EP0314759A4 - Asymmetric hydroformylations of prochiral olefins to chiral aldehydes in high enantiomeric excess. - Google Patents

Asymmetric hydroformylations of prochiral olefins to chiral aldehydes in high enantiomeric excess.

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Publication number
EP0314759A4
EP0314759A4 EP19880904854 EP88904854A EP0314759A4 EP 0314759 A4 EP0314759 A4 EP 0314759A4 EP 19880904854 EP19880904854 EP 19880904854 EP 88904854 A EP88904854 A EP 88904854A EP 0314759 A4 EP0314759 A4 EP 0314759A4
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Prior art keywords
diphenylphosphino
hydroformylation
methyl
platinum
pyrrolidine
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EP19880904854
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German (de)
French (fr)
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EP0314759A1 (en
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John K Stille
Giovanni Parrinello
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Colorado State University Research Foundation
Colorado State University
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Colorado State University Research Foundation
Colorado State University
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Publication of EP0314759A1 publication Critical patent/EP0314759A1/en
Publication of EP0314759A4 publication Critical patent/EP0314759A4/en
Withdrawn legal-status Critical Current

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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
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    • B01J31/165—Polymer immobilised coordination complexes, e.g. organometallic complexes
    • B01J31/1658—Polymer immobilised coordination complexes, e.g. organometallic complexes immobilised by covalent linkages, i.e. pendant complexes with optional linking groups, e.g. on Wang or Merrifield resins
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    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
    • B01J31/2414—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom comprising aliphatic or saturated rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/49—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with carbon monoxide
    • C07C45/50—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with carbon monoxide by oxo-reactions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/49—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with carbon monoxide
    • C07C45/50—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with carbon monoxide by oxo-reactions
    • C07C45/505—Asymmetric hydroformylation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/10—Preparation of carboxylic acids or their salts, halides or anhydrides by reaction with carbon monoxide
    • C07C51/14—Preparation of carboxylic acids or their salts, halides or anhydrides by reaction with carbon monoxide on a carbon-to-carbon unsaturated bond in organic compounds
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0213—Complexes without C-metal linkages
    • B01J2531/0219—Bimetallic complexes, i.e. comprising one or more units of two metals, with metal-metal bonds but no all-metal (M)n rings, e.g. Cr2(OAc)4
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/40—Complexes comprising metals of Group IV (IVA or IVB) as the central metal
    • B01J2531/42—Tin
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/828—Platinum
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    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms

Definitions

  • This patent disclosure teaches improved processes for the hydroformylation of prochiral olefins to chiral aldehydes.
  • these improved processes comprise contacting, under hydroformylation conditions, an olefin containing a prochiral center with hydrogen and carbon monoxide in the presence of a catalyst comprising a complex of platinum II and N-(t-butoxycarbonyl)-(2S,4S)-4-(diphenylphosphino)-2- [(diphenylphosphino)methyl pyrrolidine and stannous chloride, and removing the resulting chiral aldehyde from the reaction system as it is formed.
  • the reaction goes slower than it does in benzene, but the reaction gives a chiral acetal of particularly high enantiomeric purity which does not undergo racemization under hydroformylation conditions. Moreover, no solvent effect is observed in the product distribution (98.6% selectively and 0.5 b/n ratio).
  • the triethyl orthoformate trapping agent is also particularly effective in hydroformylation reactions of vinyl acetate, p-isobutylstyrene, 2-vinylnapthalene, 2-ethenyl-6-methoxynaphthalene, 4- (2-thienylcarbonyl) styrene, methyl methacrylate, and norborene.
  • the polymer containing the chiral phosphine ligand was then converted to the platinum catalysts by reaction with bis (benzonitrile) dischloroplatinum(II).
  • the hydroformylation of styrene with this polymer-supported complex was carried out in the presence of stannous chloride to generate the active catalyst.
  • This particular polymer would not swell in triethyl orthoformate, and therefore this solvent could not be used as a hydroformylation catalyst in this instance.

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  • Engineering & Computer Science (AREA)
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  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Asymmetric hydroformylations of chiral olefins can be achieved by contacting, under hydroformylation conditions, an olefin containing a prochiral center with hydrogen and carbon monoxide in the presence of a catalyst comprising a complex of platinum II and N-(t-butoxycarbonyl)-(2S, 4S)-4-(diphenylphosphino)-2-[(diphenylphosphino)methyl] pyrrolidine and stannous chloride, and removing the resulting chiral aldehyde as it is formed. A preferred method of removing the resulting chiral aldehyde is through the use of a trapping agent such as triethyl orthoformate, trimethyl orthoformate, triethyl orthoacetate, trimethyl orthoacetate, acetone diethyl ketal and acetone dimethyl acetal used in the presence of a solid catalyst support such as cross-linked polystyrene.

Description

ASYMMETRIC HYDROFORMYLATIONS OF PROCHIRAL OLEFINS TO CHIRAL ALDEHYDES IN HIGH ENANTIOMERIC EXCESS
BACKGROUND OF THE INVENTION
1. Field of the Invention This invention generally relates to hydroformylation reactions. More specifically it relates to hydroformylation reactions involving the use of transition metal complex catalysts, such as those of platinum, to achieve stereospecific additions of hydrogen and carbon monoxide to olefins containing a prochiral center. Such additions are important in synthetic organic chemistry because they involve both carbon-carbon bond formation and the introduction of a synthetically useful functionality into such molecules. Once this is accomplished, syntheses of a wide variety of chiral compounds is then possible.
2. Description of the Prior Art
The prior art discloses use of a wide variety of homogeneous and heterogeneous transition metal catalysts (e.g., those of rhodium, ruthenium and platinum) to promote reactions of olefins with carbon monoxide and hydrogen in hydroformylation reactions. Very often such transition metals are used in complexes having phosphine ligand components . For example, it is known that various transition metal/phosphine ligand catalysts can be used to "fine tune" particular hydroformylation reactions e.g., the optical yield in certain rhodium catalyzed hydroformylations can be increased by increasing the phosphine/metal ratio, whereas in certain platinum catalyzed hydroformylations this is not always possible since the use of large excesses of phosphine ligand tends to slow such reactions to impractical conversion rates. Nevertheless, some platinum complexes have been employed as hydroformylation catalysts (see for example, U.S. Patent No. 2,876,254). However, most platinum complex catalysts have not been particularly effective in the context of hydroformylation reactions. Among other things, they tend to (1) give low reaction rates, (2) encourage competitive hydrogenation reactions under hydroformylation conditions and (3) give relatively low branched/normal ratios.
For example, the highest heretofore reported enantiomeric excesses in hydroformylation reactions of styrene, have been achieved with a platinum catalyst containing the chiral ligand, N-(t-butoxycarbonyl)-(2S,4S)-4-(diphenylphosphino)-2- [ (diphenylphosphino) methyl ] pyrrolidine-- [ (-) BPPM] -PtCl2SnCl2 (see Stille, J.K., Parrinello, G.J., Mol. Catal., 1983, 21, 203). However, even though hydroformylations of olefins in the presence of [(- ) BPPM]PtCl2/SnCl2 are known to give the corresponding aldehydes in relatively higher enantiomeric excess, such aldehydes are also known to undergo a high degree of racemization in the presence of this particular catalyst under hydroformylation reaction conditions. This circumstance has imposed some severe limitations upon the utility of hydroformylation reactions using this catalysts, particularly when the substrate requires a long reaction time.
SUMMARY OF THE INVENTION This patent disclosure teaches improved processes for the hydroformylation of prochiral olefins to chiral aldehydes. Generally, these improved processes comprise contacting, under hydroformylation conditions, an olefin containing a prochiral center with hydrogen and carbon monoxide in the presence of a catalyst comprising a complex of platinum II and N-(t-butoxycarbonyl)-(2S,4S)-4-(diphenylphosphino)-2- [(diphenylphosphino)methyl pyrrolidine and stannous chloride, and removing the resulting chiral aldehyde from the reaction system as it is formed. A preferred method of removing the resulting chiral aldehyde is by contacting it with a trapping agent. Some highly preferred trapping agents which can be employed in such hydroformylation reactions include, but are not limited to, triethyl orthoformate, ethyl orthoformate, triethyl orthoacetate, trimethyl orthoacetate and acetone dimethyl ketal. Generally speaking such hydroformylation conditions will generally includes H2/CO ratios between about .025 and about 4, pressures between about 600 and about 4,500 psi, temperatures between about 20 degrees centigrade and about 120 degrees centigrade and reaction times between about 0.1 to about 150 hours. Reaction times less than about 24 hours are of course much more desirable. In any event, it is believed that such trapping agents serve to convert the resulting aldehyde to an acetal compound that does not easily undergo racemization under hydroformylation conditions. Moreover, these reductions in racemization of the chiral aldehyde products of the herein disclosed processes take place in both homogenous and heterogeneous catalyst systems. By way of example only, when hydroformylations of styrene by use of a [(-)BPPM]PtCl2/SnCl2 complex catalyst are carried out using triethyl orthoformate as the solvent, it acts as a trapping agent. The reaction goes slower than it does in benzene, but the reaction gives a chiral acetal of particularly high enantiomeric purity which does not undergo racemization under hydroformylation conditions. Moreover, no solvent effect is observed in the product distribution (98.6% selectively and 0.5 b/n ratio). The triethyl orthoformate trapping agent is also particularly effective in hydroformylation reactions of vinyl acetate, p-isobutylstyrene, 2-vinylnapthalene, 2-ethenyl-6-methoxynaphthalene, 4- (2-thienylcarbonyl) styrene, methyl methacrylate, and norborene. Similar results can be obtained using various other trapping agents which include, but are not limited to, triethyl orthoacetate, trimethyl orthoacetate, trimethyl orthoformate, acetone dimethyl ketal and acetone diethyl ketal. These hydroformylation reactions can be carried out using solid catalyst support materials as well as in homogeneous systems. The triethyl orthoformate trapping agent, is particularly effective in the context of hydroformylation reactions carried out in conjunction with solid catalyst support systems.
DESCRIPTION OF PREFERRED EMBODIMENTS
Experimental Methods
All reactions involving synthesis of phosphinated compounds were performed under an inert atmosphere of nitrogen or argon. Manipulations involving phosphines in solution were carried out in a glove bag or by Schlenk techniques.
All 1H NMR spectra were obtained on either an IBM WP-270 (270 MHz) or on a Nicolet NT-360 (360 MHz) spectrometer with tetramethylsilane as the internal standard. The 13C NMR spectra were obtained on an IBM WP-200 spectrometer (50.3 MHz) or an IBM WP-270 spectrometer (67.9 MHz), with tetramethylsilane ( δ 0.00) or chloroform (δ 77.00) as the internal standard. The 31P NMR spectra were obtained on an IBM WP-200 spectrometer (81 MHz) or a Nicolet NT-150 spectrometer (60.7 MHz) with 85% phosphoric acid (δ 0.00) as the external reference. Unless otherwise stated, the spectra were obtained in deuterochloroform. Optical rotations were measured on an Autopol III automatic polarimeter.
All melting points are uncorrected. Gas chromatographic analyses were carried out on a Varian Model 3700 using 10% OV-101 Chromosoborb W-HP, 80/100 (2 m x 1/8 in.), with a thermal conductivity detector or a DB1 Durabond fused silica capillary column (30m length x 0.25 mm i.d.) with a flame ionization detector and helium as the carrier gas. The chromatograph was interfaced with a Varian Chromatographic Data System III C for determining relative peak areas by electronic integration.
Synthesis gas (Isl, H2/CO) was purchased as a custom mixture from SAP Inc. and was used as received. Styrene, vinylacetate, and methyl methacrylate, were purchased from Aldrich, and freshly distilled and stabilized with p-methoxyphenol before use as hydroformylation substrates. Norbornene and 2-vinylnaphthalene were purchase from Aldrich and purified by sublimation before use. N- vinylphthalimide was purchased from Monomer-Polymer and Dajac Laboratories, Inc., and used as received. The NMR chiral shift reagents Eu(hfc)3 and Eu(tfc)3 were purchased from Aldrich. The reaction of free ligand (-) BPPM (see structure 1, Scheme 1 below) with norbornadienedichloroplatinum(II) give [(-)BPPM]PtCl2 (see structure 2 of Scheme 1) which can be used in the presence of stannous chloride dihydrate as a homogeneous catalyst precursor for hydroformylation reactions. Alternatively, a pre-formed [(-)-BPPM]Pt (SnCl3)Cl (see structure 3 of Scheme 1) can be prepared by the reaction of structure 2 with stannous chloride.
Structure 3 of Scheme 1, in which the tin ligand is trans to the phosphorous attached to the exomethylene carbon (phosphorous 1), was assigned on the basis of the following 31P nmr chemical shifts. In the uncomplexed ligand (structure 1) and the platinum complex (structure 2), the chemical shifts of the phosphorous bound to the exomethylene carbon are farther upfield ( δ -20.5 and 4.6, 4.8 respectively) than those for the ring-attached phosphorous (δ-8.5 and 28.8), respectively). When the tin complex is formed, phosphorus 1 (structure 1, scheme 1) experiences the greatest chemical shift (δ
14.3 and 13.3) in comparison with phosphorus 2
(structure 2, scheme 2), ( 26.8). The two chemical shifts for phosphorus 1 in complexes 2 and 3 are due to the two amide conformations of the t-Boc (tertiary butylcarboxy) group, syn and anti to the phosphorus
1.
N- (t-Butoxycarbonyl ) - ( 2S , 4S) -4-(diphenylphosphino)-2-[(diphenylphosphino)methyl]-pyrrolidine [(-)BPPM (1) was synthesized according to the method taught by Baker, G.L., Fritshcel, S.J., Stille, J.R., Stille, J.K., J. Org. Chem., 4, 1981, 46, 2954 and gave a product with m.p. 103-105°C (lit. 103.5-105°C); 31P NMR (CDCl3) -8.5 (s, 1P) , -20.5 (s,1P). [(-)BPPM]PtCl2. A deoxygenated solution of 300 mg (0.542 mmol) of (-)BPPM (1) in 5 ml of dichlorome thane was added to a refluxing solution of 109 mg ( 0.304 mmo l ) o f norbor nadienedichloroplatinum(II) in 10 ml of dichloromethane. The solution was heated to reflux for 1 hour under argon. Half the volume of the solvent was evaporated and the product was precipitated with diethyl ether, filtered, washed with diethyl ether and dried under reduced pressure to give 232 mg (93.0%) as a white powder. M.p. 180-220°C(dec); 31P NMR (CDCl)3 (P2) 28.8 [d,2J (P2,P1) = 16Hz]; (P1A) 4.6 [d,2J (P1,P2) = 16 Hz]; (P1B) 4.4 [d, 2J(P1, P2)=16 Hz]; [1J(Pt,P2)=3573 Hz, 1J(Pt,P1A)= 3511 Hz, 1J(Pt, P1B)=3478]. P2 is the phosphorus of the 2° phosphino group and P1 is the phosphorus of the 1° phosphino group. The two peaks P1A and P1B result from the two conformations of the t-BOC group at room temperature.
Production of [(-)BPPM]Pt(SnCl3)Cl. A deoxygenated solution of 200 mg (0.244 mmol) of (2) in 20 mL of dichloromethane was added to a stirred suspension of 92 mg (0.48 mmol) of anhydrous stannous chloride in 15 mL of dichloromethane. The mixture was stirred at room temperature for 7 hours under argon. The suspension was filtered to eliminate the excess stannous chloride. The solution was concentrated to 5 mL, and 15 mL of deoxygenated hexane was added. The precipitate (215 mg;87.0%) was filtered, washed with hexane, and dried under reduced pressure: m.p. 280°C (dec); 31P NMR (CH2Cl2/CDCl3) (P2) 26.8 [d,2J(P1, P2)=7.9 Hz] (P1A) 14.3 [d, 2J(P1A, P2)=13.8 Hz], (P1B) 13.3 [d,2J(P1B, P2)=13.8 Hz], [1J(Pt,P2)=3240 Hz, 1J(Pt, P1A)=2856 Hz, 1J(Pt,P1B)=2850 Hz]. Construction of Polystyrene Supported Catalyst. A s o l u t i o n o f 3 9 . 9 m g o f bis (benxonitrile) dichloroplatinum(II) in dichloromethane was added to 200 mg of 60 um crosslinked beads obtained from the copolymerization of N-acryloyl-(2S,4S)-4-(diphenylphosphine-2- [diphenylphosphino)methyl]pyrrolidine with styrene and divinylbenzene, and the mixture was stirred under argon for 8 hours. (Ratio of P2:Pt=1.7). The mixture was filtered in a Schlenck tube, dried under reduced pressure and stored under argon.
Various prior art hydroformylation reactions with homogeneous platinum catalysts were carried out under conventional conditions in order to further optimize the reaction conditions for the processes described in this patent disclosure. For example, a styrene hydroformylation with [(-)BPPM]PtCl2 and SnCl2 was carried out in benzene, at different reaction pressures, (1500-2650 psi), temperatures, (50-95°) and times (2-15h), to yield a mixture of 2- and 3-phenylpropanal. The ratio of 2-phenylpropanal to 3-phenylpropanal (branched to normal ratio, b/n) was constant with (0.4-0.5), approximately the same ratio as had been obtained with a [(-)DIOP]PtCl2/SnCl2 catalyst. The selectivity to aldehyde was high, less than 2% of ethylbenzene being obtained in each case. Branched aldehyde, 2-phenylpropanal, was obtained in relatively high enantiomeric excess, ("ee) particularly when the reaction times were short and the temperature was low, e.g., 78-80% ee being obtained at 56-57°C after 2-4 hours and low conversion.
Lower enantiomeric excesses were obtained at longer reaction times. This is most probably the result of product racemization under the reaction conditions. For example, when a mixture of 2- and 3- phenylpropanal was stirred in the presence of the catalyst under the reaction conditions (2800 psi, and a 1:1 H2/CO mixture at 60°C) for 60 hours, the enantiomeric excess of the added 2-phenylpropanal was reduced from 48% to 33.5%. Varying the H2/CO ratio (within the range 0.25-4) and the total pressure (between 600 and 4500 psi) only affected the reaction rate, but did not influence the product distribution significantly. The enantiomeric excess changed only as a function of conversion. Addition of free ligand, (-)BPPM, to the catalyst caused a dramatic decrease in reaction rate (2% conversion in 6 hours); however >96% ee was achieved. This high ee also could be obtained when the reaction was carried out at 25 degrees centigrade for 20 hours, but the conversion was only 5%. Under the same reaction conditions a 12% conversion was achieved after 6 days, but the ee decreased to 58%. Thus the extent of racemization appears to be a function of the concentration of the chiral aldehyde in the reaction mixture, the temperature, and the reaction time.
Hydroformylation of styrene in solvents other than benzene (1,2-dichlorobenzene, 1,2-dichloroethane, dichloromethane, THF, and ethanol), gave comparable b/n ratios, but somewhat slower rates and lower enantiomeric excesses. Similarly, hydroformylations of several other olefin substrates also were carried out in various solvents, the results were likewise compared to those results obtained from representative reactions disclosed in this patent application. The results obtained with vinyl acetate were particularly encouraging because this substrate is known to give 2-acetoxypropanal, a precursor in the Strecker synthesis of threonine. The product then can be converted to 2- hydroxypropanal, a useful intermediate in the synthesis of steroids, pheromones, antibiotics and peptides. By way of a similar comparison, it is known that an asymmetric hydroformylation of vinyl acetate has been achieved with Rh/DIOP or Rh/DBP-DIOP catalysts, but only in 24-32% or 51% ee, respectively. Again by way of further comparison, when [(-)DBP-DIOP]PtCl2/SnCl was used as the catalyst, 2-acetoxypropanal was obtained in 60% ee. On the other hand, hydroformylation of vinyl acetate catalyzed by [(-)BPPM]PtCl2 /SnCl2 gave 2-acetoxypropanal and large amounts of 3-acetoxyproponal in 70% conversion, but the 3-acetoxypropanal partially decomposed to acetic acid and acrolein, which in turn hydrogenated to propanal under the reaction conditions. GC analysis showed that 70% of the product was acrolein and propanal; 2- acetoxypropanal was obtained in 82% ee.
Several other comparative experiments were also conducted; for example, hydroformylation of N-vinylphthalimide in the presence of a [(-)-BPPM]PtCl2/SnCl2 catalyst system gave a 52% conversion to branched and normal aldehydes (b/n = 0.5) with relatively low aldehyde selectivity (85%). The (R)-(+) branched isomer, obtained in 73% ee was isolated by medium pressure liquid chromatography and oxidized to the corresponding acid in 72% optical purity.
Hydroformylation of norbornene with [(-) BPPM]PtCl2/SnCl2 proceeded slowly in spite of the expected reactivity of the strained double bond. A higher ee (60%) could be obtained when the reaction was carried out at 30°C, with the (1S,2S,4R) -(+) enantiomer being obtained in excess. It was concluded that racemization of the product aldehyde did not occur, since reaction at 30°C for 7 hours or 20 hours gave the same enantiomeric excess. The configuration of the aldehyde was established by its conversion to the corresponding acid in 60.7% optical purity.
Hydroformylation of monosubstituted olefins with 2, (structure 2, scheme 1) SnCl2 had the disadvantage that the unwanted linear aldehyde is obtained in larger amounts than the desired branched aldehyde. However, when an unsymmetrically 1,2-disubstituted olefin is hydroformylated, the prevailing regioisomer obtained has a chiral center generated from carbon hydrogen bond formation.
When methyl methacrylate was hydroformylated in the presence of the material depicted by structure 2, scheme 1, one aldehyde, the (R)-(+) enantiomer, was obtained in 60% ee. The enantiomeric excess increased with increasing the H2/CO ratio to 3. The importance of this particular reaction is derived from the usefulness of this chiral synthon and the fact that it is regioselective.
Homogeneous Hydroformylations. A 125 ml Parr Monel bomb was charged with 0.02 mmol of platinum catalyst and 0.04 mmol of stannous chloride dihydrate. The bomb was brought into an argon-filled glove bag and charged with 8.7 mmol of olefinic substrate dissolved in 3 ml of benzene. The bomb was sealed, pressurized and vented three times with the synthesis gas mixture (1:1, H2:CO) and pressurized (usually to 2400 psi at room temperature) and heated with stirring in an oil bath at 60°C. At the end of the reaction, the bomb was quenched in a dry ice bath, the pressure was vented, and the solvent was removed by distillation. The product mixture was vacuum transferred or flash chromatographed from the catalyst and analyzed by GLC by 1H NMR to determine the conversion and the product composition. The ee's were determined within an accuracy of positive, +3% by 1H NMR using Eu(hfc)3 or Eu(tfc)3 chiral shift reagents.
A typical experiment for the determination of enantiomeric excesses were as follows. Approximately 0.1 ml of a reaction mixture containing 2-phenylpropanal was diluted with deuterochloroform and placed in an NMR tube. Eu(hfc)3 was added in small portions until a neat splitting of the peak of the formyl proton (doublet at 9.6 ppm) was observed in the 1H NMR spectrum. The integration of the two peaks [14.46 ppm for the (S)-(+) and 14.34 ppm for the (R)-(-)-enantiomer] was used to calculate the enantiomeric excess according to the equation, %ee = [(S-R)/(S(+)R)] x 100.
Hydroformylations with Polymer-Supported Catalyst. The procedure for hydroformylation utilizing the heterogeneous catalysts was the same as that followed in the homogeneous hydroformylation, except that at the end of the reaction, the bomb was opened in a glove bag and the catalyst was recovered by filtration. Further Representative Hydroformylation Reactions
By way of further example and comparison, hydroformylation of styrene with a [(-)BPPM]PtCl2/SnCl2 catalyst system was carried out using triethyl orthoformate as the solvent. The reaction was considerably slower than in benzene (60% conversion in 96 hours), but gave a chiral acetal which did not undergo racemization under hydroformylation reaction conditions. However, no solvent effect was observed in the product distribution (98.6% selectivity and 0.5 b/n ratio). The branched acetal was submitted to 1H NMR analysis in the presence of the chiral shift reagent Eu(hfc)3, but no splitting of the acetal proton was observed. It was also found that, in general, hydroformylation of styrene in triethyl orthoformate was not readily carried out in the presence of a polymer-supported analog of BPPM due to the inefficient swelling of such polymer in such a solvent. Moreover, when the polymer beads were swollen in benzene before the addition of the substrate and triethyl orthoformate, the reaction gave 22% conversion in 10 days. The product distribution and the ee were the same as those observed in the homogeneous case.
A racemic acetal also was prepared by reaction of (±) -2-phenylpropanal with triethyl orthoformate in the presence of ammonium nitrate. A solution prepared by mixing 90% of the branched acetal obtained by asymmetric hydroformylation and 10% of the racemic compound in deuterochloroform was submitted to 1H NMR analysis in the presence of Eu(hfc)3. The acetal proton (doublet at ± 4.45) gave two peaks 143.2 Hz apart (0.53 ppm) in a 95:5 ratio. A number of methods were attempted for the hydrolysis of the branched acetal to the corresponding aldehyde. Reaction with BF3 Et2Oh in acetone gave a mixture of aldol products. Hydrolysis in the presence of p- toluenesulfonic acid in acetone at room temperature for 1 hour gave the corresponding aldehyde in 90% ee. However, some racemization took place during this reaction. This was proven by the fact that longer reaction times gave the aldehyde in lower ee. Reaction with pyridinium p-toluenesulfonate (PPTS) in refluxing acetone gave the corresponding aldehyde in 5 hours. % NMR analysis of this aldehyde in the presence of Eu(hfc)3 gave no splitting of the formyl proton. Experiments carried out with mixtures of this aldehyde and its racemate showed that 2% of the minor enantiomer could be detected in the NMR spectrum in the presence of Eu(hfc)3. Therefore, it was concluded that the hydrrformylation of styrene with [(-)BPPM]PtCl2/SnCl2 in the presence of triethyl orthoformate gave at least 96% ee. Use of the preformed catalyst [(-) BPPM]Pt(SnCl3)Cl allowed a faster reaction (100% conversion in 150 hours) giving the same product distribution and the same asymmetric induction.
Hydroformylations with [(-)BPPM]Pt(SnCl3)Cl in triethyl orthoformate were extended to a number of the other substrates, including those listed in Table 1.] Among other things, Table 1 shows that hydroformylation of 2-ethenyl-6-methoxynaphthalene gave a low conversion rate, but the corresponding branched acetal was obtained enantiomerically pure. N-Vinylphthalimide gave the same ee although the conversion was rather low. The same asymmetric induction was obtained in the case of vinyl acetate. The b/n ratio was 1.5 however, products of decomposition of the linear acetal also were observed. Hydroformylation of norborene in triethyl orthoformate gave the "exo" acetal in 60% ee. The last case shows that for norbornene the catalyst is not able to induce 100% enantioselectively under the conditions employed. In any case, the results of the above experiments indicate that it is possible to obtain optically pure aldehydes by hydroformylation of olefins in the presence of [(-)BPPM]Pt(SnCl3)Cl when the resulting aldehyde is removed from the reaction system as it is formed. Again, a highly preferred method for removing the resulting chiral aldehyde is through the use of a trapping agent. However, other methods of removal can also be employed. For example, in the industrial context this removal can be accomplished by using flow type reactors from which the aldehyde resulting from the disclosed process can be removed continuously from the reaction ambient. This could be achieved, for example, by utilization of a tubular reactor with a fixed bed (e.g., a polymer supported catalyst) to give relatively low conversion to aldehyde in each pass and recycling the olefin or by, converting the aldehyde to a product that is less susceptible to racemization. In one highly preferred embodiment of this invention, the catalyst is used in conjunction with a solid catalyst support system. Polymer-supported catalysts systems such as those that employ catalyst support materials such as cross linked polystyrene are particularly useful for this purpose.
This was shown in various way, for example, styrene also was hydroformylated with a polymer-supported analog of structure 2 of scheme 1. The ligand was incorporated into a polystyrene resin by converting it to an aerylate. The monomer, N-acryloyl-(2S,4S)-4-(diphenylphosphino)-2[(diphenylphosphino)-methyl] pyrrolidine was synthesized by the deprotection of (-)BPPM(1) with trifluroacetic acid and subsequent acylation of the free amine with acryloyl chloride. This monomer was copolymerized with styrene and divinylbenzene and divinylbenzene by suspension polymerization to yield crosslinked beads, averaging 60 urn in diameter, containing 10 mol% of the phosphine monomer and 10 mol % divinylbenzene. These beads swelled (203 times their original volume) in relatively non-polar solvents such as benzene, tetrahydrofuran and methylene chloride.
The polymer containing the chiral phosphine ligand was then converted to the platinum catalysts by reaction with bis (benzonitrile) dischloroplatinum(II). The hydroformylation of styrene with this polymer-supported complex was carried out in the presence of stannous chloride to generate the active catalyst. This particular polymer would not swell in triethyl orthoformate, and therefore this solvent could not be used as a hydroformylation catalyst in this instance. However, if the beads were swollen in benzene prior to addition of styrene and triethyl orthoformate, a 22% conversion was realized after 10 days, with the product distribution and enantiomeric excess (98%), the same as achieved in the homogeneous case.
In triethyl orthoformate, most of the reaction rates are at least an order of magnitude slower, but, the branched to normal ratios are the same. In all reactions, except for that with norbornene, enantiomerically pure products were obtained. Since the aldehyde obtained from norbornene is not racemized in benzene under the reaction conditions, a higher enantiomer excess would not be expected by running the reaction in triethyl orthoformate. In any event, the above data indicates that it is possible to obtain enantiomerically pure aldehydes by the hydroformylation of certain olefins in the presence of 2, [(-)BPPM]PtCl2/SnCl2 or 3, [(- )BPPM]Pt(SnCl3)Cl when the aldehyde is effectively removed from the system as it is formed. This is further shown in the following examples which are intended to illustrate some of the preferred embodiments of this invention.
EXAMPLE I Production of p-Isobutylacetophenone. A solution of 58.6 ml (0.375 of isobutylbenzene and 36.3 ml (0.375 mol) of acetic anhydride was added dropwise over 4 hours to a stirred suspension of 110 g (0.825 mol) of aluminum trichloride in 300 ml dichloromethane kept at 0°C. After the addition was complete, the mixture was stirred at 0°C for 1 hour and then allowed to warm up to room temperature. The mixture was then poured into 100 ml of concentrated hydrochloric acid in 400 ml of crushed ice, extracted with dichloromethane and washed with 2N sodium hydroxide solution and brine. The solution was dried over magnesium sulfate and removal of the solvent under reduced pressure gave a light brown liquid. Distillation of this liquid afforded 57.7 g (88% yield) of the colorless product: b.p. 94-100°C at 1.5 mm; 1H NMR 7.3 (d, J=8 Hz,2 hour), 7.1 (d, J=8 Hz,2H)2.6 (s,3H), 2.5(d,J=7 Hz,2H), 1.8 (m,1H),0.9 (d,J=6.4 Hz,6H).
Production of p-Isobutylphenylmethylcarbinol. A solution of 4.80 g (0.27 mol) of p-isobutyl acetophene in 50 ml of ethanol was added over a 10 minute period to a stirred solution of 1.30 g (0.035 mol) of sodium borohydride in 10 ml of water at room temperature. After stirring for an additional 20 min, a concentrated solution of sodium hydroxide was added and the mixture was boiled for 5 minutes to destroy the excess of sodium borohydride and hydrolyze the borate ester formed. The mixture was then poured over ice, extracted with diethyl ether, washed with 2N aqueous sodium hydroxide, 2N aqueous hydrochloric acid, and brine and dried over magnesium sulfate. Removal of the solvent gave an oil which was distilled to obtain 58.4 g (85.3% yield) of the pure products b.p. 100°C at 0.75 mm; H NMR 7.3 (d, J=8.1 Hz,2H), 7.1 (d,J=8 Hz,2 hours), 4.7 ) q, 6.0 Hz, 1H) , 2.8 (s, 1 hour, disappeared by shaking with D2O) , 2.5 (d, J=7.2 Hz, 2hours), 1.8 (m, 1 hour), 1.5 (d,J=6.0 Hz,3H), 0.9 (d, J=6.4 Hz, 6 hours).
EXAMPLE II Production of p-Isobutylstyrene. A mixture of 20.0 g (0.112 mol) of p-isobutylphenylmethylcarbinol, 0.6 g of fused potassium bisulfate and 10 mg of p-methoxyphenol was heated at 200°C and the product water azeotrope was distilled out (0.5mm). The wet product was dried over magnesium sulfate. Removal of the solvent and fractional distillation afforded 14 g (78% yield) of product: b.p. 60°C at 0.5 mm; 1H NMR 7.3 (d, J=8 Hz, 2hours), 7.1 (d, J=8 Hz, 2hours), 6.7 (d, J=17.9, 10.9 Hz,lhour), 5.6 (d,J=17.9 Hz , 1hour), 5.2 (d,J=10.9 Hz, 1hour), 2.4 (d, J=7.2 Hz,2 hours), 1.8 (m, 1 hour), 0.9 (d,J=6.4 Hz, 6 hours). This spectrum was consistent with published data.
Hydroformylation of p-Isobutylstyrene. A mixture of 3.00 g (18.7 mmol) of p-isobutylstyrene, 26.2 mg (0.032 mmol) of [(-)BPPM]PtCl2, 18.0 mg (0.080 mmol) of SnCl2.2H2O and a few crystals of p-methoxyphenol in 5 ml of benzene was placed into a 125 ml Parr Monel bomb. The bomb was pressurized with H2/CO to 2400 psi and heated to 60°C for 9 hours. The reaction mixture was analyzed by GC to determine the conversion (50%) , aldehyde selectivity (98%), and b/n ratio (0.5). 1H NMR of the mixture with the chiral shift reagent Eu(hfc)2 determined that the branched aldehyde was obtained in 78% ee. The (S) (+) enantiomer was obtained in excess.
EXAMPLE III Production of (S)-(+)-2(2-Naphthyl)propanal. A mixture of 3.50 g (22.7 mmol) of 2-vinylnapthalene, 72.0 mg (0.088 mmol) of [(-)BPPM]PtCl2, 49.3 mg of SnCl2.2H2O and a few crystals of p-methoxyphenol in 15 ml of benzene was placed into a 125 ml Parr Monel bomb. The bomb was pressurized with H2/CO to 2400 psi and heated to 60°C for 18 hours. The reaction gave 100% conversion to the corresponding branched and normal aldehydes (b/n = 0.5 by 1H NMR) . The mixture was submitted to medium pressure chromatography (silica, benzene) and afforded to 0.90 g (22%) of the branched aldehyde (6): m.p. 136°C (lit. 134-135°C); 1H NMR 9.7 (d, J=4.1 Hz,3H), 7.7-7.2 (m,7 hours), 3.7 (dq, J=6.3, 4.1 Hz, 1 hour), 1.2 (d, J=6.3 Hz, 3 hours). % NMR of (6) in the presence of Eu(hfc)3 determined that the aldehyde was obtained in 78% ee.
Production of (S)-(+)-2(2-Naphthyl)propionic acid. To a stirred mixture of 350 mg (1.90 mmol) of (6) and 350 mg of magnesium sulfate in 50 ml of acetone was added 331 mg (2.10 mmol) of potassium permanganate over 2 hours. The solvent was evaporated under reduced pressure and the solid residue was treated with 3 x 50 ml of hot water and filtered. The cold aqueous solution was washed with chloroform, then acidified with hydrochloric acid to pH=2 and extracted with chloroform. The organic layer was dried over magnesium sulfate. Removal of the solvent under reduced pressure gave 230 mg (60.5%) of the product (7) as white crystals: m.p. 143°C (lit. 139. 4-141°C); [α] D plus 51° (c 2.5, CHCl3); 77% O.P. (based on [α] D plus 66.4° reported for the pure (S)-enantiomer).
EXAMPLE IV P r o d u c t i o n o f ( S ) - 2 - ( 6 -M e t h o xy - 2 -naphthyl)propanal. A deoxygenated solution of 1.0 g (5.4 mmol) of 2-vinyl-6-methoxynaphthalene in 15 ml of benzene was charged into a 125 ml Parr Monel bomb with 16 mg (0.02 mmol) of [(-) BPPM]PtCl2 and 11 mg (0.05 mmol) of stannous chloride dihydrate. The bomb was sealed, pressurized to 2700 psi and heated with stirring to 60°C for 9 hours. At the end of the reaction the bomb was quenched in a dry ice bath, the pressure was vented and the mixture was eluted with benzene through an MPLC apparatus to afford 350 mg (30.1%) of the branched aldehyde: m.p. 145°C; 81% ee (determined by 1H NMR using Eu(hfc)3 as chiral shift reagent); 1H NMR 9.7 (d, J=4.1 Hz, 1H), 7.7-7.1 (m, 6 hours), 3.9 (s, 3 hours) 3.7 (dq, J=6.3, 4.1 Hz, 1 hour), 1.6 (d, 6.3 Hz, 3 hours). The analytical calculation for C14, H14, and O2 was C, 78.50; H, 6.54, and we found: C, 78, 38 and H, 6.59.
Production of (S)-(+)-2-(6-Methoxy-2-naphthy1) propionic acid (Naproxen)R. A suspension containing 250 mg (1.17 mmol) of (S)-2 (6-methoxy-2-naphthyl) propanol (9) and 280 mg (1.13 mmol) of magnesium sulfate in 50 ml of acetone, was treated with a solution of 269 mg (1.70 mmol) of potassium permanganate in 10 ml of acetone added dropwise over 1 hour. The solvent was then removed and the residue was extracted with hot water and filtered. The cold aqueous solution was washed with chloroform and then acidified with HCl to pH=2 to obtain a white precipitate which was filtered, washed with water and dried under reduced pressure to yield 200 mg (74.3%) of product: m.p. 154°C (lit. 152-154°C) ; [α]D + 54.1 (cl, CHCl3); 82% O.P. (based on [α]D + 66°C reported for the pure enantiomer). The product was recrystallized from acetone/hexane to afford a first crop of crystals with [α]D + 65.8° (cl, CHCl3) (100 % O.P.). A second crop of crystals were recovered from the mother liquors ([α]D + 52.4°C; 80% O.P.).
EXAMPLE V Hydroformylation of 4-(2-Thienylcarbonyl) styrene. A deoxygenated mixture of 1.00 g (4.67 mmol) of 4- (2-thienylcarbonyl) styrene, 7.70 mg (0.009 mmol) of [(-)BPPM]PtCl2, 5.30 mg (0.023 mmol) of stannous chloride dihydrate and a few crystals of p-methoxyphenol in 7 ml of benzene was placed into a 125 ml Parr Monel bomb. The bomb was pressurized with H2/C0 to 2600 psi and heated to 60°C for 9 hours. The reaction mixture was analyzed by 1H NMR to determine the conversion (73%), aldehyde selectively (98%), and b/n ratio (0.5). 1H NMR of the mixture with the chiral shift reagent Eu(hfc)3 determined that the branched aldehyde was obtained in 78% ee. The (S)-(+) enantiomer was obtained in excess.
EXAMPLE VI Hydroformylation of Vinyl Acetate. A deoxygenated mixture of 1.00 ml (0.934 g, 10.6 mmol) of vinyl acetate, 10.9 mg (0.013 mmol) of [(-)BPPM]PtCl2 and 7.50 mg (0.033 mmol) of stannous chloride dihydrate in 3 ml of benzene was placed into a 125 ml Parr Monel bomb. The bomb was pressurized with 1:1 H2/CO to 2700 psi and heated to 60°C for 40 hours. The reaction mixture was analyzed by GC to determined the conversion (75%), the amount of volatile aldehydes (70%) and the b/n ratio (0.5). The mixture was washed with sodium bicarbonate saturated solution and dried over magnesium sulfate.1H NMR in the presence of the chiral shift reagent Eu(tfc)3 determined that the branched aldehyde was obtained in 76% ee. The (S)-(+) enantiomer was obtained in excess.
EXAMPLE VII Production of (R)-(+)-2-N-Phthalylpropanal. This compound was obtained in 25% yield by the hydroformylation of N-vinylphthalimide in the presence of [(-)-BPPM]PtCl2/SnCl2. The reaction yielded the branched and the linear aldehydes in 0.5 b/n ratio. The branched aldehyde was isolated by MPLC (1:1 hexane/ethyl acetate): m.p. 105-107°C (lit. 112-113°C); 73% ee (determined by % NMR using Eu(hfc)3 as chiral shift reagent).
(R)-(+)-N-Phthalylalanine. This compound was obtained by oxidation of (R)-(+)-2-N-phthalylpropanal following known procedures: m.p. 148°C (lit. 150-151°C) ; [α]D24 + 17.6° (c8, EtOH); 72% O.P. (based on [α]D25 + 24.5° reported for the pure enantiomer. EXAMPLE VIII
Hydroformylation of Norbornene. A deoxygenated mixture of 1.00 g (10.6 mmol) of norbornene, 10.9 mg (0.013 mmol) of [(-)BPPM]PtCl2, 7.50 mg (0.033 mmol) of stannous chloride and a few crystals of p-methoxyphenol in 3 ml of benzene was placed into a 125 ml Parr Monel bomb. The bomb was pressurized with 1:1 H2/CO to 2700 psi and heated to 30°C for 20 hours. The reaction mixture was analyzed by GC to determine the conversion (84%) and the aldehyde selectivity (98.7%). 1H NMR of the mixture in the presence of Eu(hfc)3 determined that the aldehyde was obtained in 60% ee. This mixture was dissolved in 50 ml of acetone containing 1.5 g of magnesium sulfate and 1.6 mg of potassium permanganate was added over 1 hour with stirring at room temperature. The solvent was removed under reduced pressure and the black solid was extracted with hot water and filtered. The solution was allowed to cool to room temperature and washed with chloroform. The aqueous layer was acidified to pH=2 with concentrated hydrochloric acid and extracted with chloroform. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure to afford a white solid. Recrystallization from water afforded white crystals: m.p. 57-58°C (lit. 58-58.5°C); [α]D 24 + 6.5 (C 2.45, EtOH) (lit. [α]D 25 + 10.7 (C 2.4, EtOH) ] : O.P. = 60.7%. Comparison of these physical data with those reported in the literature established that the exo-(1S,2S,4R)-(+) enantiomer was obtained in excess.
EXAMPLE IX Hydroformylation of Methyl Methacrylate. A deoxygenated mixture of 1.00 ml (0.936 g; 9.30 mmol) of methyl methacrylate, 10.9 mg (0.013 mmol) of [(-)BPPM]PtCl2 and 7.50 mg (0.033 mmol) of stannous chloride dihydrate in 3 ml of benzene was placed into a Parr Monel bomb. The bomb was pressurized with 3:1 H2/CO to 2600 psi and heated to 60°C for 50 hours. The reaction mixture was analyzed by GC to determine the conversion (36%) and aldehyde selectivity (98%). The product, methyl B-formylisobutyrate was identified by comparison of the 1H NMR data to those eeported in the literature. 1H NMR in the presence of Eu(hfc)3 determined that the product was obtained in 60% ee. The (S)-(+) enantiomer was obtained in
Comparative Procedures for Hydroformylations in the Presence of Triethyl Orthoformate. This procedure was identical to those for the hydroformylations described above except that trapping agents such, as for example triethyl orthoformate can be used as the solvent (or cosolvent in the case of substrates which are insoluble in triethyl orthoformate). At the end of the reaction, the solvent was removed by vacuum distillation and the resulting mixture was analyzed by GC or 1H NMR to determine the conversion and the product composition. Those skilled in the art will appreciate that the above examples do not limit this invention and that various modifications of the processes of this invention may be made without departing from the spirit or scope thereof and it is to be understood that this invention is intended to be limited only by the appended claims.

Claims

Thus having disclosed the invention, what is claimed is:
1. A process for asymmetric hydroformylation of a prochiral olefin which comprises contacting, under hydroformylation conditions, a prochiral olefin with hydrogen and carbon monoxide in the presence of a catalyst comprising a complex of platinum II and N- (t-butoxycarbonyl)-(2S, 4S)-4-(diphenylphosphino)-2- [(diphenylphosphino) methyl] pyrrolidine and stannous chloride, and removing a resulting chiral aldehyde product.
2. The process according to claim 1 wherein the complex of platinum II and N-(t-butoxycarbonyl)-(2S,4 S ) - 4 - ( d i p h e n y l p h o s p h i n o ) - 2 - [(diphenylphosphino)methyl] pyrrolidine and stannous chloride is bound to a solid catalyst support.
3. The process according to claim 1 wherein hydroformylation of the prochiral olefin is carried out under homogeneous catalysis conditions.
4. A process for asymmetric hydroformylation of a prochiral olefin which comprises contacting, under hydroformylation conditions, a prochiral olefin with hydrogen and carbon monoxide in the presence of a catalyst comprising a complex of platinum II and N-(t-butoxycarbonyl)-(2S, 4S)-4-(diphenylphosphino)-2- [(diphenylphospino)methyl]pyrrolidine and stannous chloride in the presence of a trapping agent and removing a resulting chiral aldehyde product.
5. The process according to claim 4 wherein the complex of platinum II and N-(t-butoxycarbonyl) ( 2 S , 4 S ) - 4 - ( dipheny lpho sp ino ) -2 - [(diphenylphosphino)methyl]pyrrolidine and stannous chloride is bound to a solid catalyst support.
6. The process according to claim 4 wherein the trapping agent is selected from the group consisting of triethyl orthoformate, trimethyl orthoformate, triethyl orthoacetate, trimethyl orthoacetate, acetone diethyl ketal and acetone dimethyl acetal.
7. A process for the asymmetric hydroformylation of styrene which comprises contacting, under hydroformylation conditions, styrene with hydrogen and carbon monoxide in the presence of a catalyst comprising a complex of platinum II and N-(t-butoxycarbonyl)-(2S,4S)-4-(diphenylphosphino)-2- [(diphenylphospino methyϊ] pyrrolidine and stannous chloride while in the presence of a trapping agent selected from the group consisting of triethyl orthoformate, trimethyl orthoformate, triethyl orthoacetate, trimethyl orthoacetate, acetone diethyl ketal and acetone dimethyl acetal to produce 2-phenylpropanal.
8. The process according to claim 7 wherein the complex of platinum II and N-(t-butoxycarbonyl)- ( 2 S , 4S ) -4- (diphenylphosphino) -2- [(diphenylphosphino)methyl] pyrrolidine and stannous chloride is bound to a solid catalyst support.
9. The process according to claim 7 wherein the complex of platinum II and N-(t-butoxycarbonyl)- ( 2 S , 4S ) -4- (diphenylphosphino) -2- [(diphenylphosphino)methyl] pyrrolidine and stannous chloride is bound to be a crosslinked catalyst support pretreated in benzene.
10. A process for the asymmetric hydroformylation of styrene which comprises contacting, under hydroformylation conditions, styrene with hydrogen and carbon monoxide in the presence of a catalyst comprising a complex of platinum II and N-(t-butoxycarbonyl)-(2S,4S)-4-(diphenylphosphino)-2- [(diphenylphosphino)methyl] pyrrolidine and stannous chloride while in the presence of a trapping agent selected from the group consisting of triethyl orthoformate, trimethyl orthoformate, triethyl orthoacetate, trimethyl orthoacetate, acetone diethyl ketal and acetone dimethyl acetal to produce an acetal of 2-phenylpropanal.
11. A process for the asymmetric hydroformylation of p-isobutylstyrene which comprises contacting, under hydroformylation conditions, p-isobulylstyrene with hydrogen and carbon monoxide in the presence of a catalyst comprising a complex of platinum II and N- (t-butoxycarbonyl)-(2S,4S)-4-(diphenylphosphino)-2- [(diphenylphosphino)methyl] pyrrolidine and stannous chloride while in the presence of a trapping agent selected from the group consisting of triethyl orthoformate, trimethyl orthoformate, triethyl orthoacetate, trimethyl orthoacetate, acetone diethyl ketal and acetone dimethyl acetal to produce a 2-(4-isobutylphenyl)propanal.
12. The process according to claim 11 wherein the complex of platinum II N-(t-butoxycarbonyl)-(2S,4S)-4-(diphenylphosphino)-2-[(diphenylphosphino)methyl] pyrrolidine and stannous chloride is bound to be a solid catalyst support.
13. The process according to claim 11 wherein the hydroformylation of the p-isobutylstyrene is carried out under homogeneous catalyst conditions.
14. A process for the asymmetric hydroformylation of 2-vinylnaphthalene which comprises contacting, under hydroformylation conditions, 2-vinylnapthalene with hydrogen and carbon monoxide in the presence of a catalyst comprising a complex of platinum II and N- (t-butoxycarbonyl)-(2S,4S)-4-(diphenylphosphino)-2-[(diphenylphosphino)methyl] pyrrolidine and stannous chloride while in the presence of a trapping agent selected from the group consisting of triethyl orthoformate, trimethyl orthoformate, triethyl orthoacetate, trimethyl orthoacetate, acetone diethyl ketal and acetone dimethyl acetal to produce (S)-(+)-2(2 napthyl) propanal.
15. The process according to claim 14 wherein the complex of platinum II and N-(t-butoxycarbonyl)- ( 2 S , 4S ) -4- (diphenylphosphino) -2- [(diphenylphosphino)methyl] pyrrolidine and stannous chloride is bound to a solid catalyst support.
16. The process according to claim 14 wherein the hydroformylation of the 2-vinylnaphthalene is carried out under homogeneous catalysis conditions.
17. A process for the asymmetric hydroformylation of 2-vinyl-6-methoxynaphthalene which comprises contacting, under hydroformylation conditions, 2-vinyl-6-methoxynaphthalene with hydrogen and carbon monoxide in the presence of a catalyst comprising a complex of platinum II and N-(t-butoxycarbonyl)- ( 2 S , 4S ) -4- (diphenylphosphino) -2- [(diphenylphosphino)methyl] pyrrolidine and stannous chloride, and removing a resulting chiral aldehyde product.
18. A process for the asymmetric hydroformylation of 2-vinyl-6-methoxynaphthalene which comprises contacting, under hydroformylation conditions, 2-vinyl-6-methoxynaphthalene with hydrogen and carbon monoxide with in the presence of a catalyst comprising a complex of platinum II and N-(t-butoxycarbonyl)-(2S,4S)-4-(diphenylphosphino)-2- [(diphenylphosphino)methyl] pyrrolidine and stannous chloride "While in the presence of a trapping agent selected from the group consisting of triethyl orthoformate, trimethyl orthoacetate, trimethyl orthoformate, acetone dimethyl ketal, and acetone diethyl ketal to produce (S)-(+)-2-(6-methoxy-2-naphthyl) propionic acid.
19. The process according to claim 18 wherein the complex of platinum II and N-(t-butoxycarbonyl)- ( 2 S , 4S ) -4- (diphenylphosphino) -2 -[(diphenylphosphino)methyl] pyrrolidine and stannous chloride is bound to a solid catalyst support.
20. The process according to claim 18 wherein the hydroformylation of the 2-ethenyl-6-methoxynapthalene is carried out under homogeneous catalysis conditions.
21. A process for the asymmetric hydroformylation of 4-(2-thienylcarbonyl) styrene which comprises contacting, under hydroformylation conditions, 4-(2- thienylcarbonyl) styrene with hydrogen and carbon monoxide in the presence of a catalyst comprising a complex of platinum II and N-(t-butoxycarbonyl)- ( 2 S , 4S ) -4- (diphenylphosphino) -2-[(diphenylphosphino)methyl] pyrrolidine and stannous chloride while in the presence of a trapping agent selected from the group consisting of triethyl orthoformate, trimethyl orthoformate, trimethyl orthoacetate, triethyl orthoacetate, acetone diethyl ketal and acetone dimethyl acetal to produce an (S)- (+) enantiomer chiral aldehyde product.
22. The process according to claim 21 wherein the complex of platinum II and N-(t-butoxycarbonyl)- ( 2S , 4S ) -4- (diphenylphosphino) -2- [(diphenylphosphino)methyl] pyrrolidine and stannous chloride is bound to a solid catalyst support.
23 o The process according to claim 21 wherein the hydroformylation of the 4- (2-thienylcarbonyl) styrene is carried out under homogeneous catalysis conditions.
24. A process for the asymmetric hydroformylations of vinyl acetate which comprises contacting, under hydroformylation conditions, vinyl acetate with hydrogen and carbon monoxide in the presence of a catalyst comprising a complex of platinum II and N- (t-butoxycarbonyl)-(2S,4S)-4-(diphenylphosphino)-2- [(diphenylphosphino)methyl] pyrrolidine and stannous chloride while in the presence of a trapping agent selected from the group consisting of triethyl orthoformate, trimethyl orthoformate, triethyl orthoacetate, trimethyl orthoacetate, acetone diethyl ketal and acetone dimethyl acetal to produce 2- acetoxypropanal.
25. The process according to claim 24 wherein the complex of platinum II and N-(t-butoxycarbonyl)- ( 2 S , 4S ) -4- (diphenylphosphino) -2- [(diphenylphosphino)methyl] pyrrolidine and stannous chloride is bound to a crosslinked polystyrene catalyst support.
26. The process according to claim 24 wherein the hydroformylation of the vinyl acetate is carried out under homogenous catalyst conditions.
27. A process for the asymmetric hydroformylation of N-vinylphthalimide which comprises contacting, under hydroformylation conditions, N-vinylphthalimide with hydrogen and carbon monoxide in the presence of a catalyst comprising a complex of platinum II and N- (t-butoxycarbonyl)-(2S,4S)-4-(diphenylphosphino)-2- [(diphenylphosphino) methyl] pyrrolidine and stannous chloride in the presence of a trapping agent selected from the group consisting of triethyl orthoformate, trimethyl orthoformate, triethyl orthoacetate, trimethyl orthoacetate, acetone diethyl ketal and acetone dimethyl acetal to produce (R)-(+)-2-N-Phalylpropanal.
28. The process according to claim 27 wherein the complex of platinum II and N-(t-butoxycarbonyl)- ( 2 S , 4S ) -4- (diphenylphosphino) -2-[(diphenylphosphino)methyl] pyrrolidine and stannous chloride is bound to a solid catalyst support.
29. The process according to claim 27 wherein the hydroformylation of the N-vinylthalimide is carried out under homogeneous catalysis conditions.
30. A process for the asymmetric hydroformylation of methyl methacrylate which comprises contacting, under hydroformylation conditions, methyl methacrylate with hydrogen and carbon monoxide in the presence of a catalyst comprising a complex of platinum II and N- (t-butoxycarbonyl)-(2S,4S)-4-(diphenylphosphino)-2- [(diphenylphosphino)methyl] pyrrolidine and stannous chloride to produce B-formylisobutyrate.
31. A process for the asymmetric hydroformylation of methyl methacrylate which comprises contacting, under hydroformylation conditions, methyl methacrylate with hydrogen and carbon monoxide in the presence of a catalyst comprising a complex of platinum II and N- (t-butoxycarbonyl)-(2S,4S)-4-(diphenylphosphino)-2- [(diphenylphosphino)methyl] pyrrolidine and stannous chloride in the presence of a trapping agent selecred from the group consisting of triethyl orthoformate, trimethyl orthoformate, triethyl orthoacetate, trimethyl orthoacetate, acetone diethyl ketal and acetone dimethyl acetal to produce B-formylisobutyrate.
32. The process according to claim 31 wherein the complex of platinum II and N-(t-butoxycarbonyl)- (2 S , 4S) -4- (diphenylphosphino) -2- [(diphenylphosphino)methyl] pyrrolidine and stannous chloride is bound to a solid catalyst support.
33. The process according to claim 31 wherein the hydroformylation of the prochiral olefin is carried out under homogeneous catalysis conditions.
34. A process for asymmetric hydroformylation of norborene which comprises contacting, under hydroformylation conditions, norborene with hydrogen and carbon monoxide in the presence of a catalyst comprising a complex of platinum II and N-(t-butoxycarbonyl)-(2S,4S)-4-(diphenylphosphino)-2- [(diphenylphosphino)methyl] pyrrolidine and stannous chloride in the presence of a trapping agent selected from the group consisting of triethyl orthoformate, trimethyl orthoformate, triethyl orthoacetate, trimethyl orthoacetate, acetone diethyl ketal and acetone dimethyl acetal to produce 2-formylnorborane.
35. The process according to claim 34 wherein the complex of platinum II and N-(t-butoxycarbonyl)- ( 2 S , 4S ) -4- (diphenylphosphino) -2-[(diphenylphosphino)methyl] pyrrolidine and stannous chloride is bound to a solid catalyst support.
36. The process according to claim 34 wherein the. hydroformylation of the norborene is carried out under homogeneous catalysis conditions.
EP19880904854 1987-05-14 1988-05-05 Asymmetric hydroformylations of prochiral olefins to chiral aldehydes in high enantiomeric excess. Withdrawn EP0314759A4 (en)

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Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5360938A (en) * 1991-08-21 1994-11-01 Union Carbide Chemicals & Plastics Technology Corporation Asymmetric syntheses
BE1007410A3 (en) * 1993-08-23 1995-06-06 Dsm Nv PROCESS FOR THE PREPARATION OF A acetal.
US5430194A (en) * 1994-06-24 1995-07-04 Union Carbide Chemicals & Plastics Technology Corporation Process for improving enantiomeric purity of aldehydes
US8884072B2 (en) 2010-11-12 2014-11-11 Dow Technology Investments Llc Mitigation of fouling in hydroformylation processes by water addition
US9174907B2 (en) 2012-06-04 2015-11-03 Dow Technology Investments Llc Hydroformylation process
MY176756A (en) 2012-09-25 2020-08-21 Dow Technology Investments Llc Process for stabilizing a phosphite ligand against degradation
EP2740535A1 (en) 2012-12-04 2014-06-11 Dow Technology Investments LLC Bidentate ligands for hydroformylation of ethylene
KR102098429B1 (en) 2012-12-06 2020-04-07 다우 테크놀로지 인베스트먼츠 엘엘씨. Hydroformylation process
CN104045532B (en) 2013-03-15 2018-05-25 陶氏技术投资有限责任公司 Hydroformylation process
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BR112018016320B1 (en) 2016-02-11 2022-07-12 Dow Technology Investments Llc PROCESS TO CONVERT OLEFINS INTO ALCOHOLS, ETHERS OR COMBINATIONS THEREOF
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TW201840362A (en) 2016-11-08 2018-11-16 美商陶氏科技投資有限公司 Methods to rejuvenate a deactivated hydroformylation catalyst solution
TW201840363A (en) 2016-11-08 2018-11-16 美商陶氏科技投資有限公司 Methods of treating a hydroformylation catalyst solution
RU2020115090A (en) 2017-10-25 2021-10-29 Дау Текнолоджи Инвестментс Ллк METHOD FOR REDUCING THE FORMATION OF HEAVY FRACTIONS IN A SOLUTION CONTAINING ALDEHYDE COMPOUNDS FORMED IN THE PROCESS OF HYDROFORMYLATION
EP3710161B1 (en) 2017-11-13 2024-10-16 Dow Technology Investments LLC Processes for recovery of rhodium from a hydroformylation process
CN112055614A (en) 2018-05-30 2020-12-08 陶氏技术投资有限责任公司 Catalyst composition comprising a combination of monophosphine and tetraphosphine ligands and hydroformylation process using the same
CA3100779A1 (en) 2018-05-30 2019-12-05 Dow Technology Investments Llc Methods of controlling hydroformylation processes
KR20210013702A (en) 2018-05-30 2021-02-05 다우 테크놀로지 인베스트먼츠 엘엘씨. How to slow the deactivation of the catalyst and/or slow the use of tetraphosphine ligands in the hydroformylation process
TW202126385A (en) 2019-11-05 2021-07-16 美商陶氏科技投資有限公司 Processes for recovery of rhodium from a hydroformylation process
US11976017B2 (en) 2019-12-19 2024-05-07 Dow Technology Investments Llc Processes for preparing isoprene and mono-olefins comprising at least six carbon atoms
EP4430218A1 (en) 2021-11-11 2024-09-18 Dow Technology Investments LLC Processes for recovering rhodium from hydroformylation processes
WO2024129290A1 (en) 2022-12-13 2024-06-20 Dow Technology Investments Llc Process to minimize polyphosphine usage by making use of degradation products

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4482748A (en) * 1967-05-29 1984-11-13 Celanese Corporation Hydrocarbonylation

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DISSERTATION ABSTRACTS INTERNATIONAL, vol. 47, no. 11, May 1987, order no. DA8705475; G. PARRINELLO: "Asymmetric hydroformylation catalyzed by homogeneous and polymer-supported chiral platinum complexes" *
J. AM. CHEM. SOC., vol. 109, no. 23, 1987, pages 7122-7127, American Chemical Society; G. PARRINELLO et al.: "Asymmetric hydroformylation catalyzed by homogeneous and polymer-supported platinum complexes containing chiral phosphine ligands" *
POLYM. PREPRINT (AM. CHEM. SOC., DIV. POLYM. CHEM.), vol. 27, no. 2, 1986, pages 9-10; G. PARRINELLO et al.: "Asymmetric hydroformylation by polymer-supported chiral catalysis" *
See also references of WO8808835A1 *

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