafins, cycloparafins, and aromatic hydrocarbons.
  • substituents are carbonyl, carbonyloxy, oxy, hydroxy, alkoxy, phenyl and the like.
  • alpha olefins or olefins unsaturated in the 1-position, include alkenes, alkyl alkenoates, alkenyl alkyl ethers, alkenols, and the like, e.g., ethylene, propene, 1-butene, 1-pentene, 1-hexene, 1-hepene, 1-octene, vinyl acetate, allyl alcohol, and the like.
  • the feed is contacted with the homogeneous catalyst, while carbon monoxide and hydrogen are added, at temperature, pressure and time sufficient to convert the alkene to aldehydes, at high selectivities.
  • the temperature of the reaction ranges from about 50°C to about 150°C, preferably from about 60°C to about 120°C.
  • total pressures range from about 20 pounds per square inch (psi) to about 300 psi, preferably from about 50 psi to about 200 psi.
  • the ratios of H 2 :CO ranges generally from about 10:90 to about 90:10 volume percent, preferably from about 40:60 to 60:40 volume percent.
  • the catalyst is generally employed in the reaction mixture in concentrations ranging from about 10 "5 M to about Iff 2 M (molarity).
  • the catalyst is added to the reaction vessel as a slurry or a solution, the reaction is pressurized and brought to the desired operating temperature.
  • the feed and the carbon monoxide and hydrogen in desired ratios are then introduced into the reaction vessel to commence an operation.
  • Alkene feeds that are liquids at or near room temperature e.g., 1-hexene, 1-octene
  • the process is suited to batchwise operation, or to continuous operation via the use of suitable apparatus.
  • a binucleating tetratertiaiyphosphine ligand (CH-jCHjPEt-*), was prepared by reacting two equivalents of PhPH 2 and one equivalent of CHjClj with KOH in DMF solution to produce Phr ⁇ PCH j pr ⁇ Ph which is isolated.
  • the pressure of the reservoir cylinder was constantly monitored by a pressure transducer.
  • the reservoir pressure and temperature, autoclave temperature, and stir rate data were collected and stored on a Parr 4851 controller and the data transferred periodically to a PC computer for permanent storage and for calculating reaction rates. Analysis of products was performed by GC, NMR and GC/MS measurements.
  • electronrich phosphine ligands generally cause decreases in product selectivities. For these reasons, electron-rich phosphine ligands have proven to be very poor ligands for rhodium hydroformylation catalysts.
  • the bimetallic LTTP-based dirhodium catalyst of this invention has both high activities and very high selectivities giving an initial rate of 370 rurnovers/hr and a linear to branched aldehyde product ratio of at least 30:1. Furthermore, because of the strong rhodium coordinating abilities of this electron-rich LTTP ligand system, an excess of phosphine ligand is not required either for catalyst stability or to enhance linear aldehyde production.
  • Rh j t ⁇ ort j O-TTP 80 30 30 30 1.3 217.5 23
  • Rh ⁇ norb ⁇ TTP Rh ⁇ norb ⁇ TTP
  • Counter anion is BF 4 " for cationic species.
  • Asymmetric synthesis is of importance, for example, in the pharmaceutical industry, since frequently only one optically active isomer (enantiomer) is therapeutically active.
  • An example of such a pharmaceutical product is the non-steroidal anti- inflammatory drug Naproxen.
  • the S enantiomer is a potent anti-arthritic agent, while the R enantiomer is a liver toxin. It is therefore oftentimes desirable to selectively produce one particular enantiomer over its mirror image.
  • asymmetric synthesis desirably affords the ability to control both regioselectivity (branched/normal ratio), e.g., hydroformylation, and stereoselectivity.
  • Various asymmetric synthesis catalysts have been described in the art. For example, Wink, Donald J. et al., Inorg. Chem. 1990, 29, 5006-5008 discloses syntheses of chelating bis(dioxaphospholane) ligands through chlorodioxaphospholane intermediates and the demonstration of catalytic competence of bis(phosphite)rhodium cations.
  • a complex derived from dihydrobenzoin was tested as a precursor in the hydroformylation of olefins and gave a racemic mixture.
  • Catonic rhodium complexes of bis(dioxaphospholane) ligands were tested in the hydrogenation of enamides and gave enantiomeric excesses (ee) on the order of two to ten percent.
  • East Germany patent nos. 275,623 and 280,473 relate to chiral rhodium carbohydrate-phosphinite catalyst production.
  • the catalysts are stated to be useful as stereospecific catalysts for carrying out carbon-carbon bond formation, hydroformylation, hydrosilylation, carbonylation, and hydrogenation reactions to give optically active compounds.
  • Sakai et al., J. Am. Chem. Soc. 1993, 115, 7033-7034 disclose highly enantioselective hydroformylation of olefins catalyzed by new phosphinephosphite-Rh(I) complexes.
  • the search for more effective asymmetric synthesis processes is a constant one in the art. It would be desirable if asymmetric synthesis processes could be provided having good yields of optically active products without the need for optical resolution. It would be further desirable if asymmetric synthesis processes could be provided having the characteristics of high stereoselectivity, high regioselectivity, e.g., hydroformylation, and good reaction rate.
  • This facet of the present invention relates to asymmetric syntheses in which a prochiral or chiral compound is reacted in the presence of optically pure, metal-ligand complex catalyst, in enantiomeric form, to produce an optically active product.
  • a prochiral or chiral compound is reacted in the presence of optically pure, metal-ligand complex catalyst, in enantiomeric form, to produce an optically active product.
  • the separate SS and RR enantiomers (in substantially pure form) of the racemic form of the general catalyst disclosed in the earlier part of this specification, can effect asymmetric synthesis in various processes with various substrates to produce a specific isomeric material with high enantiomeric excess (ee) and which is optically active.
  • the meso form of this general catalyst is somewhat inactive, notwithstanding the fact that when both the meso and racemic diastereomers of the catalyst are together, there are disclosed to be highly reactive.
  • the processes of this invention are distinctive in that they provide good yields of optically active products having high stereoselectivity, high regioselectivity, and good reaction rate without the need for optical resolution.
  • the processes of this invention stereoselectively produce a chiral center.
  • An advantage of this invention is that optically active products can be synthesized from optically inactive reactants. Another advantage is that yield losses associated with the production of an undesired enantiomer can be substantially reduced.
  • the asymmetric syntheses processes of this invention are useful for the production of numerous optically active organic compounds, e.g., aldehydes, alcohols, ethers, esters, amines, amides, carboxylic acids and the like, which have a wide variety of applications.
  • optically active organic compounds e.g., aldehydes, alcohols, ethers, esters, amines, amides, carboxylic acids and the like, which have a wide variety of applications.
  • the part of the subject invention encompasses the carrying out of any known conventional syntheses in an asymmetric fashion in which the catalyst thereof is replaced by eitiier the SS or RR enantiomers of the racemic form of the optically active metal- ligand complex catalyst as disclosed in the prior art
  • the ligand is symmetrical when referred to as the SS or RR enantiomers of the racemate form of the metal-ligand complex catalyst
  • the term, “optically pure metal- ligand complex catalyst”, “optically pure metal catalyst”, and/or “optically pure catalyst” only refers to the individual SS or RR enantiomers (i.e.
  • Illustrative asymmetric syntheses reactions include, for example, hydroformylation, hydro acylation (intramolecular and intermolecular), hydrocyanation, olefin and ketone hydrosilylation, hydrocarboxylation, hydroamidation, hydroesterification, hydrogenation, hydrogenolysis, aminolysis, alcoholysis, carbonylation, decarbonylation, olefin isomerization, Grignard cross coupling, transfer hydrogenation, olefin hydroboration, olefin cyclopropanation, aldol condensation, allelic alkylation, olefin codimerization, Diels-Alder reactions, and the like.
  • asymmetric syntheses reactions involve the reaction of organic compounds with carbon monoxide, or carbon monoxide and a third reactant, e.g., hydrogen, in the presence of a catalytic amount of an optically active metal-ligand complex catalyst.
  • a third reactant e.g., hydrogen
  • the subject invention relates to asymmetric hydroformylation which involves the use of an optically pure metal-ligand complex catalyst in the production of optically active aldehydes wherein a prochiral or chiral olefinic compound is reacted with carbon monoxide and hydrogen.
  • optically active aldehydes produced correspond to the compounds obtained by the addition of a carbonyl group to an olefinically unsaturated carbon atom in the starting material with simultaneous saturation of the olefinic bond.
  • the processing techniques of this invention may correspond to any of the known processing techniques heretofore employed in conventional asymmetric syntheses reactions including asymmetric hydroformylation reactions.
  • the asymmetric syntheses processes can be conducted in continuous, semi-continuous, or batch fashion and involve a liquid recycle and/or gas recycle operation as desired.
  • the manner or order of addition of the reaction ingredients, catalyst, and solvent are also not critical and may be accomplished in any conventional fashion.
  • the asymmetric syntheses reactions are carried out in a liquid reaction medium that contains a solvent for the optically pure catalyst preferably one in which the reaction ingredients, including catalyst, are substantially soluble.
  • the subject invention encompasses the carrying out of any known conventional syntheses in an asymmetric fashion in which the catalyst thereof is replaced by an optically pure metal-ligand complex catalyst as disclosed herein.
  • Asymmetric intramolecular hydroacylation can be carried out in accordance with conventional procedures known in the art For example, aldehydes containing an olefinic group with three to seven carbons removed can be converted to optically active cyclic ketones under hydroacylation conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
  • optically active ketones can be prepared by reacting a prochiral olefin and an aldehyde under hydroacylation conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
  • optically active nitrile compounds can be prepared by reacting a prochiral olefinic compound and hydrogen cyanide under hydrocyanation conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
  • Asymmetric olefin hydro silylation can be carried out in accordance with conventional procedures known in d e art
  • optically active silyl compounds can be prepared by reacting a prochiral olefin and a silyl compound under hydrosilylation conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
  • Asymmetric ketone hydrosilylation can be carried out in accordance with conventional procedures known in the art
  • optically active silyl ethers or alcohols can be prepared by reacting a prochiral ketone and a silyl compound under hydrosilylation conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
  • Asymmetric hydrocarboxylation can be carried out in accordance with conventional procedures known in the art
  • prochiral olefins can be converted to optically active carboxylic acids under hydrocarboxylation conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
  • optically active amides can be prepared by reacting a prochiral olefin, carbon monoxide, and a primary or secondary amine or ammonia under hydroamidation conditions in the presence of an optically pure metal- ligand complex catalyst described herein.
  • optically active esters can be prepared by reacting a prochiral olefin, carbon monoxide, and an alcohol under hydroesterification conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
  • Asymmetric olefin hydrogenations and other asymmetric hydrogenations can be carried out in accordance with conventional procedures known in the art.
  • hydrogenation can be used to reduce a carbon-carbon double bond to a single bond.
  • Other double bonds can also be hydro genated, for example, a ketone can be converted to an optically active alcohol under hydrogenation conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
  • Asymmetric hydrogenolysis can be carried out in accordance with conventional procedures known in the art
  • optically active alcohols can be prepared by reacting an epoxide with hydrogen under hydrogenolysis conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
  • optically active amines can be prepared by reacting a prochiral olefin with a primary or secondary amine under aminolysis conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
  • optically active ethers can be prepared by reacting a prochiral olefin with an alcohol under alcoholysis conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
  • Asymmetric carbonylation can be carried out in accordance with conventional procedures known in the art
  • optically active lactones can be prepared by treatment of allyl alcohols with carbon monoxide under carbonylation conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
  • Asymmetric decarbonylation can be carried out in accordance with conventional procedures known in the art
  • acyl or aroyl chlorides can be decarbonylated under decarbonylation conditions with retention of configuration in the presence of an optically pure metal-ligand complex catalyst described herein.
  • allelic alcohols can be isomerized under isomerization conditions to produce optically active aldehydes in the presence of an optically pure metal-ligand complex catalyst described herein.
  • Asymmetric Grignard cross coupling can be carried out in accordance with conventional procedures known in the art
  • optically active products can be prepared by reacting a chiral Grignard reagent with an alkyl or aryl halide under Grignard reagent with an alkyl or aryl halide under Grignard cross coupling conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
  • optically active alcohols can be prepared by reacting a prochiral ketone and an alcohol under transfer hydrogenation conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
  • Asymmetric olefin hydroboration can be carried out in accordance with conventional procedures known in the art
  • optically active alkyl boranes or alcohols can be prepared by reacting a prochiral olefin and a borane under hydroboration conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
  • Asymmetric olefin cyclopropanation can be carried out in accordance with conventional procedures known in the art
  • optically active cyclopropanes can be prepared by reacting a prochiral olefin and a diazo compound under cyclopropanation conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
  • optically active aldols can be prepared by reacting a prochiral ketone or aldehyde and a silyl enol ether under aldol condensation conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
  • Asymmetric olefin codimerization can be carried out in accordance with conventional procedures known in the art
  • optically active hydrocarbons can be prepared by reacting a prochiral alkene and an alkene under codimerization conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
  • optically active hydrocarbons can be prepared by reacting a prochiral ketone or aldehyde and an allelic alkylating agent under alkylation conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
  • optically active olefins can be prepared by reacting a prochiral diene and an olefin under cycloaddition conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
  • Illustrative starting material reactants include, for example, substituted and unsubstituted aldehydes (intramolecular hydroacylation, aldol condensation, allelic alkylation), prochiral olefins (hydroformylation, intermolecular hydroacylation, hydrocyanation, hydrosilylation, hydrocarboxylation, hydroamidation, hydroesterification, aminolysis, alcoholysis, cyclopropanation, hydroboration, Diels-Alder reaction, codimerization), ketones
  • olefin starting material reactants useful in certain of the asymmetric syntheses processes of this invention include tiiose which can be terminally or internally unsaturated and be of straight chain, branched-chain, or cyclic structure.
  • Such olefins can contain from four to forty carbon atoms or greater and may contain one or more ethylenic unsaturated groups. Moreover, such olefins may contain groups or substituents which do not essentially adversely interfere with the asymmetric syntheses process such as carbonyl, carbonyloxy, oxy, hydroxy, oxycarbonyl, halogen, alkoxy, aryl, haloalkyl, and d e like.
  • Illustrative olefinic unsaturated compounds include substituted and unsubstituted alpha olefins, internal olefins, alkyl alkenoates, alkenyl alkanoates, alkenyl alkyl ethers, alkenols, and die like, e.g., 1-butene, 1-pentene, 1-hexene, 1-octene, 1-decene, 1-dodecene, 1-octadecene, 2-butene, isoamylene, 2-pentene, 2-hexene, 3-hexene, 2-heptene, cyclohexene, propylene dinners, propylene trimers, propylene tetramers, 2-ethylhexene, 3-phenyl-l-propene, 1,4-hexadiene, 1,7-octadiene, 3-cyclohexyl- 1-butene, allyl alcohol, hex
  • Illustrative preferred olefinic unsaturated compounds include, for example, p-isobutylstyrene, 2-vinyl-6-methoxynaphthylene, 3-ethenylphenyl phenyl ketone, 4-ethylphenyl-2-thienylketone, 4-ethenyl-2-fluorobiphenyl, 4-(lm,3-dihydro- l-oxo-2H-isoindol-2-yl)styrene, 2-ethyl-5-benzoylthiophene, 3-ethenylphenyl phenyl ether, propenylbenzene, isobutyl-4-propenylbenzene, phenyl vinyl ether, vinyl chloride, and d e like.
  • Suitable olefinic unsaturated compounds useful in certain asymmetric syntheses processes of this invention include substituted aryl ediylenes described in U.S. 4,329,507, incorporated herein by reference in its entirety. Of course, it is understood that mixtures of different olefinic starting materials can be employed, if desired, by d e asymmetric syntheses processes of the subject invention. More preferably, the subject invention is especially useful for the production of optically active aldehydes, by hydroformylating alpha olefins containing from four to forty carbon atoms or greater, as well as starting material mixtures of such alpha olefins and internal olefins. Illustrative prochiral and chiral olefins useful in the processes of this invention include tiiose represented by die formula:
  • R protest R j , R 3 , and « are die same or different (provided Rj is different from Rj and R 3 is different from R and are selected from hydrogen; alkyl; substituted alkyl, said substitution being selected from amino including alkylamino and dialkylamino, such as benzylamino and dibenzylamino, hydroxy, alkoxy, such as methoxy and ethoxy, acyloxy, such as acetoxy, halo, nitro, nitrile, thio, carbonyl, carboxamide, carboxaldehyde, carboxyl, carboxylic ester; aryl including phenyl; substituted aryl including phenyl, said substitution being selected from alkyl, amino including alkylamino and dialkylamino such as benzylamino and dibenzylamino, hydroxy, alkoxy such as methoxy and etiioxy, acyloxy such as acetoxy, halo, nit
  • prochiral and chiral olefins of this definition also include molecules of die above general formula where the R-groups are connected to form ring compounds, e.g., 3-med ⁇ yl-l-cyclohexene, and the like.
  • Illustrative epoxide starting material reactants useful in certain of the asymmetric syntheses processes of this invention, e.g., hydroformylation, include those represented by die formula: R.
  • R s , R ⁇ R 7 , and R g are die same or different (provided R 5 is different from R* and/or R, is different from R 8 ) and are selected from hydrogen, monovalent aliphatic or aromatic groups containing one to about twelve carbon atoms, and divalent aliphatic groups containing four to about six carbon atoms in which any permissible combination of R 5 , Re, R-i, and Riker may be linked together to form a substituted or unsubstituted, carboxylic or heterocyclic ring system such as a monocyclic aromatic or nonaromatic ring system, e.g., cyclohexene oxide.
  • epoxides examples include propylene oxide, 1,2-epoxyoctane, cyclohexene oxide, styrene oxide, and d e like.
  • the catalyst useful in this part of the invention is the optically pure metal-ligand complex catalyst characterized structurally, in general, by formula (I) as follows:
  • M and M' can be die same or different, and each is a Group VIII metal of the Periodic Table of die Elements (E_H. Sargent & Co. Scientific Laboratory Equipment, Copyright 1962) preferably a metal selected from the group consisting of rhodium, rudienium, cobalt, iron, and palladium, or a Group IB metal, preferably copper, X is selected from the group consisting of metiiylene, substituted memylene CR !
  • R 1 and R 2 can be die same or different and each consists of a hydrocarbon moiety which can be saturated or unsaturated and which contains up to twenty carbon atoms and is a C, to C 5 alkyl (e.g., methyl, ediyl, n-butyl), C-.
  • alkyenyl e.g., vinyl, allyl, 1-butenyl
  • C, to C 5 alkoxy e.g., medioxy, ethoxy, butoxy
  • C, to C-a, alcohol e.g., -CH 2 OH, -C ⁇ 2 CH 2 O ⁇
  • C 3 to C 6 cycloalkyl e.g., cyclopropyl, cyclophentyl
  • C 3 to C 6 cycloalkoxy e.g., cyclopropoxy, cyclopentoxy
  • C 10 aryl e.g., phenyl, naphthyl
  • C 6 to C 10 alkaryl e.g., tolyl, xylyl
  • C, 0 aralkyl e.g., benzyl, betaphenylediyl
  • X is methylene, oxygen, NR 3 where R 3 is a hydrocarbon moiety which can be saturated or unsaturated
  • X is methylene
  • Y is an ediyl, propyl, or metasubstituted aryl linkage with hydrogen, F, or methyl substituents, and preferably Y is an ediyl group
  • R is a hydrocarbon moiety which can be saturated or unsaturated and which contains up to twenty carbon atoms and is a C, to C
  • the ligands L and ____.' attached to each of die metal atoms, M and M', can be die same or different and can be H, CO, alkenes, alkyls, or other related ligands present initially in die catalyst precursor.
  • the precursor catalyst in non-isomer form, may be prepared by the disclosure set forth in die earlier part of this specification.
  • the amount of optically pure complex catalyst present in the reaction medium of a given process of tiiis invention need only be that minimum amount necessary to provide d e given metal concentration desired to be employed and which will furnish the basis for at least that catalytic amount of metal necessary to catalyze the particular asymmetric syntheses process desired.
  • metal concentrations in die range of from about 1 ppm to about 10,000 ppm, calculated as free metal, and ligand to metal mole ratios in die catalyst ranging from about 0.5:1 to about 200:1, should be sufficient for most asymmetric syntheses processes.
  • rhodium catalyzed asymmetric hydroformylation processes of this invention it is generally preferred to employ from about 10 to 1000 ppm of rhodium and more preferably from 25 to 750 ppm of rhodium, calculated as free metal.
  • the process conditions employable in the asymmetric processes of this invention are, of course, chosen depending on die particular asymmetric syntheses desired. Such process conditions are well known in the art. All of the asymmetric syntheses processes of this invention can be carried out in accordance witii conventional procedures known in the art. Illustrative reaction conditions for conducting the asymmetric syntheses processes of this invention are described, for example, in Bosnich, B., Asymmetric Catalysis, Martinus Nijhoff Publishers, 1986 and Morrison, James D., Asymmetric Synthesis, Vol. 5, Chiral Catalysis, Academic Press, Inc., 1985, bodi of which are incorporated herein by reference in their entirety.
  • operating temperatures can range from about -80°C or less to about 500°C or greater and operating pressures can range from about 1 psia or less to about 10,000 psia or greater.
  • the reaction conditions of effecting, for example, the asymmetric hydroformylation process of this invention may be those heretofore conventionally used and may comprise a reaction temperature of from about -25°C or lower to about 200°C and pressures ranging from about 1 to 10,000 psia.
  • asymmetric syntheses process is the hydroformylation of olefinically unsaturated compounds and more preferably olefinic hydrocarbon, witii carbon monoxide and hydrogen to produce optically active aldehydes
  • tiiat the optically active metal-ligand complexes may be employed as catalysts in otiier types of asymmetric syndieses processes to obtain good results.
  • otiier asymmetric syndieses may be performed under their usual conditions, in general it is believed tiiat they may be performed at lower temperatures than normally preferred due to d e optically pure metal-ligand complex catalysts.
  • the total gas pressure of hydrogen, carbon monoxide, and, for example, olefinic unsaturated starting compound of one asymmetric (hydroformylation) process of this invention may range from about 1 to about 10,000 psia. More preferably, however, in the asymmetric hydroformylation of prochiral olefins to produce optically active aldehydes, it is preferred tiiat the process be operated at a total gas pressure of hydrogen, carbon monoxide, and olefinic unsaturated starting compound of less tiian about 1500 psia, and more preferably less than about 1000 psia.
  • the minimum total pressure of the reactants is not particularly critical and is limited predominately only by die amount of reactants necessary to obtain a desired rate of reaction. More specifically, the carbon monoxide partial pressure of the asymmetric hydroformylation process is preferably from about 1 to about 360 psia, and more preferably from about 3 to about 270 psia, while die hydrogen partial pressure is preferably about 15 to about 480 psia and more preferably from about 30 to about 300 psia.
  • the molar ratio of gaseous hydrogen to carbon monoxide may range from about 1:10 to 100:1 or higher, the more preferred hydrogen to carbon monoxide molar ratio being from about 1:1 to about 1:10. Higher molar ratios of carbon monoxide to gaseous hydrogen may generally tend to favor higher branched/normal ratios.
  • the processes of this invention may be conducted at a reaction temperature from about -25°C or lower to about 200°C.
  • the preferred reaction temperature employed in a given process will, of course, be dependent upon die particular starting material and optically pure metal-ligand complex catalyst employed as well as die efficiency desired. Lower reaction temperatures may generally tend to favor higher enantiomeric excesses (ee) and branched normal ratios. For example, asymmetric hydroformylations at reaction temperatures of about 0°C to about 120°C are preferred for all types of olefinic starting materials.
  • alpha-olefins can be effectively hydroformylated at a temperature of from about 0°C to about 90°C while even less reactive olefins than conventional linear alpha-olefins and internal olefins, as well as mixtures of alpha-olefins and internal olefins, are effectively and preferably hydroformylated at a temperature of from about 25°C to about 120°C.
  • the processes are conducted for a period of time sufficient to produce die optically active products. The exact reaction time employed is dependent in part, upon factors such as temperature, nature, and proportion of starting materials, and die like.
  • the reaction time will normally be within the range of from about one-half to about 200 hours or more, and preferably from less than about one to ten hours.
  • the asymmetric syntheses process (for example, asymmetric hydroformylation process) of this invention can be carried out in either the liquid or gaseous state and involve a batch, continuous liquid or gas recycle system, or combination of such systems. A batch system is preferred for conducting die processes of this invention.
  • asymmetric hydroformylation of this invention involves a batch homogeneous catalysis process wherein the hydroformylation is carried out in the presence of any suitable conventional solvent as further outlined herein.
  • suitable organic solvents include, for example, alcohols, alkanes, alkenes, alkynes, ethers, aldehydes, ketones, esters, acids, amides, amines, aromatics, and die like. Any suitable solvent which does not unduly adversely interfere with the intended asymmetric syndieses process can be employed and such solvents may include tiiose heretofore commonly employed in known metal catalyzed processes. Increasing the dielectric constant or polarity of a solvent may generally tend to favor increased reaction rates. Mixtures of one or more different solvents may be employed if desired.
  • the amount of solvent employed is not critical to the subject invention and need only be tiiat amount sufficient to provide die reaction medium with the particular metal concentration desired for a given process.
  • the amount of solvent when employed may range from about five percent by weight up to about ninety-five percent by weight or more, based on d e total weight of the reaction medium.
  • optically active compounds prepared by the processes of this invention include, for example, substituted and unsubstituted alcohols or phenols; amines; amides; ethers or epoxides; esters; carboxylic acids or anhydrides; ketones; olefins; acetylenes; halides or sulfonates; aldehydes; nitrites; and hydrocarbons.
  • Illustrative preferred optically active aldehyde compounds prepared by the asymmetric hydroformylation process of this invention include, for example, S-2-(p- isobutylphenyl)propionaldehyde, S-2-(6-methoxynaphthyl)propionaldehyde, S-2-(3- b ⁇ nzoylphenyl)propionaldehyde, S-2-(p-thenoylphenyl)propionadenhyde, S-2-(3-fluoro-4- phenyl)phenylpropionaldehyde, S-2-[4-(l,3-dihydro-l-oxo-2H-isoindol-2-yl)phenyl]- propionaldehyde, S-2-(2-methylacetaldehyde)-5-benzoylthiophene, and die like.
  • the processes of this invention can provide optically active products having very high enantioselectivity and regioselectivity, e.g., hydroformylation.
  • Enantiomeric excesses (sometimes referred to herein as "ee") of preferably greater than fifty percent, more preferably greater than 75 percent, and most preferably greater than ninety percent can be obtained by die processes of this invention.
  • Branched/normal molar ratios of preferably greater than 5:1, more preferably greater than 10:1, and most preferably greater than 25:1 can be obtained by the processes, e.g., hydroformylation, of this invention.
  • the processes of this invention can also be carried out at highly desirable reaction rates suitable for commercial use.
  • the desired optically active products may be recovered in any conventional manner. Suitable separation techniques include, for example, solvent extraction, crystallization, distillation, vaporization, wiped film evaporation, falling film evaporation, and the like. It may be desired to remove the optically active products from the reaction system as they are formed through the use of trapping agents as described in WO patent 88/08835.
  • optically active products produced by die asymmetric syntheses processes of this invention can undergo further reaction(s) to afford desired derivatives thereof.
  • Such permissible derivatization reactions can be carried out in accordance with conventional procedures known in the art
  • Illustrative derivatization reactions include, for example, esterification, oxidation of alcohols to aldehydes, N-alkylation of amides, addition of aldehydes to amides, nitrile reduction, acylation of ketones by esters, acylation of amines, and the like.
  • illustrative derivatization reactions include, for example, oxidation to carboxylic acids, reduction to alcohols, aldol condensation to alpha, beta-unsaturated compounds, reductive amination to amines, amination to imines, and d e like. This invention is not intended to be limited in any manner by the permissible derivatization reactions.
  • An example of a derivatization reaction involves oxidation of an optically active aldehyde prepared by asymmetric hydroformylation to give the corresponding optically active carboxylic acid.
  • Such oxidation reactions can be carried out by conventional procedures known in the art
  • a number of important pharmaceutical compounds can be prepared by this process including, but not limited to, S-ibuprofen, S-naproxen, S-ketoprofen, S-suprofen, S-flurbiprofen, S-indoprofen, S-tiaprofenic acid, and the like.
  • Illustrative preferred derivatization, i.e. oxidation reactions encompassed within the scope of this invention include, for example, the following reactant/aldehyde intermediate/product combinations:
  • Suitable optically active products prepared by the asymmetric syntheses processes of this invention include by way of example: AL alcohols
  • the processes of this invention can be conducted in a batch or continuous fashion, with recycle of unconsumed starting materials if required.
  • the reaction can be conducted in a single reaction zone or in a plurality of reaction zones, in series, or in parallel, or it may be conducted batchwise or continuously in an elongated tubular zone or series of such zones.
  • the materials of construction employed should be inert to the starting materials during the reaction and the fabrication of the equipment should be able to withstand die reaction temperatures and pressures.
  • Means to introduce and/or adjust the quantity of starting materials or ingredients introduced batchwise or continuously into the reaction zone during the course of the reaction can be conveniently utilized in the processes especially to maintain the desired molar ratio of the starting materials.
  • reaction steps may be effected by die incremental addition of one of the starting materials to the otiier. Also, the reaction steps can be combined by die joint addition of the starting materials to the optically pure metal-ligand complex catalyst. When complete conversion is not desired or not obtainable, the starting materials can be separated from the product and then recycled back into the reaction zone.
  • the processes may be conducted in either glass lined, stainless steel or similar type reaction equipment.
  • the reaction zone may be fitted with one or more internal and/or external heat exchanger(s) in order to control undue temperature fluctuations, or to prevent any possible "runaway" reaction temperatures.
  • d e optically active products of the process of this invention have a wide range of utility that is well known and documented in die prior art, e.g. they are especially useful as pharmaceuticals, flavors, fragrances, agricultural chemicals, and die like.
  • Illustrative therapeutic applications include, for example, non-steroidal anti-inflammatory drugs, ACE inhibitors, beta-blockers, analgesics, bronchodilators, spasmolytics, antihistamines, antibiotics, antitumor agents, and d e like.
  • Achiral molecules or processes which do not include or involve at least one center of asymmetry are symmetrical molecules or processes which do not include or involve at least one center of asymmetry.
  • Prochiral molecules which have the potential to be converted to a chiral product in a particular process.
  • Racemic a 50/50 mixture of two (2) enantiomers of a chiral compound Racemic a 50/50 mixture of two (2) enantiomers of a chiral compound.
  • Stereoisomers compounds which have identical chemical construction, but differ as regards the arrangement of the atoms or groups in space.
  • Enantiomeric a measure of the relative amounts of two (2) Excess (ee) enantiomers present in a product, ee may be calculated by die formula [amount of major enantiomer - amount of minor enantiomer]/[ amount of major enantiomer + amount of minor enantiomer].
  • Optical Activity an indirect measurement of the relative amounts of stereoisomers present in a given product. Chiral compounds have die ability to rotate plane polarized light When one enantiomer is present in excess over the other, the mixture is optically active.
  • Optically Active a mixture of stereoisomers which rotates plane polarized light due to an excess of one of die stereoisomers over the others.
  • (+)-Rh 2 (nbd) 2 (et,ph-P4> SS form of the general formula I compound where nbd is norbomadiene and is for a symmetrical ligand.
  • (+)-Rh 2 (n 3 -allyl) 2 SS form of the general formula I compound where it
  • (etph-P4) is an allyl anion racemic-Rh ⁇ -allyl ⁇ racemate form of the general formula I compound (etph-P4) where it is an allyl anion
  • hydrocarbon is contemplated to include all permissible compounds having at least one hydrogen and one carbon atom.
  • die permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds which can be substituted or unsubstituted.
  • the term "substituted" is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described hereinabove.
  • the permissible substituents can be one or more and die same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms.
  • This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • the following procedures were utilized to prepare the RR and SS enantiomers from the racemic form of the ligands, described in die earlier part of this specification, and also the SS or RR catalyst form, i.e. the optically pure catalyst, herein described.
  • HPLC column 250mm x 20 mm that employs cellulose tris-(3,5- dimemylphenylcarbamate) coated onto 10 um silica gel as a stationary phase.
  • the mobile phase was filtered through a 0.45 um membrane filter and then purged with argon for "20 minutes. Solutions of " 100 mg/ml of the ligand were prepared in d e glovebox and filtered through a 0.45 um membrane filter.
  • a volume of " 500 uL of the ligand solution was injected onto the column.
  • the two enantiomers were resolved with retention times of 13.2 minutes and 14.8 minutes respectively.
  • the first enantiomer is (+)-et,ph-P4, while the second is (-)-et,ph-P4 (determined by polarimetry).
  • the eluted compounds were collected in separate Schlenk flasks under a continuous purge of nitrogen. The flasks were taken into the glovebox where the solvent was removed under reduced pressure. Enantiomeric purity of the ligands was confirmed by NMR and polarimetry.
  • the 150 mL Parr autoclave used is equipped with a packless magnetic drive stirring system and designed to introduce die gas mixture through a dip tube directly into the solution. Turbine type impellers are used to obtain optimum solution/gas mixing. Stir rates of 1000 rpm are typically used.
  • the autoclave is also equipped with a pressure transducer for monitoring the pressure of the autoclave and a thermocouple for determining the temperature of the reaction mixture in the autoclave.
  • (+)-Rh 2 (a_lyl) 2 ((+)-etph-P4)(0.019 g, 0.0253 mmol) was dissolved in 80 ml of acetone in the autoclave in a glove box.
  • the autoclave is closed and removed from the glove box.
  • the autoclave is connected to die high pressure synthesis gas line.
  • the transfer lines and die olefin addition cylinder are evacuated to remove all oxygen.
  • HBF 4 0.16 g of a one percent ether solution, 0.05 mmol
  • 10 ml of acetone is added to the addition cylinder.
  • Syntiiesis gas (1:1 mixture of __ and CO) is introduced into d e autoclave and bubbled through the autoclave to displace the N 2 present.
  • the pressure is adjusted to 45 psi and die stirring begins at 1000 rpm at room temperature for 10 minutes.
  • the pressure inside die addition cylinder is adjusted to 90 psi to force the HBF 4 solution into the autoclave.
  • Begin temperature ramp to 90°C and the pressure inside autoclave is adjusted to 45 psi.
  • the addition cylinder and die transfer lines are reevacuated for 15 minutes.
  • Vinyl acetate (5 ml, 54 mmol, diluted to 10 ml volume with acetone) was added to the addition cylinder and die pressure inside die cylinder is adjusted to 90 psi.
  • die autoclave When die autoclave reaches 90°C, the pressure inside die autoclave is adjusted to 45 psi and the olefin is added. A small aliquot (1 ml) of the reaction solution is then removed for GC analysis (initial sample). The pressure is adjusted to 90 psi and die data logger is turned on. Samples of die reaction solution are typically taken for product analysis at regular intervals throughout the runs that are usually left to run for six to twenty hours.
  • Rate data was obtained by monitoring the decrease in pressure of a 0.3 liter reservoir cylinder tiiat contained approximately 750 psi of H--/CO that was delivered to die autoclave at constant pressure by a two-stage gas regulator.
  • the pressure of the reservoir cylinder was constantly monitored by an electronic pressure transducer.
  • the reservoir pressure and temperature, autoclave temperature, and stir rate data are collected and stored on a Parr 4851 controller and die data transferred at die end of die reaction to a PC computer for permanent storage and for calculating reaction rates.
  • Analysis of products was performed by GC and NMR. Analyses of the product mixtures showed tiiat vinyl acetate was very cleanly hydroformylated to die branched and linear aldehydes in a 4:1 branched to linear ratio.
  • Synthesis gas (1:1 mixture of H ⁇ and CO) is introduced into die autoclave and bubbled through the autoclave to displace the N 2 present.
  • the pressure is adjusted to 45 psi and die stirring begins at 1000 rpm at room temperature for 10 minutes.
  • the pressure inside die addition cylinder is adjusted to 90 psi to force the HBF 4 solution into the autoclave.
  • Begin temperature ramp to 90°C and die pressure inside autoclave is adjusted to 45 psi.
  • the addition cylinder and the transfer lines are reevacuated for 15 minutes.
  • Vinyl propionate (5.319 g, 53 mmol, diluted to 10 ml volume with acetone) was added to die addition cylinder and the pressure inside die cylinder is adjusted to 90 psi.
  • die autoclave When die autoclave reaches 90°C, the pressure inside die autoclave is adjusted to 45 psi and die olefin is added. A small aliquot (1 ml) of the reaction solution is then removed for GC analysis (initial sample). The pressure is adjusted to 90 psi and die data logger is turned on. Samples of the reaction solution are typically taken for product analysis at regular intervals throughout the runs that are usually left to run for 6 to 20 hours.
  • a catalyst solution is prepared as in Example 4 except tiiat it contains para-isobutyl styrene. This solution is charged to a 100 ml rector and is charged to a pressure of 67 psi with hydrogen gas and to 200 psi with CO. The rate of the reaction is determined by monitoring the drop in pressure as die synthesis gas is consumed. Reaction rate is approximately 0.1 g-mole/liter/hour. When the rate has slowed due to consumption of the styrene starting material, the reaction mixture is removed from die reactor under a nitrogen atmosphere. A portion of the reaction mixture is analyzed by gas chromatography to determine product composition. An isomer ratio of 66:1 (2-(4-isobutyl)phenyl-propionaldehyde:3-(4- isobutyl)phenyl-propionaldehyde) is observed.
  • Three ml of the solution is diluted in 50 ml acetone and is treated with 0.3 g potassium permanganate and 0.32 g magnesium sulfate to effect oxidation of the product aldehydes to tiieir respective acids.
  • the mixture is stirred at room temperature for 30 minutes after which time the solvent is removed under reduced pressure.
  • the residue is extracted 3 times with 50 ml of hot water.
  • the three aqueous solutions are then combined, filtered, and washed with 50 ml chloroform.
  • the aqueous layer is then acidified with HC1 to a pH of 2.0 and then is extracted with 50 ml of chloroform.
  • a catalyst solution is prepared as in Example 4 except that it contains 5 g methoxyvinylnaphthalene and 24.5 g acetone. This solution is charged to a 100 ml reactor and is charged to a pressure of 40 psi witii hydrogen gas and 200 psi with CO. The rate of die reaction is determined by monitoring die drop in pressure as synthesis gas is consumed. Reaction rate is approximately 0.1 g-mole/liter/hour. When the rate has slowed due to consumption of the styrene starting material, the reaction mixture is removed from die reactor under a nitrogen atmosphere.
  • reaction mixture A portion of the reaction mixture is analyzed by GC to determine product composition. An isomer ratio of 80:1 (2-(6-methoxy)-naphthylpropionaldehyde:3-(6- methoxy)naphti ⁇ yl-propionaldehyde) is observed.
  • Three ml of the solution is diluted in 50 ml acetone and is treated with 0.3 g potassium permanganat and 0.32 g magnesium sulfate to effect oxidation of the product aldehydes to tiieir respective acids.
  • the mixture is stirred at room temperature for 30 minutes, after which time the solvent is removed under reduced pressure.
  • the residue is extracted three times with 50 ml of hot water.
  • the three aqueous solutions are then combined, filtered, and washed witii 50 ml chloroform.
  • the aqueous layer is then acidified witii HC1 to a pH of 2.0 and dien is extracted widi 50 ml of chloroform.
  • the chloroform is removed in vacuo and die resulting residue dissolved in 0.5 ml toluene.
  • Example 4 Asymmetric Hydrosilylation of Acetophenone
  • the catalyst (0.020 g) of Example 4 is charged to a 50 ml Schlenk flask under nitrogen. Tetrahydrofuran (THF) (5.0 ml) is added to dissolve die catalyst 0.58 ml of acetophenone and 0.93 ml of diphenylsilane are added to die flask via syringe. The solution is stirred under nitrogen for 18 hours. The solution is treated with 10 ml of 10% hydrochloric acid and is extracted two times with 10 ml of diethyl ether.
  • THF Tetrahydrofuran
  • Example 4 Asymmetric Hydrocyanation of Styrene
  • the catalyst (0.15 g) of Example 4 is charged to a 50 ml Schlenk flask under nitrogen.
  • Deoxygenated THF (10 ml) is added, and die solution is stirred for 30 minutes.
  • 2.0 ml of styrene and 2.00 ml of acetone cyanohydrin are added to the flask via syringe.
  • the solution is stirred for 24 hours at 25°C.
  • Example 4 The catalyst (0.046 g) of Example 4 is charged to a 50 ml Schlenk flask under nitrogen. Deoxygenated THF (5.0 ml) is added, and die solution is stirred under nitrogen for 30 minutes. 0.500 g of norbomene and 1.00 ml of acetone cyanohydrin are added to the flask via syringe. The solution is refluxed under nitrogen for five hours.
  • This reaction mixture is analyzed by GC on a Chiraldex B-PH column which can separate the two enantiomers of the resulting 2-norbornane carbonitrile. Only a single regioisomer of 2-norbornane carbonitrile is observed by this analysis. This analysis indicates a 75:25 ratio of the enantiomers for an ee (enantiomeric excess) of 50%.
  • Example 4 The catalyst (0.173 g) of Example 4 is charged to a 50 ml Schlenk flask under nitrogen. Deoxygenated THF (10 ml) is added and the solution is stitred for 30 minutes. 2.0 ml of styrene and 2.00 ml of acetone cyanohydrin are added to die flask via syringe. The solution is stitred for 24 hours at 25°C.
  • This reaction mixture is analyzed by gas chromatography on a Chiraldex B-PH column which can separate the two enantiomers of the resulting sec-phenylethyl alcohol. This analysis indicates a 60:40 ratio of die S and R enantiomers for an ee (enantiomeric excess) of 20%.
  • EXAMPLE 13 Asymmetric Hydrogenation of Itaconic Acid
  • a catalyst solution is prepared as in Example 4 except acetone is replaced witii 10 ml of tetrahydrofuran.
  • the solution is charged to a 100 ml reactor and is heated to 35°C.
  • the reactor is pressurized to 100 psi with hydrogen and is stirred for 15 minutes.
  • the reactor is vented, and a solution of 0.50 g of itaconic acid and 5 ml of tetrahydrofuran is added to the reactor.
  • the reactor is pressurized witii 1000 psi of hydrogen and stirred for two hours.
  • reaction mixture is analyzed by GC on a Chiraldex B-PH column which can separate the two enantiomers of the resulting 2-methylsuccinate. This analysis indicates a 60:40 ratio of the enantiomers for an ee (enantiomeric excess) of 20%.
  • EXAMPLE 14 Asymmetric Hydroboration of Styrene
  • the catalyst (0.050 g) of Example 4, excluding acetone, is charged to a 50 ml Schlenk flask under nitrogen.
  • Distilled 1,2-dimed ⁇ oxyed ⁇ ane (2.0 ml) is added to die flask.
  • 0.23 ml of styrene and 0.23 ml of catecholborane are added to die flask via syringe.
  • the solution is stirred under nitrogen for two hours.
  • the solution is treated witii 4 ml of metiianol, 4.8 ml of 3.0 mol/liter sodium hydroxide solution and 0.52 ml of 30% hydrogen peroxide.
  • the solution is stirred for three hours and is extracted with 10 ml of diethyl ether. A portion of this solution is analyzed by GC to determine product composition. An isomer ratio of 3:1 (sec-phenethyl alcohol:2-phenylethanol) is observed. A second portion of this solution is analyzed by GC on a Chiraldex B-PH column which can separate the two enantiomers of the resulting sec-phenethyl alcohol. This analysis indicates a 61:39 ratio of the S and R enantiomers for an ee (enantiomeric excess) of 22%.
  • EXAMPLE 15 Asymmetric Cyclopropanation of Styrene
  • the catalyst (0.085 g) of Example 4 is charged to a 25 ml Schlenk flask under nitrogen.
  • Toluene (5.0 ml) is added to the flask under nitrogen.
  • 0.10 ml of triethylamine is added to die flask via syringe, and die solution is stirred under nitrogen for 15 minutes.
  • 5.0 ml of styrene is added by syringe followed by 0.250 ml of ethyldiazoacetate. The solution is stirred under nitrogen for two hours.
  • reaction mixture A portion of the reaction mixture is analyzed by GC to determine product composition. An isomer ratio of 2.1:1 (transxis) is observed for die product cyclopropanes. A second portion of this solution is analyzed by gas chromatography on a Chiraldex B-PH column which can separate the two enantiomers of the resulting cis-ethyl- 2-phenylcyclopropanecarboxylate. This analysis indicates a 63:37 ratio of the cis cyclopropane enantiomers for an ee (enantiomeric excess) of 26%.
  • Example 4 The catalyst (0.050 g) of Example 4 is charged to a 50 ml Schlenk flask under nitrogen. Toluene (5.0 ml) is added to die flask. 0.55 ml of styrene and 0.55 ml of trichlorosilane are added to the solution via syringe, and die solution is stirred under nitrogen for 24 hours. A portion of the reaction mixture is analyzed by GC to determine die product composition. Only a single regioisomer, 2-trichlorosilylethylbenzene, is observed.
  • reaction mixture is concentrated to an oil under vacuum and is dissolved in 5.0 ml of absolute ethanol. 1.0 ml of triethylamine is added to the solution. This solution is analyzed by GC on a Chiraldex B-PH column which can separate the two enantiomers of the resulting 2-triethoxysilylethylbenzene- This analysis indicates a 65:35 ratio of the enantiomers for an ee (enantiomeric excess) of 26%.
  • Example 4 The catalyst (0.050 g) of Example 4 is charged to a 50 ml Schlenk flask under nitrogen. Dichloromethane (2.0 ml) is added to die flask under nitrogen. 0.20 ml of benzaldehyde and 0.40 ml of methyl trimethylsilyl dimetiiylketene acetal is added to the flask via syringe. The solution is stirred under nitrogen for 18 hours. The solution is treated witii 10 ml of 10% hydrochloric acid and is extracted two times with 10 ml of diethyl ether.
  • EXAMPLE 18 Asymmetric Hydroformylation of Vinyl Benzoate (+)-Rh 2 (allyl) 2 (et,ph-P4)(0.020 g, 0.0266 mmol) was dissolved in 70 ml of acetone in the autoclave in a glovebox. The autoclave is closed and removed from the glovebox. The autoclave is connected to die high pressure synthesis gas line. The transfer lines and die olefin addition cylinder are evacuated to remove all oxygen. HBF 4 (0.816 g of a 1% ether solution, 0.05 mmol) in 10 ml of acetone is added to die addition cylinder.
  • Synthesis gas (1:1 mixture of H 2 and CO) is introduced into the autoclave and bubbled through the autoclave to displace die N 2 present.
  • the pressure is adjusted to 45 psi and die stirring begins at 1000 rpm at room temperature for 10 minutes.
  • the pressure inside die addition cylinder is adjusted to 90 psi to force the HBF 4 solution into the autoclave.
  • Begin temperature ramp to 90°C and die pressure inside autoclave is adjusted to 45 psi.
  • the addition cylinder and die transfer lines are reevacuated for 15 minutes.
  • Vinyl benzoate (7.900 g, 53.3 mmol, diluted to 10 mL volume with acetone) was added to die addition cylinder and die pressure inside the cylinder is adjusted to 90 psi.
  • the pressure inside die autoclave is adjusted to 45 psi and die olefin is added.
  • a small aliquot (1 ml) of the reaction solution is then removed for GC analysis (initial sample).
  • the pressure is adjusted to 90 psi and die data logger is turned on. Samples of the reaction solution are typically taken for product analysis at regular intervals throughout the runs that are usually left to run for 6 to 24 hours.

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Abstract

Novel homogeneous bimetallic hydroformylation catalysts, and processes utilizing these catalysts to convert alkenes, particularly alpha olefins, under mild conditions to a product rich in aldehydes, particularly a product containing a high ratio of linear: branched chain aldehydes. The catalysts can be produced from a binucleating tetratertiaryphosphine ligand capable of strongly coordinating two metal centers and holding them in general proximity to one another. Bimetallic catalyst precursors are produced which, on reaction with carbon monoxide and hydrogen, forms the active bimetallic hydroformylation catalyst system. This invention also relates to asymmetric synthesis in which a prochiral or chiral compound is contacted in the presence of an optically pure metal-ligand complex catalyst, in enantiomeric form, to produce an optically active product.

Description

HOMOGENEOUS BIMETALLIC HYDROFORMYLATION CATALYSTS
AND PROCESSES UTILIZING THESE CATALYSTS FOR
CONDUCTING HYDROFORMYLATION REACTIONS
RELATED APPLICATIONS
This patent application, attorney's docket number N-7364, is a Continuation-In-Part application of that commonly assigned U.S. patent application serial number 08/028,415 filed March 9, 1993, which in turn is a Divisional case of U.S. patent application serial number 07/573,355 filed August 27, 1990 (now U.S. 5,200,539, which issued April 6, 1993). Both the Parent case (07/573,355) and the Divisional case (08/028,415) are incorporated herein by reference in their entirety .
FIELD OF THE INVENTION This invention relates to novel homogeneous hydroformylation catalysts, and processes for the use of such catalysts in conducting hydroformylation reactions. In particular, it relates to novel bimetallic catalyst complexes which selectively convert alkenes to linear aldehydes when a feed constituted of alkenes, hydrogen, and carbon monoxide is reacted in the presence of said catalyst complexes.
This invention also relates to asymmetric syntheses in which a prochiral or chiral compound is contacted in the presence of an optically pure metal-ligand complex catalyst, in enantiomeric form, to produce an optically active product.
BACKGROUND OF THE INVENTION Hydroformylation, earlier termed the oxo reaction, is an established process used by the chemical industry for converting alkenes to aldehydes, and sometimes alcohols, by reaction with hydrogen and carbon monoxide. Typically a feed stream constituted of alkenes, hydrogen and carbon monoxide is reacted over soluble rhodium- or cobalt-based transition metal catalyst at relatively low temperatures and pressures. Rhodium catalysts, the catalysts of choice for hydroformylation reactions, has long been recognized as more active than cobalt for promoting the "oxo" reaction, especially at low temperatures and pressures, even when the catalyst is used in relatively low concentrations. Rhodium catalysts, which produce primarily aldehydes, have also provided generally good selectivities in the production of linear aldehydes. Rhodium catalysts, however, require, inter alia, the use of an excess of a phosphine ligand in the reaction to stabilize the catalyst against the formation of decomposition products, and to maintain acceptably high product selectivities.
In U.S. Patent 3,939,188 to Gary B. McVicker there is disclosed a laundry list of complex zero valent rhodium catalysts useful for conducting hydroformylation reactions. These catalysts are represented by the formulae [(L)(L Rh°]2, [(L3)Rh°]2, [(L')2Rh°]2, [(L")Rh°]2, where L is a monodentate ligand, V is a bidentate ligand, and L" is a tri or quadradentate ligand, wherein L, V and L" can be the same or different and each is one selected from the group consisting of:
1. R3Q, RzR'Q, (RRTT)Q
2. R2Q(CR2')xQ'R2
3. R2Q(CY)Q'(R'')(CR2')xQR2
4. R2Q,(CR2 ,)χQ(R")(CR2 ,)xQ(R")(CR2')xQ'R2
5. RQ'KCRj xQRJj 6. Q'KCRj xQRJs
wherein R, R' and R" can be the same or different and each is selected from the group consisting of hydrogen, F, Cl, Br, and I, C, to C^, alkyl, to CJO alkoxy, to Cg cycloalkyl, C3 to cycloalkoxy, phenyl, phenyl substituted with F, Cl, Br, and I, phenyl substituted with C, to CJO alkyl, phenyl substituted with G, to cycloalkyl, phenyl substituted with C,to Cjo alkoxy, oxyphenyl, oxyphenyl substituted with C3 to cycloalkyl, oxyphenyl substituted with F, Cl, Br, and I, oxyphenyl substituted with C3 to Cg cycloalkoxy; Q and Q' can be the same or different and each is selected from the group consisting of P, As and Sb, and X is an integer ranging from 1 to 5.
These catalysts were prepared in accordance with one or the other of the following reactions: 2(L)3RhIX + excess Mg(Hg) → [(L)3Rh°]2 + MgX2
2(L)(L')RhIX + excess Mg(Hg) → [(L)(L')Rh°]2 + MgX2
2(L')2RhIX + excess Mg(Hg) → [(L')2Rh°]2 + MgX2
2(L")RhIX + excess Mg(Hg) → [(L")Rh°]2 + MgX2 X = Cl, Br, I, F, preferably Cl, Br, and I
The reduction of the rhodium (I) complex is performed in an inert atmosphere, at low to moderate temperature and pressure, with an excess of magnesium amalgam in the presence of solvent
These catalysts, like other homogeneous catalyst systems employed for hydroformylation reactions, require the use of an excess of phosphine ligand to stabilize the catalyst, suppress decompostion reactions, and maintain acceptable selectivities. Better stability, particularly better stability without the use of an excess of a phosphine ligand, and improved selectivity in obtaining higher yields of the desired products are desired by the industry. Nonetheless, despite these shortcomings the Rh/PPh3 catalyst system continues in wide use throughout the chemical industry.
OBJECTS It is, accordingly, a primary objective of this invention to provide novel catalyst compositions of high activity and selectivity in carrying out hydroformylation reactions. In particular, it is an object to provide a novel bimetallic hydroformylation catalyst, particularly a catalyst which is highly active, selective, and stable under hydroformylation reaction conditions and does not require the addition of excess phosphine ligand to the reaction when conducting a hydroformylation reaction.
A further, and more specific object is to provide novel homogeneous bimetallic hydroformylation catalyst compositions, particularly rhodium- and ruthenium-based hydroformylation catalyst compositions, and process using these catalysts in conducting hydroformylation reactions to produce products rich in both linear and branched aldehydes; but particularly selective in producing products rich in linear aldehydes. STATEMENT OF INVENTION These objects and others are achieved in accordance with this invention embodying catalyst compositions, and processes using these compositions in conducting hydroformylation reactions, characterized structurally by formula (I) as follows:
wherein M and M' can be the same or different and is a Group VDI metal of the Periodic Table of the Elements (E.H. Sargent & Co. Scientific Laboratory Equipment, Copyright 1962), preferably a metal selected from the group consisting of rhodium, ruthenium, cobalt, iron, and palladium, or a Group IB metal, preferably copper, X is selected from the group consisting of methylene, substituted methylene CR'R2 (sometimes referred to herein as CSS where R1 and R2 can be the same or different and each consists of a hydrocarbon moiety which can be saturated or unsaturated and which contains up to 20 carbon atoms and is a to Cs alkyl (e.g., methyl, ethyl, n-butyl), to C5 alkyenyl (e.g., vinyl, allyl, 1-butenyl), C, to C5 alkoxy (e.g., methoxy, ethyoxy, butoxy), C to C-a, alcohols (e.g, - CHjOH, -CH-jCHjOH), to cycloalkyl (e.g., cyclopropyl, cyclopentyl), C3 to C6 cycloalkoxy (e.g., cyclopropoxy, cyclopentoxy), C6 to o aryl (e.g., phenyl, naphthyl), C6 to C,0 alkaryl (e.g., tolyl, xylyl), C6 to C|0 aralkyl (e.g., benzyl, betaphenylethyl), or the like, and preferably X is methylene, oxygen, NR3 where R3 is a hydrocarbon moiety which can be saturated or unsaturated and contain up to 20 carbon atoms and is a C, to C5 alkyl (e.g., methyl, ethyl, n-butyl), to alkyenyl (e.g., vinyl, allyl, 1-butenyl), C, to C5 alkoxy (e.g., methoxy, ethoxy, butoxy), C, to CJO alcohols (e.g, -CH2OH, -CHjCH- H), C__ to C6 cycloalkyl (e.g., cyclopropyl, cyclopentyl), C3 to C6 cycloalkoxy (e.g., cyclopropoxy, cyclopentoxy), to C^ aryl (e.g., phenyl, naphthyl), C6 to C10 alkaryl (e.g., tolyl, xylyl), to Cjo aralkyl (e.g., benzyl, betaphenylethyl), or the like, and preferably X is methylene; Y is an ethyl, propyl, or meta-substituted aryl linkage with hydrogen, F, or methyl substituents, and, preferably Y is an ethyl group; R is a hydrocarbon moiety which can be saturated or unsaturated and contain up to 20 carbon atoms and is a C, to C^, alkyl (e.g., methyl, ethyl, n-propyl, n-butyl, iso-propyl), C, to alkoxy (e.g., methoxy, ethyoxy, butoxy), C, to C^ alcohols (e.g, -CH2OH, -CH2CH2OH), to C6 cycloalkyl (e.g., cyclopropyl, cyclopentyl), C3 to C6 cycloalkoxy (e.g., cyclopropoxy, cyclopentoxy), C6 to CJO aryl (e.g., phenyl, naphthyl), C6 to C,0 alkaryl (e.g., tolyl, xylyl), C6 to Cj0 aralkyl (e.g., benzyl, betaphenylethyl), or the like, and preferably R is an aryl, suitably phenyl; R' is a hydrocarbon moiety which can be saturated or unsaturated and which contains up to 20 carbon atoms and is a C, to C-rø alkyl (e.g., methyl, ethyl, n-butyl, iso-propyl), Cj to alkoxy (e.g., methoxy, ethyoxy, butoxy), to C-a, alcohol (e.g, -CBjOH, -CH2CH2OH), C3 to cycloalkyl (e.g., cyclopropyl, cyclopentyl), to cycloalkoxy (e.g., cyclopropoxy, cyclopentoxy), to Cι„ aryl (e.g., phenyl, naphthyl), C6 to C10 alkaryl (e.g., tolyl, xylyl), Cjg to CJO aralkyl (e.g., benzyl, betaphenylethyl), or the like, and preferably R' is an alkyl, suitably ethyl. The ligands L and V attached to each of the metal atoms, M and M', can be the same or different and can be H, CO, alkenes, alkyls, or other related ligands present either initially in the catalyst precursor or as formed in situ during the hydroformylation reaction.
The bimetallic hydroformylation catalyst composition embodied by formula (I) can be written in a more simplified form as (IA):
[LwL,xM{R'P-Y-P(R)-X-P(R)-Y-PR,}MXΫL J (IA)
The catalyst embodied by formula I or IA is formed by reaction between the polyphosphine ligand characterized by formula II, hereinafter LTTP,
{R,P-Y-P(R)-X-P(R)-Y-PR'} (LTTP) (II) as follows: LTTP and two molecules of a metal complex capable of complexing with the LTTP ligand form a generalized bimetallic complex characterized by formula in, as follows:
MM1^L/(LTTP)Z+ (HI)
wherein M and M' can be the same or different, L and L' can be the same or different and are ancillary ligands such as hydrogen, halogen, carbonyl, norbomadiene, or the like. The charge on complex m will depend on the oxidation state of the metal centers and the charges and respective numbers of the ligands L and L' designated by w, x, y and z. The values of the numbers w, x, y and z for the ligands L and L' are related to the exact nature of the metal centers and are set to give 14, 16 or 18 electron metal valence electron counts. For example, in the case of:
M = M' « rhodium, L = H '= CO, w = y = l, x = z = l
LTTP, the ligand represented by formula II, acts as a template for building the bimetallic metal complex and has the ability to both bridge and chelate two metal centers, each of which will lie near the geometric center of the complex in general proximity to one another. LTTP is thus preferably a binucleating tetratertiaryphosphine ligand having a bridging-chelating framework open at its center at which reaction with two metal centers can occur to produce bischelated bimetallic complexes represented by formula HI. A prefered LTTP is one wherein the internal phosphorus atoms are linked through a methylene bridge, Y is an ethyl linkage, R is phenyl or a low molecular weight alkyl, and R' is a low molecular weight alkyl, such as ethyl (Et), as represented by the following structural formulae: rae-eLTTP
Ph Ph
meso-eLTTP
A tetratertiaryphosphine of this type is chiral at the two internal phosphorus atoms resulting in both racemic (R,R; S,S) and meso (R,S) diastereomers, a potentially desirable feature in promoting potential stereo- and enantio-selective reactions.
The catalyst of this invention is highly active and can convert alkenes, notably alpha olefins, via hydroformylation to linear and branched aldehydes at fast rates with remarkably high selectivities («30:1 linear to branched). Unlike present commerically used catalysts, there is no need to add excess phosphines to the reaction mixture to maintain the stability of the catalyst. The reason the catalysts of this invention produce a product having a high lineaπbranched aldehyde product ratio, it is believed, is due to the geometric configuration of the M2(LTTP) moiety. When, for example, an alkene coordinates to Rh2H2(CO)2(LTTP) it can only add to one of the outside axial rhodium coordination sites. As the olefin coordinates to the rhodium center, the other ligands tend to bend away, ideally to form a trigonal bipyramid or square pyramid which is the least sterically hindered geometry for a five-coordinate rhodium complex. Rh2(LTTP), however, can not attain this geometry because the other half of the complex is present and limits the extent of ligand motion toward trigonal bipyramidal or square pyramidal. By minimizing the geometry reorganization about the metal center, the steric effects are maximized and the alkene insertion into the M-H bond is directed toward the anti-Markovnikov alkene position to form a linear alkyl group which is then converted into the linear aldehyde product. The considerable activity of this bimetallic LTTP-based catalyst system is also most unusual since it is well known that electron-rich phosphine ligands generally inhibit the activity and selectivity of Rh-based hydroformylation catalysts. We believe that the dramatic rate enhancement observed in the Rh2H2(CO)2(LTTP) catalyst system is due to bimetallic cooperativity, specifically, an intramolecular hydride transfer from one metal center to the other. The rotational flexibility of Rh2(LTTP) has been probed by performing van der Waals (VDW) energy calculations on the model complex W 2(CO)2(LTTP). The molecular modeling calculations show that RhjH^CO^TTP) should have a considerable amount of conformational flexibility. Most importantly, the VDW calculation indicates that this complex can readily access a closed-mode orientation in which the two Rh centers approach one another. This rotational flexibility is significant because square-planar complexes based on the more sterically hindered binucleating hexaphosphine ligand (Et2PCH2CH2)2PCH2P(CH2CH2PEt2)2 which we have also studied (Cf., Askham, F.A; Marques, E.C.; Stanley, G.G. /. Am. Chem. Soc. 1985, 107, 3082; Lanemani S.A.; Stanley, G.G. Inorg. Chem. 1987, 26 1177; Saum, S.E.; Stanley, G.G. Polyhedron 1987,6, 1803; Saum, S.E.; Askham, F.R.; Fronczek, F.; Stanley, G.G.
Organometallics 1988, 7, 1409; Saum, S.E.; Laneman, S.A; Stanley, G.G. Inorg. Chem. 1991, 30 in press) cannot form closed-mode complexes due to severely unfavorable intramolecular steric interactions. Similarly bimetallic bis(diphenylphosphino)-methane (dppm) A-frame complexes of rhodium, Rh2(dppm)2, are terrible hydroformylation catalysts because they lack the rotational flexibility found in Rh2(LTTP) (Cf. Sanger, A R. Homogeneous Catalysis with Metal Phosphine Complexes; Pignolet, L.H. (ed.); Plenum; New York, 1983; pp 215-237.).
The VDW energy molecular modelling studies clearly support the premise that the two rhodium atoms in Rh2H2(CO)2(LTTP) can approach one another and have the proper geometry for a facile hydride transfer from one Rh atom to another. In the hydroformylation catalytic cycle, a species similar to Rh(acyl)(CO)(u-LTTP)RhH(CO) would be a key intermediate in the catalytic cycle and that this type of system could readily access a "closed-mode" conformation in which an intramolecular hydride transfer could occur. Such a proposed intermediate species is shown below.
The RhjOL-l P) unit essentially acts as a conventional monometallic hydroformylation catalyst until it reaches the acyl intermediate. Then, the rotational flexibility of the LTTP ligand comes into play and bimetallic cooperativity takes place to transfer a hydride to the acyl-bound rhodium. Reductive elimination of aldehyde product, it is believed, will then generate a Rh-Rh bonded complex which can react with Hj to regenerate the starting catalyst.
One of the unique features of the LTTP ligand system is that it is relatively straightforward to prepare monometallic analogs that incorporate "half of the LTTP ligand. EtjPCHjCHjPEtj (depe), (depmpe) and (dedppe) ligands have been prepared to act as electronically similar monometallic model ligand systems. AU these model monometallic [Rh(norbornadiene)(P2)](BF4) hydro¬ formylation catalysts turn out to have similar poor activities and selectivities, as shown in Table A. This result is completely consistant with the well known de-activating effect of electron-rich phosphine ligands on Rh-based hydroformylation catalysts.
Rh(norb)(depmpe)+ is, perhaps, the most analogous monometallic complex to our bimetallic Rh2(norb)2(LTTP)2+ system and is a very poor hydroformylation catalyst (see Table A). It has an initial turnover frequency of about 5/hr with a product aldehyde selectivity of only 2:1 linear to branched with large amounts of alkene isomerization observed. Our bimetallic LTTP-based catalyst system is, therefore, at least 70 times faster than this "electronically correct" monometallic analog and markedly more selective and effective as a hydroformylation catalyst system.
Table A Comparison of Bimetallic Rh2(LTTP) Catalyst with Mono- & Bimetallic Model Systems
Linear/
Initial Initial Branched Percent
Temp H2 CO 1-Hexene Rate C-* Aldehyde Alkene
Catalyst" ?c mis psig moles/L TO hr" Mole Ratio Isomerizatio
Rt ort^øLTTP)2* 80 30 30 1.9 370.0 30 8
Rh(nort>)(depe)* 80 30 30 1.9 4.5 3 50
Rh(norb)(depmpe)* 80 30 30 1.9 5.0 3 85
Rh(norb)(dedppe)+ 80 30 30 1.9 4.0 3 85
Rh^noΛ^TTP-pr)2* 80 30 30 1.9 10.0 4 94
Rh^noΛ^LTTP-p-xyl)* 80 30 30 1.9 2.0 2 95
* Counter anion is BF4"
** Tumovers/hr, initial rate measured during first hour of operation on a per mole catalyst basis. Bimetallic model systems have also been prepared which have "spacer" groups replacing the central methylene bridge to probe the importance of having two metal centers present and near one another. Bimetallic rhodium norbomadiene complexes based on p-xylene and pro pylene bridged tetraphosphine ligands (LTTP-p-xyl and LTTP-pr) shown below have been prepared and studied as hydroformylation catalysts.
PhP PPh
( )
Et2P PEt2 eLTTP-p-xylene
PhP PPh
(
Et2P PEt2
eLTTP-propyl
Bimetallic Rh-norbomadiene complexes based on these spaced binucleating tetraphosphine ligands produce very poor hydroformylation catalysts giving results that essentially mirror those seen for the monometallic model systems. The hydroformylation catalytic results for the mono- and bi-metallic complexes discussed here are also summarized in Table A. Molecular modelling studies of the Rh2H2(CO)2(LTTP-p-xylene) and Rh2H2(CO)2(LTTP-pro pyl) catalyst systems clearly indicate that it will be very difficult, if not impossible for the metal centers in these systems to approach one another to do an intramolecular hydride transfer. Thus, the presence of the single atom bridge in LTTP which constrains the two square planar rhodium centers to adopt a rotationally flexible face-to-face orientation may well be the key design feature in the Rh2(LTTP) complex. This, once again, allows facile intramolecular hydride transfer between the metal centers greatly enhancing the rate and efficency of the hydroformylation reaction.
Techniques for the preparation of LTTP are described in the literature, e.g., Inorg. Chem. 1989, 28, 1872 by Laneman et al. The preparation described involves the building of the central bis(phosphino)methane unit by reaction of KP(H)Ph with CH-.C_2, and treatment of the isolated PhrøPCHjPrøPh species with two equivalents of R2P(HC=CH2) under AIBN free radical catalyzed conditions to produce LTTP, e.g.:
Scheme I - eLTTP Synthesis
DMP 2PhPH, + 2K0H *» 2PhPH~
CHjClg (H)PhPCH,PPh(H)
rac-eLTTP meso-eLTTP
The ethylene-linked terminal phosphines in LTTP simplify the synthetic procedure and gives higher yields of the final tetraphosphine (88-92%) based on Ph(H)PCH2P(H)Ph, or 39-43% yields based on the starting PhPH2. The presence of the phenyl groups on the central P-CH2-P bridge allows more facile crystallizations of bimetallic complexes. The electron-rich alkylated terminal and mostly alkylated internl phosphines coordinate strongly with metal centers and provide a very effective means for inhibiting ligand dissociation and bimetallic fragmentation.
The meso and racemic diastereomers of LTTP are both highly reactive binucleating ligands that can bridge and chelate two metal centers, albeit each can form complexes that have different overall geometrical orientations of the phosphines about the two metal centers. The reaction of a metal compound as described by reference to formula HI, however, will produce a large amount of the hydroformylation catalyst composition of the general geometrical configuration described by reference to formula I. For example, the reaction of [Rh(norbornadiene)2](BF4) with LTTP produces the bimetallic hydroformylation catalyst composition described by formula I wherein X = CH2, Y = CH2CH2,R = phenyl (Ph), R'= ethyl/(Et), L = L' = norbomadiene, and M = Rh, viz.
[Rh2(norbomadiene)2(LTTP)](BF4)2 in 80-90% isolated yield; the first diastereomer of this complex to crystallize out of a tetrahydrofuran (THF) solution being the racemic-tRh^norbomadiene^^TTPJKBF^ complex. This complex has been characterized by *H and 31P NMR, elemental analysis, and single-crystal X-ray diffraction. The process of this invention contemplates using these highly active bimetallic catalysts for converting alkenes to aldehydes, at high selectivity, by reacting the alkenes with the catalyst in a homogeneous reaction phase in the presence of carbon monoxide, CO, and hydrogen, Hj. The catalyst or catalyst precursor is introduced into the autoclave or reaction vessel dissolved in a liquid medium, or slurried, or otherwise dispersed in a liquid medium to eventually provide a homogeneous reaction phase. Suitable solvents are, e.g., alcohols, ethers, ketones, parafins, cycloparafins, and aromatic hydrocarbons.
Feeds constituted of, or feeds containing alkenes such as alpha olefins, particularly straight chain alpha olefins, having from 2 to about 20 carbon atoms (Cj to Cg,), preferably from about Cj to C12, are preferred. The alpha olefins are characterized by a terminal double bond, i.e., CH2=CH-R, and these groups may be substituted if the substituents do not interfere in the hydroformylation reaction. Exemplary of such substituents are carbonyl, carbonyloxy, oxy, hydroxy, alkoxy, phenyl and the like. Exemplary alpha olefins, or olefins unsaturated in the 1-position, include alkenes, alkyl alkenoates, alkenyl alkyl ethers, alkenols, and the like, e.g., ethylene, propene, 1-butene, 1-pentene, 1-hexene, 1-hepene, 1-octene, vinyl acetate, allyl alcohol, and the like.
The feed is contacted with the homogeneous catalyst, while carbon monoxide and hydrogen are added, at temperature, pressure and time sufficient to convert the alkene to aldehydes, at high selectivities. In general, the temperature of the reaction ranges from about 50°C to about 150°C, preferably from about 60°C to about 120°C. In general, total pressures range from about 20 pounds per square inch (psi) to about 300 psi, preferably from about 50 psi to about 200 psi. The ratios of H2:CO ranges generally from about 10:90 to about 90:10 volume percent, preferably from about 40:60 to 60:40 volume percent.
The catalyst is generally employed in the reaction mixture in concentrations ranging from about 10"5 M to about Iff2 M (molarity). The catalyst is added to the reaction vessel as a slurry or a solution, the reaction is pressurized and brought to the desired operating temperature. The feed and the carbon monoxide and hydrogen in desired ratios are then introduced into the reaction vessel to commence an operation. Alkene feeds that are liquids at or near room temperature (e.g., 1-hexene, 1-octene) are introduced to the reaction zone prior to charging the H2 and CO gases, although this is not a prerequisite for the reaction. The process is suited to batchwise operation, or to continuous operation via the use of suitable apparatus.
The following examples 1, 2, and 3, with comparative demonstrations, are further exemplary of the active and highly selective catalysts of this invention for use in conducting hydroformylation reactions. In the examples and demonstrations that follow, all parts are in terms of mole units, pressures in terms of pounds per square inch gauge, and temperatures expressed in terms of degrees Centigrade except as otherwise expressed.
In conducting this series of tests, it was found that the catalysts of this invention produce hydroformylation of the alkene feed under very mild conditions. Both linear and branched aldehyde are produced, but with remarkably high selectivity ratios of linear to branched aldehydes. This is done without any. necessity of adding excess phosphine ligand to maintain catalyst stability and high product aldehyde selectivities. Virtually all current commercial Rh/PR3 catalyst systems, in marked contrast, require excess phosphine ligand for stabilization of the Rh/PR3 catalysts.
EXAMPLES
Catalyst Preparation
A binucleating tetratertiaiyphosphine ligand (CH-jCHjPEt-*), was prepared by reacting two equivalents of PhPH2 and one equivalent of CHjClj with KOH in DMF solution to produce PhrøPCHjprøPh which is isolated. Ph(H)PCH2p(H)Ph is then treated with two equivalents of Et2P(CH=CH2) under AIBN freeradical catalyzed conditions to produce (Et2CH2CH2)(Ph)PCH2P(Ph)(CH2CH2PEt2) in 88-92% isolated yield based on Ph(H)PCH2P(H)Ph, or 39-43% yields based on the starting PhPH2. All manipulations were carried out under inert atmosphere conditions in dried degassed solvents.
One equivalent of (Et2CH2CH2)(Ph)PCH2P(Ph)(CH2CH2PEt2) was then reacted with two equivalents of [Rh(norbomadiene)2](BF4) in THF under inert atmosphere conditions to produce the bimetallic Rh(I) catalyst precursor [Rh2(norbomadiene)2{(Et2;CH2CH2)- (Ph)PCH2P(Ph)(CH2CH2PEt2)}](BF4)2, hereafter [Rh^norbomaώene^TTP)]2*, in essentially quantitative yield.
EXAMPLE 1 Hydroformylation of 1-Hexene
All operations were carried out under inert atmosphere conditions. 0.02 g (0.0195 mmol) of the [Rh2(nσrb)2(LTTP)](BF4)2 catalyst precursor was dissolved in 45 mL of acetone. 7.5 g (89.3 mmol) of 1-hexene was added and the mixture transfered to a 450 mL Parr stainless steel autoclave system. The autoclave is equipped with a packless magnetic drive stirring system and designed to introduce the gas mixture through a dip tube directly into the solution. Turbine type impellers and glass liners with built in baffles are used to obtain optimum solution/gas mixing. Stir rates of 1000-1200 rpm are typically used. The autoclave was also equipped with a pressure transducer for monitoring the pressure of the autoclave and a thermocouple for determining the temperature of the reaction mixture in the autoclave.
All runs were done under constant pressure conditions of Hj/CO. A 1:1 mixture of Hj/CO was then added to give an autoclave pressure of 30 psi. The temperature of the autoclave was increased to and stabilized at 80°C (this took =10 min). The pressure in the autoclave was then leveled off at 80 psi for the duration of the run. Small aliquots (<1 mL) of the reaction mixture were typically taken for product analysis at regular intervals throughout the runs which typically were left to run for 6 to 18 hours. Rate data was obtained by monitoring the decrease in pressure of a 1 L reservoir cylinder that contained approximately 750 psi of H^CO which was delivered to the autoclave at constant pressure by a two-stage gas regulator. The pressure of the reservoir cylinder was constantly monitored by a pressure transducer. The reservoir pressure and temperature, autoclave temperature, and stir rate data were collected and stored on a Parr 4851 controller and the data transferred periodically to a PC computer for permanent storage and for calculating reaction rates. Analysis of products was performed by GC, NMR and GC/MS measurements.
Analyses of the product mixtures showed that 1-hexene was very cleanly hydroformylated to the linear and branched aldehydes, 1-heptanal and 2-methyl-hexanal, in a 30:1 linear to branched ratio. No alcohol or alkane formation was observed that amounted to over 1% of the product mixture. The data from this run is shown in Table 1 and is compared to a commercial Rh/PPh3 catalyst system.
Table 1 Hydroformylation of 1-Hexene
Linear/
Initial Initial Branched
Temp H2 CO 1-Hexene Rate C, Aldehyde
Catalvst* m > ____ . psig psig moles/L TO/hi* Mole Ratio
HRh(CO)(PPhj)j 950 80 30 30 1.9 447.5 14
Counter anion as BF4 ' for cationic species.
Phosphine ligand to Rh molar ratio.
Turnovers/hr. initial rate measured during first hour of operation on a per mole catalyst basis. The activity of the mixture of racemic and meso bimetallic Rh2(LTTP) catalysts is only 16% slower than that of the Rh/PPh3 catalyst system which is used commerically on a large scale. This is most surprising since electron-rich phosphine ligands (either monodentate or polydentate) such as ours are well known to make rhodium centers far less active towards hydroformylation catalysis. Virtually all effective rhodium-phosphine based hydroformylation catalyst systems use more electron deficient phosphine ligands such as PPh3 (or substituted versions thereof and P(OR)3 (or substituted versions thereof). It is also known that electronrich phosphine ligands generally cause decreases in product selectivities. For these reasons, electron-rich phosphine ligands have proven to be very poor ligands for rhodium hydroformylation catalysts.
In marked contrast, however, the bimetallic LTTP-based dirhodium catalyst of this invention has both high activities and very high selectivities giving an initial rate of 370 rurnovers/hr and a linear to branched aldehyde product ratio of at least 30:1. Furthermore, because of the strong rhodium coordinating abilities of this electron-rich LTTP ligand system, an excess of phosphine ligand is not required either for catalyst stability or to enhance linear aldehyde production.
EXAMPLE 2
Hydroformylation of 1-Octene
All operations were carried out under inert atmosphere conditions. 0.02 g (0.0195 mmol) of the |R__^(nσrb)(LTTP)I(BF4)2 catalyst precursor was dissolved in 45 mL of acetone. 7.55 g (67.3 mmol) of 1-octene was added and the mixture transfered to a 450 mL Parr autoclave system. The same autoclave system and methods of product analysis as described in Example I were used here.
Analyses of the product mixtures showed that 1-octene was very cleanly hydroformylated to the linear and branched aldehydes, 1-nonanal and 2-methyl-octanal, in a 23:1 linear to branched ratio. The data from this run is shown in Table 2. Table 2
Hydroformylation of 1-Octene
Linear/
Initial Initial Branched
Temp H2 CO 1-Octene Rate Aldehyde
Catalyst* __Q psig psig TO/hi* TO/hr" Mole Ratio
Rhjtøort jO-TTP) 80 30 30 1.3 217.5 23
1 Counter anion as BF * for cationic species. k Tumovers/hr. initial rate measured during first hour of operation on a per mole catalyst basis.
EXAMPLE 3 Hydroformylation of Allyl Alcohol
All operations were carried out under inert atmosphere conditions. 0.02 g (0.0195 mmol) of the [Rh2(norb)2(LTTP)](BF4)2 catalyst precursor was dissolved in 42 mL of acetone. 7.75 g (134 mmol) of allyl alcohol was added and the mixture transfered to a 450 mL Parr autoclave system. The same autoclave system and methods of product analysis as described in Example I were used here.
Analyses of the product mixtures showed that allyl alcohol was very cleanly hydroformylated to the linear and branched aldehydes, 4-hydroxybutanal and 3-hydroxy-2- methyl-propanal, in greater than 30:1 linear to branched ratio. The data from this run is shown in Table 3. Table 3
Hydroformylation of Allyl Alcohol
Linear/
Initial Initial Branched
Temp H2 CO 1-Octene Rate Aldehyde
Catalyst" ϋQ ESi£ psig TO/hi* TO/hi* Mole Ratio
Rh^norb^TTP)2* 90 30 30 2.8 797.5 >30
Counter anion is BF4" for cationic species.
Tumovers hr. initial rate measured during first hour of operation on a per mole catalyst basis. ASYMMETRIC SYNTHESIS In another facet of the present invention, there is provided asymmetric synthesis in which a prochiral or chiral compound is contacted in the presence of an optically pure metal-ligand complex catalyst, in enantiomeric form, to produce an optically active product
Asymmetric synthesis is of importance, for example, in the pharmaceutical industry, since frequently only one optically active isomer (enantiomer) is therapeutically active. An example of such a pharmaceutical product is the non-steroidal anti- inflammatory drug Naproxen. The S enantiomer is a potent anti-arthritic agent, while the R enantiomer is a liver toxin. It is therefore oftentimes desirable to selectively produce one particular enantiomer over its mirror image.
It is known that special precautions must be taken to ensure production of a desired enantiomer because of the tendency to produce optically inactive racemic mixtures, that is equal amounts of each mirror image enantiomer whose opposite optical activities cancel out each other. In order to obtain the desired enantiomer or mirror image stereoisomer from such a racemic mixture, the racemic mixture must be separated into its optically active components. This separation, known as optical resolution, may be carried out by actual physical sorting, direct crystallization of the racemic mixture, or other methods known in the art. Such optical resolution procedures are often laborious and expensive, as well as destructive to the desired enantiomer. Due to these difficulties, increased attention has been placed upon asymmetric synthesis in. which one of the enantiomers is obtained in significantly greater amounts. Efficient asymmetric synthesis desirably affords the ability to control both regioselectivity (branched/normal ratio), e.g., hydroformylation, and stereoselectivity. Various asymmetric synthesis catalysts have been described in the art. For example, Wink, Donald J. et al., Inorg. Chem. 1990, 29, 5006-5008 discloses syntheses of chelating bis(dioxaphospholane) ligands through chlorodioxaphospholane intermediates and the demonstration of catalytic competence of bis(phosphite)rhodium cations. A complex derived from dihydrobenzoin was tested as a precursor in the hydroformylation of olefins and gave a racemic mixture. Catonic rhodium complexes of bis(dioxaphospholane) ligands were tested in the hydrogenation of enamides and gave enantiomeric excesses (ee) on the order of two to ten percent.
Pottier, Y. et al., Journal of Organometallic Chemistry, 370, 1989, 333-342 describes the asymmetric hydroformylation of styrene using rhodium catalysts modified with aminophosphine-phosphinite ligands. Enantioselectivities greater than thirty percent are reportedly obtained.
East Germany patent nos. 275,623 and 280,473 relate to chiral rhodium carbohydrate-phosphinite catalyst production. The catalysts are stated to be useful as stereospecific catalysts for carrying out carbon-carbon bond formation, hydroformylation, hydrosilylation, carbonylation, and hydrogenation reactions to give optically active compounds.
Stille, John K et al., Organometallics 1991, 10, 1183-1189 relates to the synthesis of three complexes of platinum JJ containing the chiral ligands l-(tert-butoxycarbonyl)- (2S, 4S)-2-[(diphenylphosphino)methyl]-4-(dibenzophospholyl)py_τolidine, l-(tert- butoxycarbonyl)-(2S, 4S)-2-[(dibenzophospholyl)methyl]-4-(diphenylphosphino)pyrrolidine and 1 -(tert-butoxycarbonyl)-(2S, 4S)-4-(dibenzophospholyl)-2-[(dibenzophospholyl)- methyljpyrrolidine. 1 Asymmetric hydroformylation of styrene was examined with use of platinum complexes of these three ligands in the presence of stannous chloride as catalyst. Various branched/normal ratios (0.5 to 3.2) and enantiomeric excess values (12 to 77%) were obtained. When the reactions were carried out in the presence of triethyl orthoformate, all four catalysts gave virtually complete enantioselectivity (ee >96%) and similar branched/normal ratios.
Sakai et al., J. Am. Chem. Soc. 1993, 115, 7033-7034 disclose highly enantioselective hydroformylation of olefins catalyzed by new phosphinephosphite-Rh(I) complexes. The search for more effective asymmetric synthesis processes is a constant one in the art. It would be desirable if asymmetric synthesis processes could be provided having good yields of optically active products without the need for optical resolution. It would be further desirable if asymmetric synthesis processes could be provided having the characteristics of high stereoselectivity, high regioselectivity, e.g., hydroformylation, and good reaction rate. This facet of the present invention relates to asymmetric syntheses in which a prochiral or chiral compound is reacted in the presence of optically pure, metal-ligand complex catalyst, in enantiomeric form, to produce an optically active product. Specifically, it has been unexpectedly found that the separate SS and RR enantiomers (in substantially pure form) of the racemic form of the general catalyst, disclosed in the earlier part of this specification, can effect asymmetric synthesis in various processes with various substrates to produce a specific isomeric material with high enantiomeric excess (ee) and which is optically active. It was also unexpectedly found that the meso form of this general catalyst is somewhat inactive, notwithstanding the fact that when both the meso and racemic diastereomers of the catalyst are together, there are disclosed to be highly reactive.
The processes of this invention are distinctive in that they provide good yields of optically active products having high stereoselectivity, high regioselectivity, and good reaction rate without the need for optical resolution. The processes of this invention stereoselectively produce a chiral center. An advantage of this invention is that optically active products can be synthesized from optically inactive reactants. Another advantage is that yield losses associated with the production of an undesired enantiomer can be substantially reduced.
The asymmetric syntheses processes of this invention are useful for the production of numerous optically active organic compounds, e.g., aldehydes, alcohols, ethers, esters, amines, amides, carboxylic acids and the like, which have a wide variety of applications.
The part of the subject invention encompasses the carrying out of any known conventional syntheses in an asymmetric fashion in which the catalyst thereof is replaced by eitiier the SS or RR enantiomers of the racemic form of the optically active metal- ligand complex catalyst as disclosed in the prior art In this facet the ligand is symmetrical when referred to as the SS or RR enantiomers of the racemate form of the metal-ligand complex catalyst It is to be understood that the term, "optically pure metal- ligand complex catalyst", "optically pure metal catalyst", and/or "optically pure catalyst" only refers to the individual SS or RR enantiomers (i.e. one enantiomer is present in at least 97% purity level) of the racemic form of the prior art catalyst Illustrative asymmetric syntheses reactions include, for example, hydroformylation, hydro acylation (intramolecular and intermolecular), hydrocyanation, olefin and ketone hydrosilylation, hydrocarboxylation, hydroamidation, hydroesterification, hydrogenation, hydrogenolysis, aminolysis, alcoholysis, carbonylation, decarbonylation, olefin isomerization, Grignard cross coupling, transfer hydrogenation, olefin hydroboration, olefin cyclopropanation, aldol condensation, allelic alkylation, olefin codimerization, Diels-Alder reactions, and the like. As indicated above, the processes of this invention stereoselectively produce a chiral center. Preferred asymmetric syntheses reactions involve the reaction of organic compounds with carbon monoxide, or carbon monoxide and a third reactant, e.g., hydrogen, in the presence of a catalytic amount of an optically active metal-ligand complex catalyst. More preferably, the subject invention relates to asymmetric hydroformylation which involves the use of an optically pure metal-ligand complex catalyst in the production of optically active aldehydes wherein a prochiral or chiral olefinic compound is reacted with carbon monoxide and hydrogen. The optically active aldehydes produced correspond to the compounds obtained by the addition of a carbonyl group to an olefinically unsaturated carbon atom in the starting material with simultaneous saturation of the olefinic bond. The processing techniques of this invention may correspond to any of the known processing techniques heretofore employed in conventional asymmetric syntheses reactions including asymmetric hydroformylation reactions.
For instance, the asymmetric syntheses processes can be conducted in continuous, semi-continuous, or batch fashion and involve a liquid recycle and/or gas recycle operation as desired. Likewise, the manner or order of addition of the reaction ingredients, catalyst, and solvent are also not critical and may be accomplished in any conventional fashion.
In general, the asymmetric syntheses reactions are carried out in a liquid reaction medium that contains a solvent for the optically pure catalyst preferably one in which the reaction ingredients, including catalyst, are substantially soluble.
As indicated above, the subject invention encompasses the carrying out of any known conventional syntheses in an asymmetric fashion in which the catalyst thereof is replaced by an optically pure metal-ligand complex catalyst as disclosed herein.
Asymmetric intramolecular hydroacylation can be carried out in accordance with conventional procedures known in the art For example, aldehydes containing an olefinic group with three to seven carbons removed can be converted to optically active cyclic ketones under hydroacylation conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
Asymmetric intermolecular hydroacylation can be carried out in accordance with conventional procedures known in the art For example, optically active ketones can be prepared by reacting a prochiral olefin and an aldehyde under hydroacylation conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
Asymmetric hydrocyanation can be carried out in accordance with conventional procedures known in the art For example, optically active nitrile compounds can be prepared by reacting a prochiral olefinic compound and hydrogen cyanide under hydrocyanation conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
Asymmetric olefin hydro silylation can be carried out in accordance with conventional procedures known in d e art For example, optically active silyl compounds can be prepared by reacting a prochiral olefin and a silyl compound under hydrosilylation conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
Asymmetric ketone hydrosilylation can be carried out in accordance with conventional procedures known in the art For example, optically active silyl ethers or alcohols can be prepared by reacting a prochiral ketone and a silyl compound under hydrosilylation conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
Asymmetric hydrocarboxylation can be carried out in accordance with conventional procedures known in the art For example, prochiral olefins can be converted to optically active carboxylic acids under hydrocarboxylation conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
Asymmetric hydroamidation can be carried out in accordance with conventional procedures known in the art For example, optically active amides can be prepared by reacting a prochiral olefin, carbon monoxide, and a primary or secondary amine or ammonia under hydroamidation conditions in the presence of an optically pure metal- ligand complex catalyst described herein.
Asymmetric hydroesterification can be carried out in accordance with conventional procedures known in the art For example, optically active esters can be prepared by reacting a prochiral olefin, carbon monoxide, and an alcohol under hydroesterification conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
Asymmetric olefin hydrogenations and other asymmetric hydrogenations can be carried out in accordance with conventional procedures known in the art. For example, hydrogenation can be used to reduce a carbon-carbon double bond to a single bond. Other double bonds can also be hydro genated, for example, a ketone can be converted to an optically active alcohol under hydrogenation conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
Asymmetric hydrogenolysis can be carried out in accordance with conventional procedures known in the art For example, optically active alcohols can be prepared by reacting an epoxide with hydrogen under hydrogenolysis conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
Asymmetric aminolysis can be carried out in accordance with conventional procedures known in the art For example, optically active amines can be prepared by reacting a prochiral olefin with a primary or secondary amine under aminolysis conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
Asymmetric alcoholysis can be carried out in accordance with conventional procedures known in the art For example, optically active ethers can be prepared by reacting a prochiral olefin with an alcohol under alcoholysis conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
Asymmetric carbonylation can be carried out in accordance with conventional procedures known in the art For example, optically active lactones can be prepared by treatment of allyl alcohols with carbon monoxide under carbonylation conditions in the presence of an optically pure metal-ligand complex catalyst described herein. Asymmetric decarbonylation can be carried out in accordance with conventional procedures known in the art For example, acyl or aroyl chlorides can be decarbonylated under decarbonylation conditions with retention of configuration in the presence of an optically pure metal-ligand complex catalyst described herein. Asymmetric isomerization can be carried out in accordance with conventional procedures known in the art For example, allelic alcohols can be isomerized under isomerization conditions to produce optically active aldehydes in the presence of an optically pure metal-ligand complex catalyst described herein.
Asymmetric Grignard cross coupling can be carried out in accordance with conventional procedures known in the art For example, optically active products can be prepared by reacting a chiral Grignard reagent with an alkyl or aryl halide under Grignard reagent with an alkyl or aryl halide under Grignard cross coupling conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
Asymmetric transfer hydrogenation can be carried out in accordance with conventional procedures known in the art For example, optically active alcohols can be prepared by reacting a prochiral ketone and an alcohol under transfer hydrogenation conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
Asymmetric olefin hydroboration can be carried out in accordance with conventional procedures known in the art For example, optically active alkyl boranes or alcohols can be prepared by reacting a prochiral olefin and a borane under hydroboration conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
Asymmetric olefin cyclopropanation can be carried out in accordance with conventional procedures known in the art For example, optically active cyclopropanes can be prepared by reacting a prochiral olefin and a diazo compound under cyclopropanation conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
Asymmetric aldol condensations can be carried out in accordance with conventional procedures known in the art For example, optically active aldols can be prepared by reacting a prochiral ketone or aldehyde and a silyl enol ether under aldol condensation conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
Asymmetric olefin codimerization can be carried out in accordance with conventional procedures known in the art For example, optically active hydrocarbons can be prepared by reacting a prochiral alkene and an alkene under codimerization conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
Asymmetric allylic alkylation can be carried out in accordance with conventional procedures known in the art For example, optically active hydrocarbons can be prepared by reacting a prochiral ketone or aldehyde and an allelic alkylating agent under alkylation conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
Asymmetric Diels-Alder reaction can be carried out in accordance with conventional procedures known in the art For example, optically active olefins can be prepared by reacting a prochiral diene and an olefin under cycloaddition conditions in the presence of an optically pure metal-ligand complex catalyst described herein.
The permissible prochiral and chiral starting material reactants encompassed by the processes of this invention are, of course, chosen depending on d e particular asymmetric syntheses desired. Such starting materials are well known in the art and can be used in conventional amounts in accordance with conventional methods. Illustrative starting material reactants include, for example, substituted and unsubstituted aldehydes (intramolecular hydroacylation, aldol condensation, allelic alkylation), prochiral olefins (hydroformylation, intermolecular hydroacylation, hydrocyanation, hydrosilylation, hydrocarboxylation, hydroamidation, hydroesterification, aminolysis, alcoholysis, cyclopropanation, hydroboration, Diels-Alder reaction, codimerization), ketones
(hydrogenation, hydrosilylation, aldol condensation, transfer hydrogenation, allelic alkylation), chiral and prochiral epoxides (hydroformylation, hydrocyanation, hydrogenolysis), alcohols (carbonylation), acyl and aryl chlorides (decarbonylation), a chiral Grignard reagent (Grignard cross coupling) and die like. Illustrative olefin starting material reactants useful in certain of the asymmetric syntheses processes of this invention, e.g., hydroformylation, include tiiose which can be terminally or internally unsaturated and be of straight chain, branched-chain, or cyclic structure. Such olefins can contain from four to forty carbon atoms or greater and may contain one or more ethylenic unsaturated groups. Moreover, such olefins may contain groups or substituents which do not essentially adversely interfere with the asymmetric syntheses process such as carbonyl, carbonyloxy, oxy, hydroxy, oxycarbonyl, halogen, alkoxy, aryl, haloalkyl, and d e like. Illustrative olefinic unsaturated compounds include substituted and unsubstituted alpha olefins, internal olefins, alkyl alkenoates, alkenyl alkanoates, alkenyl alkyl ethers, alkenols, and die like, e.g., 1-butene, 1-pentene, 1-hexene, 1-octene, 1-decene, 1-dodecene, 1-octadecene, 2-butene, isoamylene, 2-pentene, 2-hexene, 3-hexene, 2-heptene, cyclohexene, propylene dinners, propylene trimers, propylene tetramers, 2-ethylhexene, 3-phenyl-l-propene, 1,4-hexadiene, 1,7-octadiene, 3-cyclohexyl- 1-butene, allyl alcohol, hex-l-en-4-ol, oct-l-en-4-ol, vinyl acetate, allyl acetate, aryloates such as vinyl benzoate and d e like, 3-butenyl acetate, vinyl propionate, allyl propionate, allyl butyrate, methyl methacrylate, 3-butenyl acetate, vinyl ethyl ether, vinyl methyl ether, allyl ethyl ether, n-prσpyl-7-octenoate, 3-butenenitrile, 5-hexenamide, styrene, norbomene, alpha-methylstyrene, and the like. Illustrative preferred olefinic unsaturated compounds include, for example, p-isobutylstyrene, 2-vinyl-6-methoxynaphthylene, 3-ethenylphenyl phenyl ketone, 4-ethylphenyl-2-thienylketone, 4-ethenyl-2-fluorobiphenyl, 4-(lm,3-dihydro- l-oxo-2H-isoindol-2-yl)styrene, 2-ethyl-5-benzoylthiophene, 3-ethenylphenyl phenyl ether, propenylbenzene, isobutyl-4-propenylbenzene, phenyl vinyl ether, vinyl chloride, and d e like. Suitable olefinic unsaturated compounds useful in certain asymmetric syntheses processes of this invention include substituted aryl ediylenes described in U.S. 4,329,507, incorporated herein by reference in its entirety. Of course, it is understood that mixtures of different olefinic starting materials can be employed, if desired, by d e asymmetric syntheses processes of the subject invention. More preferably, the subject invention is especially useful for the production of optically active aldehydes, by hydroformylating alpha olefins containing from four to forty carbon atoms or greater, as well as starting material mixtures of such alpha olefins and internal olefins. Illustrative prochiral and chiral olefins useful in the processes of this invention include tiiose represented by die formula:
wherein R„ Rj, R3, and « are die same or different (provided Rj is different from Rj and R3 is different from R and are selected from hydrogen; alkyl; substituted alkyl, said substitution being selected from amino including alkylamino and dialkylamino, such as benzylamino and dibenzylamino, hydroxy, alkoxy, such as methoxy and ethoxy, acyloxy, such as acetoxy, halo, nitro, nitrile, thio, carbonyl, carboxamide, carboxaldehyde, carboxyl, carboxylic ester; aryl including phenyl; substituted aryl including phenyl, said substitution being selected from alkyl, amino including alkylamino and dialkylamino such as benzylamino and dibenzylamino, hydroxy, alkoxy such as methoxy and etiioxy, acyloxy such as acetoxy, halo, nitrile, nitro, carboxyl, carboxaldehyde, carboxylic ester, carbonyl, and thio, said aryl substitution being less than four substituents; acyloxy such as acetoxy; alkoxy such as methoxy and ethoxy; amino including alkylamino and dialkylamino such as benzylamino and dibenzylamino; acylamino and diacylamino such as acetylbenzylamino and diacetylamino; nitro; carbonyl; nitrile; carboxyl; carboxamide; carboxaldehyde; carboxylic ester, and alkylmercapto such as methylmercapto.
It is understood that the prochiral and chiral olefins of this definition also include molecules of die above general formula where the R-groups are connected to form ring compounds, e.g., 3-medιyl-l-cyclohexene, and the like. Illustrative epoxide starting material reactants useful in certain of the asymmetric syntheses processes of this invention, e.g., hydroformylation, include those represented by die formula: R.
\ / \ / c - - c /
wherein Rs, R^ R7, and Rg are die same or different (provided R5 is different from R* and/or R, is different from R8) and are selected from hydrogen, monovalent aliphatic or aromatic groups containing one to about twelve carbon atoms, and divalent aliphatic groups containing four to about six carbon atoms in which any permissible combination of R5, Re, R-i, and R„ may be linked together to form a substituted or unsubstituted, carboxylic or heterocyclic ring system such as a monocyclic aromatic or nonaromatic ring system, e.g., cyclohexene oxide. Examples of specific epoxides which are useful in this invention include propylene oxide, 1,2-epoxyoctane, cyclohexene oxide, styrene oxide, and d e like. The catalyst useful in this part of the invention is the optically pure metal-ligand complex catalyst characterized structurally, in general, by formula (I) as follows:
wherein M and M' can be die same or different, and each is a Group VIII metal of the Periodic Table of die Elements (E_H. Sargent & Co. Scientific Laboratory Equipment, Copyright 1962) preferably a metal selected from the group consisting of rhodium, rudienium, cobalt, iron, and palladium, or a Group IB metal, preferably copper, X is selected from the group consisting of metiiylene, substituted memylene CR!R2 where R1 and R2 can be die same or different and each consists of a hydrocarbon moiety which can be saturated or unsaturated and which contains up to twenty carbon atoms and is a C, to C5 alkyl (e.g., methyl, ediyl, n-butyl), C-. to alkyenyl (e.g., vinyl, allyl, 1-butenyl), C, to C5 alkoxy (e.g., medioxy, ethoxy, butoxy), C, to C-a, alcohol (e.g., -CH2OH, -CΑ2CH2OΑ)_ C3 to C6 cycloalkyl (e.g., cyclopropyl, cyclophentyl), C3 to C6 cycloalkoxy (e.g., cyclopropoxy, cyclopentoxy), to C10 aryl (e.g., phenyl, naphthyl), C6 to C10 alkaryl (e.g., tolyl, xylyl), to C,0 aralkyl (e.g., benzyl, betaphenylediyl), or the like, and preferably X is methylene, oxygen, NR3 where R3 is a hydrocarbon moiety which can be saturated or unsaturated and which contains up to twenty carbon atoms and is a C, to Cs alkyl (e.g., metiiyl, ethyl, n-butyl), to alkenyl (e.g., vinyl, allyl, 1-butenyl), C, to C5 alkoxy (e.g. methoxy, ethoyoxy, butoxy), C, to to C6 cycloalkyl (e.g., cyclopropyl, cyclopentyl), to C6 cycloalkoxy (e.g., cyclopropoxy, cyclopentoxy), to Cj0 aryl (e.g., phenyl, naphthyl), C6 to o alkaryl (e.g., tolyl, xylyl), C6 to CJO aralkyl (e.g., benzyl, betaphenylethyl), or the like, and preferably X is methylene; Y is an ediyl, propyl, or metasubstituted aryl linkage with hydrogen, F, or methyl substituents, and preferably Y is an ediyl group; R is a hydrocarbon moiety which can be saturated or unsaturated and which contains up to twenty carbon atoms and is a C, to CJO alkyl (e.g., metiiyl, ethyl, n-butyl, iso-propyl), to alkoxy (e.g., methoxy, ediyoxy, butoxy), C, to C^ alcohol (e.g., -CH2OH, -CHjOLOH), C3 to C6 cycloalkyl (e.g., cyclopropyl, cyclopentyl), to cycloalkoxy (e.g., cyclopropoxy, cyclopentoxy), C6 to CJO aryl (e.g., phenyl, naphthyl), C6 to o alkaryl (e.g., tolyl, xylyl), C6 to C10 aralkyl (e.g., benzyl, betaphenylethyl), or die like, and preferably R is an aryl, suitably phenyl; R' is a hydrocarbon moiety which can be saturated or unsaturated and which contains up to twenty (20) carbon atoms and is a C, to C^, alkyl (e.g., methyl, ediyl, n-butyl, iso-propyl), Ci to alkoxy (e.g., methoxy, ethyoxy, propoxy, butoxy), Cj to C^, alcohols (e.g., - CH2OH, -CH2CH2OH), C-, to cycloalkyl (e.g., cyclopropyl, cyclopentyl), C3 to C6 cycloalkoxy (e.g., cyclopropoxy, cyclopentoxy, C6 to C^ aryl (e.g., phenyl, naphthyl), C6 to C,0 alkaryl (e.g., tolyl, xylyl), to C,0 aralkyl (e.g., benzyl, betaphenylethyl), or the like, and preferably R' is an alkyl, suitably ethyl. The ligands L and ____.' attached to each of die metal atoms, M and M', can be die same or different and can be H, CO, alkenes, alkyls, or other related ligands present initially in die catalyst precursor.
The precursor catalyst, in non-isomer form, may be prepared by the disclosure set forth in die earlier part of this specification.
The amount of optically pure complex catalyst present in the reaction medium of a given process of tiiis invention need only be that minimum amount necessary to provide d e given metal concentration desired to be employed and which will furnish the basis for at least that catalytic amount of metal necessary to catalyze the particular asymmetric syntheses process desired. In general, metal concentrations in die range of from about 1 ppm to about 10,000 ppm, calculated as free metal, and ligand to metal mole ratios in die catalyst ranging from about 0.5:1 to about 200:1, should be sufficient for most asymmetric syntheses processes. For example, in the rhodium catalyzed asymmetric hydroformylation processes of this invention, it is generally preferred to employ from about 10 to 1000 ppm of rhodium and more preferably from 25 to 750 ppm of rhodium, calculated as free metal.
The process conditions employable in the asymmetric processes of this invention are, of course, chosen depending on die particular asymmetric syntheses desired. Such process conditions are well known in the art. All of the asymmetric syntheses processes of this invention can be carried out in accordance witii conventional procedures known in the art. Illustrative reaction conditions for conducting the asymmetric syntheses processes of this invention are described, for example, in Bosnich, B., Asymmetric Catalysis, Martinus Nijhoff Publishers, 1986 and Morrison, James D., Asymmetric Synthesis, Vol. 5, Chiral Catalysis, Academic Press, Inc., 1985, bodi of which are incorporated herein by reference in their entirety. Depending on die particular process, operating temperatures can range from about -80°C or less to about 500°C or greater and operating pressures can range from about 1 psia or less to about 10,000 psia or greater. The reaction conditions of effecting, for example, the asymmetric hydroformylation process of this invention may be those heretofore conventionally used and may comprise a reaction temperature of from about -25°C or lower to about 200°C and pressures ranging from about 1 to 10,000 psia. While one example of the asymmetric syntheses process is the hydroformylation of olefinically unsaturated compounds and more preferably olefinic hydrocarbon, witii carbon monoxide and hydrogen to produce optically active aldehydes, it is to be understood tiiat the optically active metal-ligand complexes may be employed as catalysts in otiier types of asymmetric syndieses processes to obtain good results. Moreover, while such otiier asymmetric syndieses may be performed under their usual conditions, in general it is believed tiiat they may be performed at lower temperatures than normally preferred due to d e optically pure metal-ligand complex catalysts.
The total gas pressure of hydrogen, carbon monoxide, and, for example, olefinic unsaturated starting compound of one asymmetric (hydroformylation) process of this invention may range from about 1 to about 10,000 psia. More preferably, however, in the asymmetric hydroformylation of prochiral olefins to produce optically active aldehydes, it is preferred tiiat the process be operated at a total gas pressure of hydrogen, carbon monoxide, and olefinic unsaturated starting compound of less tiian about 1500 psia, and more preferably less than about 1000 psia. The minimum total pressure of the reactants is not particularly critical and is limited predominately only by die amount of reactants necessary to obtain a desired rate of reaction. More specifically, the carbon monoxide partial pressure of the asymmetric hydroformylation process is preferably from about 1 to about 360 psia, and more preferably from about 3 to about 270 psia, while die hydrogen partial pressure is preferably about 15 to about 480 psia and more preferably from about 30 to about 300 psia. In general, the molar ratio of gaseous hydrogen to carbon monoxide may range from about 1:10 to 100:1 or higher, the more preferred hydrogen to carbon monoxide molar ratio being from about 1:1 to about 1:10. Higher molar ratios of carbon monoxide to gaseous hydrogen may generally tend to favor higher branched/normal ratios.
In general, the processes of this invention may be conducted at a reaction temperature from about -25°C or lower to about 200°C. The preferred reaction temperature employed in a given process will, of course, be dependent upon die particular starting material and optically pure metal-ligand complex catalyst employed as well as die efficiency desired. Lower reaction temperatures may generally tend to favor higher enantiomeric excesses (ee) and branched normal ratios. For example, asymmetric hydroformylations at reaction temperatures of about 0°C to about 120°C are preferred for all types of olefinic starting materials. More preferably, alpha-olefins can be effectively hydroformylated at a temperature of from about 0°C to about 90°C while even less reactive olefins than conventional linear alpha-olefins and internal olefins, as well as mixtures of alpha-olefins and internal olefins, are effectively and preferably hydroformylated at a temperature of from about 25°C to about 120°C. The processes are conducted for a period of time sufficient to produce die optically active products. The exact reaction time employed is dependent in part, upon factors such as temperature, nature, and proportion of starting materials, and die like. The reaction time will normally be within the range of from about one-half to about 200 hours or more, and preferably from less than about one to ten hours. The asymmetric syntheses process (for example, asymmetric hydroformylation process) of this invention can be carried out in either the liquid or gaseous state and involve a batch, continuous liquid or gas recycle system, or combination of such systems. A batch system is preferred for conducting die processes of this invention. Preferably, asymmetric hydroformylation of this invention involves a batch homogeneous catalysis process wherein the hydroformylation is carried out in the presence of any suitable conventional solvent as further outlined herein.
The asymmetric syndieses processes of this invention may be conducted in die
» presence of an organic solvent for the optically pure metal-ligand complex catalyst. Depending on die particular catalyst and reactants employed, suitable organic solvents include, for example, alcohols, alkanes, alkenes, alkynes, ethers, aldehydes, ketones, esters, acids, amides, amines, aromatics, and die like. Any suitable solvent which does not unduly adversely interfere with the intended asymmetric syndieses process can be employed and such solvents may include tiiose heretofore commonly employed in known metal catalyzed processes. Increasing the dielectric constant or polarity of a solvent may generally tend to favor increased reaction rates. Mixtures of one or more different solvents may be employed if desired. It is obvious tiiat the amount of solvent employed is not critical to the subject invention and need only be tiiat amount sufficient to provide die reaction medium with the particular metal concentration desired for a given process. In general, the amount of solvent when employed may range from about five percent by weight up to about ninety-five percent by weight or more, based on d e total weight of the reaction medium.
The processes of this invention are useful for preparing substituted and unsubstituted optically active compounds. The processes of this invention stereo- sel ectively produce a chiral center. Illustrative optically active compounds prepared by the processes of this invention include, for example, substituted and unsubstituted alcohols or phenols; amines; amides; ethers or epoxides; esters; carboxylic acids or anhydrides; ketones; olefins; acetylenes; halides or sulfonates; aldehydes; nitrites; and hydrocarbons. Illustrative preferred optically active aldehyde compounds prepared by the asymmetric hydroformylation process of this invention include, for example, S-2-(p- isobutylphenyl)propionaldehyde, S-2-(6-methoxynaphthyl)propionaldehyde, S-2-(3- bεnzoylphenyl)propionaldehyde, S-2-(p-thenoylphenyl)propionadenhyde, S-2-(3-fluoro-4- phenyl)phenylpropionaldehyde, S-2-[4-(l,3-dihydro-l-oxo-2H-isoindol-2-yl)phenyl]- propionaldehyde, S-2-(2-methylacetaldehyde)-5-benzoylthiophene, and die like. Illustrative of suitable optically active compounds which can be prepared by the processes of this invention (including derivatives of the optically active compounds as described hereinbelow and also prochiral and chiral starting material compounds as described hereinabove) include those permissible compounds which are described in Kirk-Othmer, Encyclopedia of Chemical Technology, Third Edition, 1984, the pertinent portions of which are incorporated herein by reference in its entirety, and The Merck Index, An Encyclopedia of Chemicals, Drugs, and Biologicals, Eleventh Edition, 1989, die pertinent portions of which are incorporated herein by reference in their entirety.
The processes of this invention can provide optically active products having very high enantioselectivity and regioselectivity, e.g., hydroformylation. Enantiomeric excesses (sometimes referred to herein as "ee") of preferably greater than fifty percent, more preferably greater than 75 percent, and most preferably greater than ninety percent can be obtained by die processes of this invention. Branched/normal molar ratios of preferably greater than 5:1, more preferably greater than 10:1, and most preferably greater than 25:1 can be obtained by the processes, e.g., hydroformylation, of this invention. The processes of this invention can also be carried out at highly desirable reaction rates suitable for commercial use.
The desired optically active products, e.g., aldehydes, may be recovered in any conventional manner. Suitable separation techniques include, for example, solvent extraction, crystallization, distillation, vaporization, wiped film evaporation, falling film evaporation, and the like. It may be desired to remove the optically active products from the reaction system as they are formed through the use of trapping agents as described in WO patent 88/08835.
The optically active products produced by die asymmetric syntheses processes of this invention can undergo further reaction(s) to afford desired derivatives thereof. Such permissible derivatization reactions can be carried out in accordance with conventional procedures known in the art Illustrative derivatization reactions include, for example, esterification, oxidation of alcohols to aldehydes, N-alkylation of amides, addition of aldehydes to amides, nitrile reduction, acylation of ketones by esters, acylation of amines, and the like. For optically active aldehydes prepared by asymmetric hydroformylation, illustrative derivatization reactions include, for example, oxidation to carboxylic acids, reduction to alcohols, aldol condensation to alpha, beta-unsaturated compounds, reductive amination to amines, amination to imines, and d e like. This invention is not intended to be limited in any manner by the permissible derivatization reactions.
An example of a derivatization reaction involves oxidation of an optically active aldehyde prepared by asymmetric hydroformylation to give the corresponding optically active carboxylic acid. Such oxidation reactions can be carried out by conventional procedures known in the art A number of important pharmaceutical compounds can be prepared by this process including, but not limited to, S-ibuprofen, S-naproxen, S-ketoprofen, S-suprofen, S-flurbiprofen, S-indoprofen, S-tiaprofenic acid, and the like. Illustrative preferred derivatization, i.e. oxidation reactions encompassed within the scope of this invention include, for example, the following reactant/aldehyde intermediate/product combinations:
Reactant Aldehyde Intermediate Product
p-isobutylstyrene S-2-(p-isobutylphenyl)- S-ibύprofen propionaldehyde
2-vinyl-6-methoxy- S-2-(6-methoxynaphthyl)- S-naproxen naphthalene propionaldehyde
3-ethenylphenyl phenyl S-2-(3-benzoylρhenyl)- S-ketoprofen ketone propionaldehyde 4-ethenylphenyl- S-2-(p-thienoylphenyl)- S-suprofen 2-thienylketone propionaldehyde
4-ethenyl-2-fluoro- S-2-(3-fluoro-4-phenyl)- S-flurbiprofen biphenyl phenylpropionaldehyde
4-( 1 ,3-dihydro- 1 -oxo- S-2-[4-(l,3-dihydro-l- S-indoprofen 2H-isoindol-2-yl)- oxo-2H-isoindol-2-yl)- styrene phenyl]propionaldehyde
2-ethenyl-5-benzoyl- S-2-(2-methyl0 S-tiaprofenic thiophene acetaldehyde)-5-benzoyl- thiophene 3-ethenylphenyl phenyl S-2-(3-phenoxy)propion- S-fenoprofen ether aldehyde propenylbenzene S-2-phenylbutyraldehyde S-phenetamid, S-butetamate isobutyl-4-propenyl- S-2-(4-isobutylphenyl)- S-butibufen benzene butyraldehyde phenyl vinyl ether S-2-phenoxypropional- phenethicillin dehyde vinyl chloride S-2-chloropropional- S-2-chloropropionic acid dehyde
2-vinyl-6-methoxy- S-2-(6-methoxynaphdιyl)- S-naproxol naphthalene propionaldεhyde Reactant Aldehyde Intermediate Product
2-vinyl-6-methoxy- S-2-(6-methoxynaphthyl)- S-naproxen sodium naphdialene propionaldehyde
5-(4-hydroxy)benzoyl- 5-(4-hydroxy)benzoyl-l- ketorolac or derivative 3H-pyrrolizine formyl-2,3-dihydro- pyrrolizine
Illustrative of suitable reactants in effecting the asymmetric syntheses processes of this invention include by way of example:
AL alcohols
PH phenols
THP thiophenols
MER mercaptans
AMN amines
AMD amides
ET ethers
EP epoxides
ES esters
H hydrogen
CO carbon monoxide
HCN hydrogen cyanide
HS hydrosilane
W water
GR grignard reagent
AH acyl halide
UR ureas
OX oxalates
CN carbamates
CNA carbamic acids
CM carbonates
CMA carbonic acids
CA carboxylic acids
31 ANH anhydrides
KET ketones
OLE olefins
ACE acetylenes HAL halides
SUL sulfonates
ALD aldehydes
NTT nitriles
HC hydrocarbons DZ diazo compounds
BOR boranes
ESE enol silyl ethers
Illustrative of suitable optically active products prepared by the asymmetric syntheses processes of this invention include by way of example: AL alcohols
PH phenols
THP thiophenols
MER mercaptans
AMN amines AMD amides
ET etiiers
EP epoxides
ES esters
H hydrogen CO carbon monoxide
SI silanes
UR ureas
OX oxalates
CN carbamates CNA carbamic acids
CM carbonates
CMA carbonic acids
CA carboxylic acids ANH anhydrides
KET ketones
OLE olefins
ACE acetylenes
HAL halides SUL sulfonates
ALD aldehydes
NTT nitriles
HC hydrocarbons
CYP cyclopropanes ABR alkylboranes
ADL aldols
Illustrative of asymmetric syntheses reactions encompassed within the scope of this invention include, for example, the following reactant/product combinations:
REACTANT(S) PRODUCTfS)
OLE, CO, H ALD
OLE, CO, H CA
ALD KET
OLE, ALD KET
OLE. HC HC
OLE, CO CA
OLE, CO, AMN AMD
OLE, CO, AL ES
KET. H AL REACTANT(S) PRODUCT(S)
EP, H AL
OLE, AMN AMN
OLE, AL ET
AL, CO HC
AL ALD
OLE, HCN NTT
OLE. HS SI
OLE, CO, W CA
OLE OLE
GR HC
AH HAL
OLE, H HC
OLE, BOR AL
OLE, BOR ABR
OLE, DZ CYP
KET, AL AL
ALD, ESE ADL
KET, ESE ADL
KET. HS AL
EP, CO, H ALD
EP, HCN NTT
As indicated above, the processes of this invention can be conducted in a batch or continuous fashion, with recycle of unconsumed starting materials if required. The reaction can be conducted in a single reaction zone or in a plurality of reaction zones, in series, or in parallel, or it may be conducted batchwise or continuously in an elongated tubular zone or series of such zones. The materials of construction employed should be inert to the starting materials during the reaction and the fabrication of the equipment should be able to withstand die reaction temperatures and pressures. Means to introduce and/or adjust the quantity of starting materials or ingredients introduced batchwise or continuously into the reaction zone during the course of the reaction can be conveniently utilized in the processes especially to maintain the desired molar ratio of the starting materials. The reaction steps may be effected by die incremental addition of one of the starting materials to the otiier. Also, the reaction steps can be combined by die joint addition of the starting materials to the optically pure metal-ligand complex catalyst. When complete conversion is not desired or not obtainable, the starting materials can be separated from the product and then recycled back into the reaction zone.
The processes may be conducted in either glass lined, stainless steel or similar type reaction equipment. The reaction zone may be fitted with one or more internal and/or external heat exchanger(s) in order to control undue temperature fluctuations, or to prevent any possible "runaway" reaction temperatures.
Finally, d e optically active products of the process of this invention have a wide range of utility that is well known and documented in die prior art, e.g. they are especially useful as pharmaceuticals, flavors, fragrances, agricultural chemicals, and die like.
Illustrative therapeutic applications include, for example, non-steroidal anti-inflammatory drugs, ACE inhibitors, beta-blockers, analgesics, bronchodilators, spasmolytics, antihistamines, antibiotics, antitumor agents, and d e like.
As used herein, the following terms have the indicated meanings:
Chiral molecules which have one or more centers of asymmetry.
Achiral molecules or processes which do not include or involve at least one center of asymmetry.
Prochiral molecules which have the potential to be converted to a chiral product in a particular process.
Chiral Center any structural feature of a molecule that is a site of asymmetry.
Racemic a 50/50 mixture of two (2) enantiomers of a chiral compound. Stereoisomers compounds which have identical chemical construction, but differ as regards the arrangement of the atoms or groups in space.
Enantiomer stereoisomers which are non-superimposable mirror images of one another.
Stereoselective a process which produces a particular stereoisomer in favor of others.
Enantiomeric a measure of the relative amounts of two (2) Excess (ee) enantiomers present in a product, ee may be calculated by die formula [amount of major enantiomer - amount of minor enantiomer]/[ amount of major enantiomer + amount of minor enantiomer].
Optical Activity an indirect measurement of the relative amounts of stereoisomers present in a given product. Chiral compounds have die ability to rotate plane polarized light When one enantiomer is present in excess over the other, the mixture is optically active.
Optically Active a mixture of stereoisomers which rotates plane polarized light due to an excess of one of die stereoisomers over the others.
Optically Pure a single stereoisomer which rotates plane polarized light.
Regioisomers compounds which have die same molecular formula but differing in the connectivity of the atoms:
Regioselective a process which favors the production of a particular regioisomer over all others.
(+)-Rh2(nbd)2(et,ph-P4> SS form of the general formula I compound where nbd is norbomadiene and is for a symmetrical ligand.
(-)-Rh2(nbd)2(etph-P4) ,;2+ RR form of the general formula I compound where nbd is norbomadiene and is for a symmetrical ligand.
(+)-Rh2(n3-allyl)2 SS form of the general formula I compound where it
(etph-P4) is an allyl anion racemic-Rh^-allyl^ racemate form of the general formula I compound (etph-P4) where it is an allyl anion
racemic-Rh2(nbd)2 racemate form of the general formula I compound (etph-P4)2+ where nbd is norbomadiene
racemic-et,ph-P4 racemate form of the tetraphosphine ligand of die general formula I compound
(+)-etph-P4 SS form of the tetraphosphine ligand of d e general formula I compound (-)-etph-P4 RR form of the tetraphosphine ligand of die general formula I compound
For purposes of this invention, the chemical elements are identified in accordance with die Periodic Table of die Elements, CAS version, Handbook of Chemistry and Physics, 67tiι Ed., 1986-87, inside cover. Also for purposes of this invention, the term "hydrocarbon" is contemplated to include all permissible compounds having at least one hydrogen and one carbon atom. In a broad aspect die permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds which can be substituted or unsubstituted.
As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described hereinabove. The permissible substituents can be one or more and die same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds. The following procedures were utilized to prepare the RR and SS enantiomers from the racemic form of the ligands, described in die earlier part of this specification, and also the SS or RR catalyst form, i.e. the optically pure catalyst, herein described.
Separation of Rαcem. c-etp h-P4 into (+)- and (-)-etph-P4 The separation of the enantiomers was performed on a J.T. Baker Chiracel OD
HPLC column (250mm x 20 mm) that employs cellulose tris-(3,5- dimemylphenylcarbamate) coated onto 10 um silica gel as a stationary phase. A Rainin Rabbit HPC model HPLC utilizing a Knauer Differential Refractometer as a detector was used for the separation. A mobile phase of 95:5 hexane/isopropanol was employed. The flow rate was 6.0 mlJmin. The mobile phase was filtered through a 0.45 um membrane filter and then purged with argon for "20 minutes. Solutions of " 100 mg/ml of the ligand were prepared in d e glovebox and filtered through a 0.45 um membrane filter. A volume of "500 uL of the ligand solution was injected onto the column. The two enantiomers were resolved with retention times of 13.2 minutes and 14.8 minutes respectively. The first enantiomer is (+)-et,ph-P4, while the second is (-)-et,ph-P4 (determined by polarimetry).
The eluted compounds were collected in separate Schlenk flasks under a continuous purge of nitrogen. The flasks were taken into the glovebox where the solvent was removed under reduced pressure. Enantiomeric purity of the ligands was confirmed by NMR and polarimetry.
Catalyst Preparation
Dissolve [(+)-Rh2(nbd)2((+)-et-ph-Pr)](2BF4) (2.06 g, 2.0 mmol) in 20 ml of THF and cool to -25°C. AllylMgCl (20 ml of 2.0 M THF solution, 20 eq.) is then added slowly. Undissolved rhodium starting material is dissolved very quickly with the addition of the allylMgCl solution to form a yellow/brown solution. Let the solution slowly warm to room temperature and add 30 ml of toluene and 10 ml of hexane. The flask is then placed in the freezer overnight to crystallize out the magnesium salts. Filter the solution with a glass frit and remove the solvents of the filtrate by vacuum evaporation. The product is extracted with a 3:1 mixture of toluene and hexane. Remove the solvents by vacuum evaporation and dissolve the product in DMF. Place the flask in the freezer to crystallize the product. A total of 90% yield is obtained after collecting a few batches of the crystals. The procedure set forth above is also outlined by Broussard et al., Science, 1993,
260, 1784 for the preparation of [racemic-Rh2(nbd)(etph-P4)](2BF4) and which article is incorporated herein by reference in its entirety.
The following examples are illustrative only and the invention is not limited to them. EXAMPLE 4
Asymmetric Hydroformylation of Vinyl Acetate All operations were carried out under inert atmosphere conditions. The 150 mL Parr autoclave used is equipped with a packless magnetic drive stirring system and designed to introduce die gas mixture through a dip tube directly into the solution. Turbine type impellers are used to obtain optimum solution/gas mixing. Stir rates of 1000 rpm are typically used. The autoclave is also equipped with a pressure transducer for monitoring the pressure of the autoclave and a thermocouple for determining the temperature of the reaction mixture in the autoclave.
(+)-Rh2(a_lyl)2((+)-etph-P4)(0.019 g, 0.0253 mmol) was dissolved in 80 ml of acetone in the autoclave in a glove box. The autoclave is closed and removed from the glove box. The autoclave is connected to die high pressure synthesis gas line. The transfer lines and die olefin addition cylinder are evacuated to remove all oxygen. HBF4 (0.816 g of a one percent ether solution, 0.05 mmol) in 10 ml of acetone is added to the addition cylinder. Syntiiesis gas (1:1 mixture of __ and CO) is introduced into d e autoclave and bubbled through the autoclave to displace the N2 present. The pressure is adjusted to 45 psi and die stirring begins at 1000 rpm at room temperature for 10 minutes. The pressure inside die addition cylinder is adjusted to 90 psi to force the HBF4 solution into the autoclave. Begin temperature ramp to 90°C and the pressure inside autoclave is adjusted to 45 psi. The addition cylinder and die transfer lines are reevacuated for 15 minutes. Vinyl acetate (5 ml, 54 mmol, diluted to 10 ml volume with acetone) was added to the addition cylinder and die pressure inside die cylinder is adjusted to 90 psi. When die autoclave reaches 90°C, the pressure inside die autoclave is adjusted to 45 psi and the olefin is added. A small aliquot (1 ml) of the reaction solution is then removed for GC analysis (initial sample). The pressure is adjusted to 90 psi and die data logger is turned on. Samples of die reaction solution are typically taken for product analysis at regular intervals throughout the runs that are usually left to run for six to twenty hours.
Rate data was obtained by monitoring the decrease in pressure of a 0.3 liter reservoir cylinder tiiat contained approximately 750 psi of H--/CO that was delivered to die autoclave at constant pressure by a two-stage gas regulator. The pressure of the reservoir cylinder was constantly monitored by an electronic pressure transducer. The reservoir pressure and temperature, autoclave temperature, and stir rate data are collected and stored on a Parr 4851 controller and die data transferred at die end of die reaction to a PC computer for permanent storage and for calculating reaction rates. Analysis of products was performed by GC and NMR. Analyses of the product mixtures showed tiiat vinyl acetate was very cleanly hydroformylated to die branched and linear aldehydes in a 4:1 branched to linear ratio. No hydrogenation product (ediyl acetate) is observed. The initial turnover frequency is 476 tumovers/hr at 90°C and 90 psig (1:1 H--/CO). After a reaction time of 15 hours, the percent conversion to aldehydes if 84% and die enantiomeric excess is 85% (constant throughout the run). Enantiomeric excesses were determined by GC analysis using a Chiraldex B-TA 30 meter capillary column.
EXAMPLE 5 Asymmetric Hydroformylation of Vinyl Propionate (+)-Rh2(allyl)2((+)-et,ph-P4)(0.019 g, 0.0253 mmol) was dissolved in 80 ml of acetone in the autoclave in a glovebox. The autoclave is closed and removed from me glovebox. The autoclave is connected to die high pressure synthesis gas line. The transfer lines and the olefin addition cylinder are evacuated to remove all oxygen. HBF4 (0.816 g of a one percent ether solution, 0.05 mmol) in 10 ml of acetone is added to the addition cylinder. Synthesis gas (1:1 mixture of H^ and CO) is introduced into die autoclave and bubbled through the autoclave to displace the N2 present. The pressure is adjusted to 45 psi and die stirring begins at 1000 rpm at room temperature for 10 minutes. The pressure inside die addition cylinder is adjusted to 90 psi to force the HBF4 solution into the autoclave. Begin temperature ramp to 90°C and die pressure inside autoclave is adjusted to 45 psi. The addition cylinder and the transfer lines are reevacuated for 15 minutes. Vinyl propionate (5.319 g, 53 mmol, diluted to 10 ml volume with acetone) was added to die addition cylinder and the pressure inside die cylinder is adjusted to 90 psi. When die autoclave reaches 90°C, the pressure inside die autoclave is adjusted to 45 psi and die olefin is added. A small aliquot (1 ml) of the reaction solution is then removed for GC analysis (initial sample). The pressure is adjusted to 90 psi and die data logger is turned on. Samples of the reaction solution are typically taken for product analysis at regular intervals throughout the runs that are usually left to run for 6 to 20 hours.
Analyses of the product mixtures showed that vinyl propionate was very cleanly hydroformylated to the branched and linear aldehydes in a 4:1 branched to linear ratio. No hydrogenation product (ethyl propionate) is observed. The initial turnover frequency is 420 tumovers/hr at 90°C and 90 psi (1:1 Hj/CO). After a reaction time of 13 hours, the percent conversion to aldehydes is 88% and die enantiomeric excess is 85% (constant throughout a run). Enantiomeric excesses were determined by GC analysis using a Chiraldex β-TA 30 meter capillary column.
EXAMPLE 6 Asymmetric Hydroformylation of p-Isobutylstyrene
A catalyst solution is prepared as in Example 4 except tiiat it contains para-isobutyl styrene. This solution is charged to a 100 ml rector and is charged to a pressure of 67 psi with hydrogen gas and to 200 psi with CO. The rate of the reaction is determined by monitoring the drop in pressure as die synthesis gas is consumed. Reaction rate is approximately 0.1 g-mole/liter/hour. When the rate has slowed due to consumption of the styrene starting material, the reaction mixture is removed from die reactor under a nitrogen atmosphere. A portion of the reaction mixture is analyzed by gas chromatography to determine product composition. An isomer ratio of 66:1 (2-(4-isobutyl)phenyl-propionaldehyde:3-(4- isobutyl)phenyl-propionaldehyde) is observed.
Three ml of the solution is diluted in 50 ml acetone and is treated with 0.3 g potassium permanganate and 0.32 g magnesium sulfate to effect oxidation of the product aldehydes to tiieir respective acids. The mixture is stirred at room temperature for 30 minutes after which time the solvent is removed under reduced pressure. The residue is extracted 3 times with 50 ml of hot water. The three aqueous solutions are then combined, filtered, and washed with 50 ml chloroform. The aqueous layer is then acidified with HC1 to a pH of 2.0 and then is extracted with 50 ml of chloroform. The chloroform is removed in vacuo and the resulting residue is dissolved in 0.5 ml toluene. This solution is analyzed by GC on a chiral b-cyclodextrin column which can separate the two enantiomers of the resulting 2-phenylpropionic acid. This analysis indicates a 91:9 ratio of die S and R enantiomers for an ee (enantiomeric excess) of 82%.
EXAMPLE 7
Asymmetric Hydroformylation of Methoxwinylnaphthalene A catalyst solution is prepared as in Example 4 except that it contains 5 g methoxyvinylnaphthalene and 24.5 g acetone. This solution is charged to a 100 ml reactor and is charged to a pressure of 40 psi witii hydrogen gas and 200 psi with CO. The rate of die reaction is determined by monitoring die drop in pressure as synthesis gas is consumed. Reaction rate is approximately 0.1 g-mole/liter/hour. When the rate has slowed due to consumption of the styrene starting material, the reaction mixture is removed from die reactor under a nitrogen atmosphere.
A portion of the reaction mixture is analyzed by GC to determine product composition. An isomer ratio of 80:1 (2-(6-methoxy)-naphthylpropionaldehyde:3-(6- methoxy)naphtiιyl-propionaldehyde) is observed.
Three ml of the solution is diluted in 50 ml acetone and is treated with 0.3 g potassium permanganat and 0.32 g magnesium sulfate to effect oxidation of the product aldehydes to tiieir respective acids. The mixture is stirred at room temperature for 30 minutes, after which time the solvent is removed under reduced pressure. The residue is extracted three times with 50 ml of hot water. The three aqueous solutions are then combined, filtered, and washed witii 50 ml chloroform. The aqueous layer is then acidified witii HC1 to a pH of 2.0 and dien is extracted widi 50 ml of chloroform. The chloroform is removed in vacuo and die resulting residue dissolved in 0.5 ml toluene.
This solution is analyzed by gas chromatography on a chiral b-cyclodextrin column which can separate the two enantiomers of the resulting 2-phenylpropionic acid. This analysis indicates an 92.5:7.5 ratio of the S and R enantiomers for an ee (enantiomeric excess) of 85%.
EXAMPLE 8
Asymmetric Hydrosilylation of Acetophenone The catalyst (0.020 g) of Example 4 is charged to a 50 ml Schlenk flask under nitrogen. Tetrahydrofuran (THF) (5.0 ml) is added to dissolve die catalyst 0.58 ml of acetophenone and 0.93 ml of diphenylsilane are added to die flask via syringe. The solution is stirred under nitrogen for 18 hours. The solution is treated with 10 ml of 10% hydrochloric acid and is extracted two times with 10 ml of diethyl ether.
This solution is analyzed by GC on a Chiraldex B-PH column which can separate the two enantiomers of the resulting sec-phenethyl alcohol. This analysis indicates an 80:20 ratio of the R and S enantiomers for an ee (enantiomeric excess) of 60%.
EXAMPLE 9
Asymmetric Hydrocyanation of Styrene The catalyst (0.15 g) of Example 4 is charged to a 50 ml Schlenk flask under nitrogen. Deoxygenated THF (10 ml) is added, and die solution is stirred for 30 minutes. 2.0 ml of styrene and 2.00 ml of acetone cyanohydrin are added to the flask via syringe. The solution is stirred for 24 hours at 25°C.
A portion of this solution is analyzed by GC to determine product composition. An isomer ratio of 2:1 (α-methylbenzyl cyanide:hydrocinnamonitrile) is observed. A second portion of this solution is analyzed by GC on a Chiraldex G-TA column which can separate the two enantiomers of the resulting α-methylbenzyl cyanide. This analysis indicates an 82:18 ratio of the enantiomers for an ee (enantiomeric excess) of 64%.
EXAMPLE 10 Asymmetric Hydrocyanation of Norbomene
The catalyst (0.046 g) of Example 4 is charged to a 50 ml Schlenk flask under nitrogen. Deoxygenated THF (5.0 ml) is added, and die solution is stirred under nitrogen for 30 minutes. 0.500 g of norbomene and 1.00 ml of acetone cyanohydrin are added to the flask via syringe. The solution is refluxed under nitrogen for five hours.
This reaction mixture is analyzed by GC on a Chiraldex B-PH column which can separate the two enantiomers of the resulting 2-norbornane carbonitrile. Only a single regioisomer of 2-norbornane carbonitrile is observed by this analysis. This analysis indicates a 75:25 ratio of the enantiomers for an ee (enantiomeric excess) of 50%.
EXAMPLE 11 Asymmetric Hydrocyanation of Styrene
The catalyst (0.173 g) of Example 4 is charged to a 50 ml Schlenk flask under nitrogen. Deoxygenated THF (10 ml) is added and the solution is stitred for 30 minutes. 2.0 ml of styrene and 2.00 ml of acetone cyanohydrin are added to die flask via syringe. The solution is stitred for 24 hours at 25°C.
A portion of this solution is analyzed by GC to determine product composition. An isomer ratio of 220:1 (α-methylbenzyl cyanide:hydrocinnamonitrile) is observed. A second portion of this solution is analyzed by GC on a Chiraldex G-TA column which can separate the two enantiomers of the resulting α-methylbenzyl cyanide. This analysis indicates a 68:32 ratio of the enantiomers for an ee (enantiomeric excess) of 28%. EXAMPLE 12 Asymmetric Transfer Hydrogenation of Acetophenone The catalyst (0.020 g) of Example 4 is charged to a 50 ml Schlenk flask under nitrogen. THF (5.0 ml) is added to dissolve die catalyst. To this solution is added 5.0 ml of 2-propanol, 0.58 ml of acetophenone, and 0.012 g of potassium hydroxide. The solution is stirred under nitrogen for 24 hours.
This reaction mixture is analyzed by gas chromatography on a Chiraldex B-PH column which can separate the two enantiomers of the resulting sec-phenylethyl alcohol. This analysis indicates a 60:40 ratio of die S and R enantiomers for an ee (enantiomeric excess) of 20%.
EXAMPLE 13 Asymmetric Hydrogenation of Itaconic Acid A catalyst solution is prepared as in Example 4 except acetone is replaced witii 10 ml of tetrahydrofuran. The solution is charged to a 100 ml reactor and is heated to 35°C. The reactor is pressurized to 100 psi with hydrogen and is stirred for 15 minutes. The reactor is vented, and a solution of 0.50 g of itaconic acid and 5 ml of tetrahydrofuran is added to the reactor. The reactor is pressurized witii 1000 psi of hydrogen and stirred for two hours.
A portion of the reaction mixture is analyzed by GC on a Chiraldex B-PH column which can separate the two enantiomers of the resulting 2-methylsuccinate. This analysis indicates a 60:40 ratio of the enantiomers for an ee (enantiomeric excess) of 20%.
EXAMPLE 14 Asymmetric Hydroboration of Styrene The catalyst (0.050 g) of Example 4, excluding acetone, is charged to a 50 ml Schlenk flask under nitrogen. Distilled 1,2-dimedιoxyedιane (2.0 ml) is added to die flask. 0.23 ml of styrene and 0.23 ml of catecholborane are added to die flask via syringe. The solution is stirred under nitrogen for two hours. The solution is treated witii 4 ml of metiianol, 4.8 ml of 3.0 mol/liter sodium hydroxide solution and 0.52 ml of 30% hydrogen peroxide. The solution is stirred for three hours and is extracted with 10 ml of diethyl ether. A portion of this solution is analyzed by GC to determine product composition. An isomer ratio of 3:1 (sec-phenethyl alcohol:2-phenylethanol) is observed. A second portion of this solution is analyzed by GC on a Chiraldex B-PH column which can separate the two enantiomers of the resulting sec-phenethyl alcohol. This analysis indicates a 61:39 ratio of the S and R enantiomers for an ee (enantiomeric excess) of 22%.
EXAMPLE 15 Asymmetric Cyclopropanation of Styrene The catalyst (0.085 g) of Example 4 is charged to a 25 ml Schlenk flask under nitrogen. Toluene (5.0 ml) is added to the flask under nitrogen. 0.10 ml of triethylamine is added to die flask via syringe, and die solution is stirred under nitrogen for 15 minutes. 5.0 ml of styrene is added by syringe followed by 0.250 ml of ethyldiazoacetate. The solution is stirred under nitrogen for two hours.
A portion of the reaction mixture is analyzed by GC to determine product composition. An isomer ratio of 2.1:1 (transxis) is observed for die product cyclopropanes. A second portion of this solution is analyzed by gas chromatography on a Chiraldex B-PH column which can separate the two enantiomers of the resulting cis-ethyl- 2-phenylcyclopropanecarboxylate. This analysis indicates a 63:37 ratio of the cis cyclopropane enantiomers for an ee (enantiomeric excess) of 26%.
EXAMPLE 16 Asymmetric Hydrosilylation of Styrene
The catalyst (0.050 g) of Example 4 is charged to a 50 ml Schlenk flask under nitrogen. Toluene (5.0 ml) is added to die flask. 0.55 ml of styrene and 0.55 ml of trichlorosilane are added to the solution via syringe, and die solution is stirred under nitrogen for 24 hours. A portion of the reaction mixture is analyzed by GC to determine die product composition. Only a single regioisomer, 2-trichlorosilylethylbenzene, is observed.
The reaction mixture is concentrated to an oil under vacuum and is dissolved in 5.0 ml of absolute ethanol. 1.0 ml of triethylamine is added to the solution. This solution is analyzed by GC on a Chiraldex B-PH column which can separate the two enantiomers of the resulting 2-triethoxysilylethylbenzene- This analysis indicates a 65:35 ratio of the enantiomers for an ee (enantiomeric excess) of 26%.
EXAMPLE 17 Asymmetric Aldol Condensation of Benzaldehyde
& Methyl Trimethylsilyl Dimethylketene Acetal
The catalyst (0.050 g) of Example 4 is charged to a 50 ml Schlenk flask under nitrogen. Dichloromethane (2.0 ml) is added to die flask under nitrogen. 0.20 ml of benzaldehyde and 0.40 ml of methyl trimethylsilyl dimetiiylketene acetal is added to the flask via syringe. The solution is stirred under nitrogen for 18 hours. The solution is treated witii 10 ml of 10% hydrochloric acid and is extracted two times with 10 ml of diethyl ether.
This solution is analyzed by gas chromatography on a Chiraldex B-PH column which could separate d e two enantiomers of the resulting methyl-2,2-dimedιyl-3-phenyl-3- trimethylsiloxypropionate. This analysis indicates a 75:25 ratio of the enantiomers for an ee (enantiomeric excess) of 76%.
EXAMPLE 18 Asymmetric Hydroformylation of Vinyl Benzoate (+)-Rh2(allyl)2(et,ph-P4)(0.020 g, 0.0266 mmol) was dissolved in 70 ml of acetone in the autoclave in a glovebox. The autoclave is closed and removed from the glovebox. The autoclave is connected to die high pressure synthesis gas line. The transfer lines and die olefin addition cylinder are evacuated to remove all oxygen. HBF4 (0.816 g of a 1% ether solution, 0.05 mmol) in 10 ml of acetone is added to die addition cylinder. Synthesis gas (1:1 mixture of H2 and CO) is introduced into the autoclave and bubbled through the autoclave to displace die N2 present. The pressure is adjusted to 45 psi and die stirring begins at 1000 rpm at room temperature for 10 minutes. The pressure inside die addition cylinder is adjusted to 90 psi to force the HBF4 solution into the autoclave. Begin temperature ramp to 90°C and die pressure inside autoclave is adjusted to 45 psi. The addition cylinder and die transfer lines are reevacuated for 15 minutes. Vinyl benzoate (7.900 g, 53.3 mmol, diluted to 10 mL volume with acetone) was added to die addition cylinder and die pressure inside the cylinder is adjusted to 90 psi. When the autoclave reaches 90°C, the pressure inside die autoclave is adjusted to 45 psi and die olefin is added. A small aliquot (1 ml) of the reaction solution is then removed for GC analysis (initial sample). The pressure is adjusted to 90 psi and die data logger is turned on. Samples of the reaction solution are typically taken for product analysis at regular intervals throughout the runs that are usually left to run for 6 to 24 hours.
Analyses of the product mixtures showed that vinyl benzoate was very cleanly hydroformylated to die branched and linear aldehydes in a 17:1 branched to linear ratio after 23 hours. Only small quantities of the hydrogenation product (ethyl benzoate) is observed after 23 hours (2.8%), none is observed during die first two to six hours. The initial turnover frequency is 260 turnovers/hr at 90°C and 90 psig (1:1 Hj/CO). After a reaction time of 23 hours, the percent conversion of vinyl benzoate to aldehydes is 48% and die enantiomeric excess is 87%. Enantiomeric excesses were determined by GC analysis using a Chiraldex B-TA 30 meter capillary column.
Although the invention has been illustrated by certain of the preceding examples, it is not to be construed as being limited thereby; but rather, die invention encompasses the generic area as disclosed herein. Various modifications and embodiments can be made without departing from the spirit and scope thereof.

Claims

What is Claimed Is:
1. A composition of matter comprising:
wherein M is a Group "VTfl metal or Group IB metal; M' is a Group Vffl metal or Group IB metal; X is selected from the group consisting of methylene; substituted methylene CSS' where S and S' can be the same or different and each of S and S' is a hydrocarbon moiety which can be saturated or unsaturated and which contains up to 20 carbon atoms; oxygen; and NQ where Q is a hydrocarbon moiety which can be saturated or unsaturated and which contains up to 20 carbon atoms; each Y is selected from the group consisting of ethyl; propyl; and meta-substituted aryl having hydrogen, F, or methyl substituents; where the Ys may be the same or different; each R is a hydrocarbon moiety which can be saturated or unsaturated and which contain up to 20 carbon atoms; where the Rs may be the same or different; each R' is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, methoxy, ethoxy, propoxy, and butoxy; where the R's may be the same or different; each L and V is a substituent ligand selected from the group consisting of H, CO, alkenyl, alkyl, substituted alkenyl, and substituted alky; where the L's may be the same or different; and where die L's may be the same or different; and die values of the numbers w, x, y, and z for the ligands L and L' depend on the metal centers M and M' and are selected such tiiat each metal center M and M' has 14, 16, or 18 valence electrons.
The composition of claim 1 wherein M and M' are each rhodium; X is metiiylene; Y is ethyl; each R is phenyl; and each R' is ethyl. 3. A composition of matter comprising:
M is a Group VBI metal; M' is a Group Vm metal; X is selected from the group consisting of methylene; substituted methylene CSS' where S and S' can be the same or different and each of S and S' is a hydrocarbon moiety which can be saturated or unsaturated and which contains up to 20 carbon atoms; oxygen; and NQ where Q is a hydrocarbon moiety which can be saturated or unsaturated and which contains up to 20 carbon atoms; each Y is selected from the group consisting of ethyl; propyl; and meta-substituted aryl having hydrogen, F, or metiiyl substituents; where the Ys may be the same or different; each R is a hydrocarbon moiety which can be saturated or unsaturated and which contains up to 20 carbon atoms; where the Rs may be the same or different; each R' is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, methoxy, etiioxy, propoxy, and butoxy; where the R's may be the same or different; each L and V is a substituent ligand selected from the group consisting of H, CO, alkenyl, alkyl, substituted alkenyl, and substituted alkyl; where the Ls may be the same or different; and where die L's may be the same or different; and die values of the numbers w, x, y, and z for the ligands L and L' depend on die metal centers M and M' and are selected such that each metal center M and M' has 14, 16, or 19 valence electrons.
The composition of claim 2, wherein each L is H, wherein each L' is CO, and wherein each of the numbers w, x, y, and z is 1. 5. The composition of matter set forth in claim 1 wherein said composition is substantially in its racemate form.
6. The composition of matter set forth in claim 5 wherein said composition is substantially in its S,S enantiomeric form for a symmetrical ligand.
7. The composition of matter set forth in claim 5 wherein said composition is substantially in its R,R, enantiomeric form for a symmetrical ligand.
8. A process for converting an alkene or substituted alkene to a product rich in aldehydes at a high lineaπbranched chain aldehyde ratio, which comprises contacting the alkene or substituted alkene, in d e presence of carbon monoxide and hydrogen at conditions conducive to hydroformylation, with a composition comprising:
wherein M is a Group VTH metal or Group IB metal; M' is a Group VII metal or Group IB metal; X is selected from the group consisting of methylene; substituted mediylene CSS' where S and S' can be the same or different, and each of S and S' is a hydrocarbon moiety which can be saturated or unsaturated and which contains up to 20 carbon atoms; oxygen; and NQ where Q is a hydrocarbon moiety which can be saturated or unsaturated and which contains up to 20 carbon atoms; each Y is selected from the group consisting of ethyl; propyl; and meta-substituted aryl having hydrogen, F, or methyl substituents; where the Ys may be the same or different; each R is a hydrocarbon moiety which can be saturated or unsaturated and which contains up to 20 carbon atoms; where die Rs may be the same or different; each R' is selected from the group consisting of methyl, ethyl, unpropyl, n-butyl, methoxy, ethoxy, propoxy, and butoxy; where the R's may be the same or different; each L and L' is a substituent ligand selected from die group consisting of H, CO, alkenyl, alkyl, substituted alkenyl, and substituted alkyl; where the Ls may be the same or different; and when die L's may be the same or different; and die values of the numbers w, x, y, and z for the ligands L and L' depend on the metal centers M and M' and are selected such that each metal center M and M' has 14, 16, or 18 valence electrons.
9. The process of Claim 8 wherein M and M' are each rhodium; X is mediylene; Y is ethyl; each R is phenyl; and each R' is ediyl.
10. The process of Claim 9, wherein each L' is CO, and wherein each of die numbers w, x, y, and z is 1.
11. The process of Qaim 8 wherein the composition is dispersed in a liquid medium to provide a homogeneous reaction phase.
12. The process of Claim 8 wherein the alkene comprises alkenes, or substituted alkenes, having from 2 to about 20 carbon atoms.
13. The process of Claim 8 wherein the composition is dispersed in a liquid medium to provide a homogeneous reaction phase, and die alkene or substituted alkene is contacted witii the composition while the carbon monoxide and hydrogen are added at a temperature between about 40°C and about 150°C, at a pressure between about 20 psi and about 300 psi, and at a H CO ratio between about 10:90 and about 90:10 volume percent. 14. The process of Claim 8 wherein the temperature is between about 50°C and about 125°C, at a pressure between about 40 psi and about 200 psi, and at a Hj CO ratio between about 40:60 and about 60:40 volume percent
15. The process of Claim 8 wherein the alkene or substituted alkene comprises allyl alcohol, 1-hexene, or 1-octene.
16. A process for converting an alkene or substituted akene to a product rich in aldehydes at a high linear.branched chain aldehyde ratio, which comprises contacting the alkene or substituted alkene, in the presence of carbon monoxide and hydrogen at conditions conducive to hydroformylation, with a composition comprising:
wherein M is a Group Vm metal; M' is a Group Vπi metal, X is selected from die group consisting of methylene; substituted metiiylene CSS'; where S and S', can be die same or different and each of S and S' is a hydrocarbon moiety which can be saturated or unsaturated and which contains up to 20 carbon atoms; oxygen; and NQ where Q is a hydrocarbon moiety which can be saturated or unsaturated and which contains up to 20 carbon atoms; each Y is selected from the group consisting of ethyl; propyl; and metasubstituted aryl having hydrogen, F, or methyl substituents; where the Ys may be the same or different; each R is a hydrocarbon moiety which can be saturated or unsaturated and which contains up to 20 carbon atoms; where the Rs may be the same or different; each R' is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, methoxy, ethoxy, propoxy, and butoxy; where the R's may be the same or different; each L and L' is a substi ent ligand selected from die group consisting of H, CO, alkenyl, alkyl, substituted alkenyl, and substituted alkyl; where the Ls may be the same or different; and where the L's may be the same or different; and die values of die numbers w, x, y, and z for the ligands L and L' depend on die metal centers M and M' and are selected such that each metal center M and M' has 14, 16, or 18 valence electrons.
17. A process which comprises reacting a prochiral or chiral compound in die presence of an optically pure metal-ligand complex catalyst in enantiomeric form, to produce an optically active product said optically pure metal-ligand complex catalyst having the formula:
wherein M is a Group VIE metal or Group IB metal; M' is a Group VIII metal or Group IB metal; X is selected from the group consisting of methylene; substituted methylene CSS' where S and S' can be the same or different, and each of S and S' is a hydrocarbon moiety which can be saturated or unsaturated and which contains up to 20 carbon atoms; oxygen; and NQ where Q is a hydrocarbon moiety which can be saturated or unsaturated and which contains up to 20 carbon atoms; each Y is selected from the group consisting of ethyl; propyl; and meta-substituted aryl having hydrogen, F, or methyl substituents; where the Ys may be the same or different; each R is a hydrocarbon moiety which can be saturated or unsaturated and which contains up to 20 carbon atoms; where the Rs may be the same or different; each R' is selected from the group consisting of metiiyl, ethyl, n-propyl, n-butyl, methoxy, ethoxy, propoxy, and butoxy; where the R's may be the same or different; each L and L' is a substituent ligand selected from the group consisting of H, CO, alkenyl, alkyl, substituted alkenyl, and substituted alkyl; where the Ls may the same or different; and where the Ls may the same or different; and die values of the numbers w, x, y, and z for the ligands L and L' depend on the metal centers M and M' and are selected such that each metal center M and M' has 14, 16, or 18 valence electrons.
18. The process as set forth in claim 17 wherein said catalyst is substantially in its SS enantiomeric form.
19. The process as set forth in claim 17 wherein said catalyst is substantially in its RR enantiomeric form.
20. A hydroformylation process which comprises reacting a prochiral or chiral olefinically unsaturated organic compound with carbon monoxide and hydrogen in the presence of an optically pure metal-ligand complex catalyst, in enantiomeric form, to produce an optically active product, said optically pure metal-ligand complex catalyst having die formula:
wherein M is a Group VΗI metal or Group IB metal; M' is a Group Vm metal or Group IB metal; X is selected from the group consisting of methylene; substituted methylene CSS' where S and S' can be the same or different, and each of S and S' is a hydrocarbon moiety which can be saturated or unsaturated and which contains up to 20 carbon atoms; oxygen; and NQ where Q is a hydrocarbon moiety which can be saturated or unsaturated and which contains up to 20 carbon atoms; each Y is selected from the group consisting of ethyl; propyl; and meta-substituted aryl having hydrogen, F, or metiiyl substituents; where the Ys may be the same or different; each R is a hydrocarbon moiety which can be saturated or unsaturated and which contains up to 20 carbon atoms; where the R's may be the same or different; each R' is selected from the group consisting of methyl, ediyl, n-propyl, n-butyl, methoxy, ethoxy, propoxy, and butoxy; where the Rs may be the same or different; each L and L' is a substi ent ligand selected from the group consisting of H, CO, alkenyl, alkyl, substituted alkenyl, and substituted alkyl; where the Ls may the same or different; and where the L's may the same or different; and the values of the numbers w, x, y, and z for the ligands L and L' depend on the metal centers M and M' and are selected such that each metal center M and M' has 14, 16, or 18 valence electrons. 21. A hydrogenation process which comprises reacting a prochiral or chiral compound in the presence of an optically pure metal-ligand complex catalyst, in enantiomeric form, to produce an optically active product, said optically pure metal-ligand complex catalyst having the formula:
wherein M is a Group VHI metal or Group IB metal; M' is a Group VIII metal or Group IB metal; X is selected from the group consisting of methylene; substituted methylene CSS' where S and S' can be the same or different, and each of S and S' is a hydrocarbon moiety which can be saturated or unsaturated and which contains up to 20 carbon atoms; oxygen; and NQ where Q is a hydrocarbon moiety which can be saturated or unsaturated and which contains up to 20 carbon atoms; each Y is selected from the group consisting of ethyl; propyl; and meta-substituted aiyl having hydrogen, F, or methyl substiments; where the Ys may be the same or different; each R is a hydrocarbon moiety which can be saturated or unsaturated and which contains up to 20 carbon atoms; where the R's may be the same or different; each R' is selected from the group consisting of methyl, ediyl, n-propyl, n-butyl, methoxy, ethoxy, propoxy, and butoxy; where die Rs may be the same or different; each L and L' is a substiment ligand selected from the group consisting of H, CO, alkenyl, alkyl, substituted alkenyl, and substituted alkyl; where the Ls may the same or different; and where die L's may the same or different; and die values of die numbers w, x, y, and z for die ligands L and L' depend on the metal centers M and M' and are selected such that each metal center M and M' has 14, 16, or 18 valence electrons.
22. The process of claim 17 which comprises a hydroacylation (intramolecular and intermolecular), hydrocyanation, hydrosilylation, hydrocarboxylation, hydroamidation, hydroesterification, hydrogenolysis, aminolysis, alcoholysis, carbonylation, decarbonylation, isomerization, transfer hydrogenation, hydroboration, cyclopropanation, aldol condensation, allelic alkylation, codimerization, Diels-Alder or Grignard cross coupling process.
23. The process as set forth in claim 17 wherein M and M' are each rhodium; X is methylene, Y is ethyl; each R is phenyl; and each R' is ethyl.
24. The process as set forth in claim 22 wherein M and M' are each rhodium; X is methylene; Y is ethyl; each R is phenyl; and each R' is ediyl.
25. The process of claim 17 in which the prochiral or chiral compound is selected from the group consisting of substituted or unsubstituted olefin, aldehyde, ketone, epoxide, alcohol, amine, and Grignard reagent.
26. The process of claim 17 in which the optically pure product is selected from the group consisting of substituted or unsubstituted aldehyde, ketone, carboxylic acid, amide, ester, alcohol, amine, and ether.
27. The process of claim 20 in which the prochiral or chiral olefinically unsaturated organic compound is selected from the group consisting of a substituted or unsubstituted olefin, or a substituted or unsubstituted olefin comprising p- isobutylstyrene, 2-vinyl-6-methoxynaphthylene, 3-ethenylphenyl phenyl ketone, 4- ethenylphenyl-2-thienylketone, 4-ethenyl-2-fluorobiphenyl, 4-(l,3-dihydro-l-oxo- 2H-isoindol-2-yl)styrene, 2-ethenyl-5-benzoylthiophene, 3-ethenylphenyl phenyl ether, propenylbenzene, isobutyl-4-propenylbenzene, phenyl vinyl ether and vinyl chloride.
28. The process of claim 4 in which the optically pure product is selected from die group consisting of a substituted or unsubstituted aldehyde, or a substituted or unsubstituted aldehyde comprising S-2-(p-isobutylphenyl)propionaldehyde, S-2-(6- methoxynaphthyl)propionaldehyde, S-2-(3-benzoylphenyl)propionaldehyde, S-2-(p- thienoylphenyl)propionaldehyde, S-2-(3-fluoro-4-phenyl)phenylpropionaldehyde, S- 2-[4-( 1 ,3-dihydro- 1 -oxo-2H-isoindol-2-yl)phenyl]-propionaldehyde, S-2-(2- methylacetaldehyde)-5-benzoylthiophene, S-2-(3-phenoxy0propionaldehyde, S-2- phenylbutyraldehyde, S-2-(4-isobutylphenyl)-butyraldehyde, S-2- phenoxypropionaldehyde and S-2-chloropropionaldehyde.
29. The process of claim 28 in which the optically active product has an enantiomeric excess of greater than 50%.
30. The process of claim 17 further comprising derivatizing the optically pure product.
31. The process of claim 30 in which the derivatizing reaction comprises an oxidation, reduction, condensation, amination, esterification, alkylation, or acylation reaction.
32. The process of claim 28 further comprising oxidizing die substituted or unsubstituted aldehyde to an optically active substituted or unsubstituted carboxylic acid, or an optically active carboxylic acid selected from the group consisting of S- ibuprofen, S-naproxen, S-suprofen, S-flurbiprofen, S-indoprofen, S-ketoprofen, S- tiaprofenic acid, S-fenoprofen, S-butibufen, phenethicillin, S-2-chloropropionic acid, and ketorolac.
33. An optically active product produced by the process of claim 17.
EP94907166A 1993-03-09 1994-01-07 Homogeneous bimetallic hydroformylation catalysts and processes utilizing these catalysts for conducting hydroformylation reactions. Withdrawn EP0673381A4 (en)

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WO2019237090A1 (en) * 2018-06-08 2019-12-12 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Catalyst compositions for hydroformylation and methods of use thereof

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US4987242A (en) * 1988-10-28 1991-01-22 Jagmohan Khanna Hydrogenation catalyst useful in the production of alpha-6-deoxytetracyclines
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See also references of WO9420510A1 *

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