Patent Application
20070155974
The present invention relates to stereoisomerically enriched phosphorus compounds, transition metal catalysts which can be prepared therefrom and their use in stereoselective catalytic processes, and also a process for preparing the stereoisomerically enriched phosphorus compounds.
It is known from WO 2003048175 that transition metal complexes of olefin-phosphane compounds are suitable for homogeneously catalyzed reactions such as, in particular, hydrogenations and hydrogen additions. The preparation of such olefin-phosphane compounds is usually carried out using secondary phosphanes (see also Thomaier et al., New. J. Chem. 1998, 947-958 and Deblon et al., New. J. Chem. 2001, 25, 83-92). As an alternative, they can be prepared via phosphane oxides as described in EP 1 475 384 A.
The advantage of the abovementioned olefin-phospane compounds is the ease with which they can be modified electronically and sterically, which is why there was a need to provide particularly suitable catalysts which allow organic compounds to be prepared enantioselectively in an efficient way.
It has now surprisingly been found that enantiomerically enriched compounds of the formula (I) are particularly suitable as ligands, where, in the formula (I),
For the purposes of the invention, the terms stereoisomerically enriched (enantiomerically enriched or diastereomerically enriched) refer to stereoisomerically pure (enantiomerically pure or diastereomerically pure) compounds or mixtures of stereoisomers (enantiomers or diastereomers) in which one stereoisomer (enantiomer or diastereomer) is present in a greater proportion than another or the other.
In the case of compounds of the formula (I), stereoisomerically enriched means, by way of example and preferably, a content of one stereoisomer of from 50% to 100%, particularly preferably from 70% to 100% and very particularly preferably from 95 to 100%.
Particularly preferred stereoisomerically enriched compounds are enantiomerically enriched compounds.
For the purposes of the invention, asymmetric catalytic processes are syntheses of chiral compounds which take place in the presence of catalysts and in which the products are formed in stereoisomerically enriched form.
At this point, it may be pointed out that all combinations of preferred ranges given below for compounds of the formula (I) are encompassed by the invention.
Aryl is generally, in each case independently, a heteroaromatic radical having from 5 to 14 skeletal carbon atoms in which no, one, two, three or four skeletal carbon atoms per ring, but at least one skeletal carbon atom in the total molecule, can be replaced by heteroatoms selected from the group consisting of nitrogen, sulphur and oxygen or a carbocyclic aromatic radical having from 6 to 14 skeletal carbon atoms. It may be pointed out that, for the purposes of the present invention, heteroatoms are counted as skeletal carbon atoms in the interests of simplicity. In this sense, pyridine, for example, is accordingly a C6-aryl radical.
Examples of monocyclic, bicyclic or tricyclic carbocyclic aromatic radicals having from 6 to 14 skeletal carbon atoms are phenyl, biphenyl, naphthyl, phenanthrenyl, anthracenyl and fluorenyl; monocyclic, bicyclic or tricyclic heteroaromatic radicals having from 5 to 14 skeletal carbon atoms in which no, one, two or three skeletal carbon atoms per ring, but at least one skeletal carbon atom in the total molecule, can be replaced by heteroatoms selected from the group consisting of nitrogen, sulphur and oxygen, are, for example, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, imidazolyl, oxazolyl, benzofuranyl, triazolyl, tetrazolyl, furanyl, thiophenyl, dibenzofuranyl, indolyl or quinolinyl.
Furthermore, the carbocyclic aromatic radical or heteroaromatic radical can be substituted by up to five identical or different substituents per ring which are selected from the group consisting of hydroxy, chlorine, fluorine, iodine, bromine, cyano, nitro, nitroso, tri(C1-C8-alkyl)siloxyl and radicals of the formulae (II) and (IIIa) to (IIIg).
For the purposes of the invention, the definitions and preferred ranges also apply analogously to aryloxy substituents and the aryl part of an arylalkyl radical.
Protected formyl is a formyl radical which has been protected by conversion into an aminal, acetal or mixed aminal-acetal, with the aminals, acetals and mixed aminal-acetals being able to be acyclic or cyclic.
Protected formyl is, by way of example and preferably, a 1,1-(2,4-dioxycyclopentanediyl) radical.
For the purposes of the invention, alkyl or alkylene, or alkoxy or alkenyl, are each, independently of one another, a straight-chain, cyclic, branched or unbranched alkyl or alkylene or alkenyl or alkoxy radical which may be further substituted by C1-C4-alkoxy so that each carbon atom of the alkyl or alkylene or alkoxy or alkenyl radical bears not more than one heteroatom selected from the group consisting of oxygen, nitrogen and sulphur.
The same applies to the alkylene part of an arylalkyl radical.
For the purposes of the invention, C1-C6-alkyl is, for example, methyl, ethyl, 2-ethoxyethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, cyclohexyl or n-hexyl, C1-C8-alkyl may also be, for example, n-heptyl, n-octyl or isooctyl, C1-C12-alkyl, may also be, for example, norbornyl, adamantyl, n-decyl or n-dodecyl and C1-C18-alkyl may also be n-hexadecyl or n-octadecyl.
For the purposes of the invention, C1-C4-alkylene is, for example, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 1,1-butylene, 1,2-butylene, 2,3-butylene and 1,4-butylene, and C1-C8-alkylene may also be 1,5-pentylene, 1,6-hexylene, 1,1-cyclohexylene, 1,4-cyclohexylene, 1,2-cyclohexylene and 1,8-octylene.
For the purposes of the invention, C1-C4-alkoxy is, for example, methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy or tert-butoxy, and C1-C8-alkoxy may also be cyclohexyloxy.
For the purposes of the invention, C2-C8-alkenyl is, for example, allyl, 3-propenyl or 4-butenyl.
For the purposes of the invention, haloalkyl and haloalkoxy are each, independently of one another, a straight-chain, cyclic, branched or unbranched alkyl or alkoxy radical which may be monosubstituted, polysubstituted or persubstituted by halogen atoms. Radicals which are persubstituted by fluorine are referred to as perfluoroalkyl or perfluoroalkoxy.
For the purposes of the invention, C1-C6-haloalkyl is, for example, trifluoromethyl, 2,2,2-trifluoroethyl, chloromethyl, fluoromethyl, bromomethyl, 2-bromoethyl, 2-chloroethyl, nonafluorobutyl, C1-C8-haloalkyl may also be, for example, n-perfluorooctyl, and C1-C12-haloalkyl may also be, for example, n-perfluorododecyl.
For the purposes of the invention, C1-C4-haloalkoxy is, for example, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-chloroethoxy, heptafluoroisopropoxy, and C1-C8-haloalkoxy may also be n-perfluorooctyloxy.
The preferred substitution pattern is defined below:
Very particularly preferred compounds of the formula (I) are:
(S)- and (R)-10-phenyl-5-diphenylphosphanyl-5H-dibenzo[a,d]cycloheptene (S-phtropppPh, R-PhtroppPh), (S)- and (R)-10-phenyl-5-di(o-tolyl)phosphanyl-5H-dibenzo[a,d]cycloheptene (S-Phtroppo-Tol, R-Phtroppo-Tol), (S)- and (R)-10-phenyl-5-di(m-tolyl)phosphanyl-5H-dibenzo[a,d]cycloheptene (S-Phtroppm-Tol R-Phtroppm-Tol) and (S)- and (R)-10-phenyl-5-di(p-tolyl)phosphanyl-5H-dibenzo[a,d]cycloheptene (S-Phtroppp-Tol R-Phtroppp-Tol) and greater preference being given to (S)- and (R)-10-phenyl-5-diphenylphosphanyl-5H-dibenzo[a,d]cycloheptene (S-PhtroppPh, R-PhtroppPh).
Furthermore, the invention encompasses a process for preparing compounds of the formula (I), which is characterized in that
In step a) of the process of the invention, the compounds of the formula (IV) are reacted with compounds of the formula (V) in the presence of a catalyst to form compounds of the formula (VI). The reaction can, if desired and preferably, be carried out in the presence of an organic solvent. Suitable catalysts are, in particular, ones which can be used for reactions of the Heck or Suzuki type, for example palladium complexes. In a preferred embodiment, compounds of the formula (W) are reacted with arylboronic acids of the formula (V) in the presence of tetrakis(triphenylphosphine)palladium and an alkali metal carbonate in step a).
In step b) of the process of the invention, the compounds of the formula (VI) are reacted with compounds of the formula (VII) in the presence of acid to form compounds of the formula (VIII). The reaction can, if desired and preferably, be carried out in the presence of an organic solvent, provided that the solvent is at least essentially inert toward the acid used in the particular case.
Suitable organic solvents are, for example:
Aliphatic or aromatic, halogenated or unhalogenated hydrocarbons such as various petroleum spirits, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, various petroleum ethers, hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachlorite; ethers such as diethyl ether, methyl tert-butyl ether, diisopropyl ether, dioxane, tetrahydrofuran or ethylene glycol dimethyl or -diethyl ether; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-formanilide, N-methylpyrrolidone, N-methylcaprolactam or hexamethylphosphoramide; sulphoxides, such as dimethyl sulphoxide, sulphones such as tetramethylene sulphone, alcohols such as methanol, ethanol, n- or i-propanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, or mixtures of such organic solvents. Preferred organic solvents are ethers.
Preferred acids are ones which, based on an aqueous reference scale and 25° C., a pKa of 5.5 or less.
These are, for example, (C1-C12-alkyl)carboxylic acids, (C1-C12-haloalkyl)carboxylic acids, (C1-C12-haloalkyl)sulphonic acids, (C1-C12-alkyl)sulphonic acids, (C5-C14-aryl)sulphonic acids, hydrogen chloride, hydrogen bromide and hydrogen iodide, if desired as a solution in acetic acid, sulphuric acid, orthophosphoric and polyphosphoric acids, hexafluorophosphoric acid and tetrafluoroboric acid.
In step c) of the process of the invention, the separation of stereoisomers is carried out. In the case of mixtures of diastereomers, the separation can be carried out, for example, chromatographically or by fractional crystallization, while in the case of mixtures of enantiomers it can be carried out, for example, by fractional crystallization in the presence of enantiomerically enriched auxiliary reagent or by chromatography on an at least enantiomerically enriched column material.
In step d) of the process of the invention, stereoisomerically enriched compounds of the formula (VIII) are reduced to compounds of the formula (I). This reduction preferably takes place in the presence of silicon-hydrogen compounds. Preferred silicon-hydrogen compounds are polymethylhydrosiloxane (PHMS) or compounds of the formula (IX),
(R8)xSiH(4-x) (IX)
where
The compounds of the formula (I) which can be prepared according to the invention are particularly suitable for use as ligands in asymmetric catalytic processes.
The scope of the invention therefore also encompasses a process for preparing stereoisomerically enriched chiral compounds, which is characterized in that it is carried out in the presence of compounds of the formula (I).
Catalysts suitable for use in asymmetric catalytic processes are, in particular, ones which contain isolated transition metal complexes of the compounds of the formula (I) and also ones which contain transition metal complexes produced in a reaction medium from transition metal compounds and compounds of the formula (I). The catalysts mentioned are likewise encompassed by the invention. The transition metal complexes described can, if desired, be present in the form of isomers such as cis/trans isomers, coordination isomers or solvation isomers. Such isomers are likewise encompassed by the invention.
Preferred transition metal complexes are ones which contain at least one transition metal selected from the group consisting of cobalt, rhodium, iridium, nickel, palladium, platinum, copper, osmium and ruthenium and at least one compound of the formula (I).
Preferred transition metals are selected from the group consisting of rhodium, iridium, nickel, palladium and ruthenium, and particularly preferred transition metals are selected from the group consisting of iridium and rhodium.
Suitable transition metal compounds from which transition metal complexes according to the invention can be prepared using compounds of the formula (I) are, for example, compounds of the formula (Xa)
M1(Y1)p (Xa)
where
Further suitable transition metal compounds are, for example, Ni(1,5-cyclooctadiene)2, Pd2(dibenzylideneacetone)3, Pt(norbornene)3, Ir(pyridine)2(1,5-cyclooctadiene), [Cu(CH3CN)4]BF4 and [Cu(CH3CN)4]PF6 or multinuclear bridged complexes such as [Rh(1,5-cyclooctadiene)Cl]2, [Rh(1,5-cyclooctadiene)OH]2 and [Rh(1,5-cyclooctadiene)Br]2, [Rh(ethene)2Cl]2, [Rh(cyclooctene)2Cl]2 or the analogous iridium compounds.
Preferred metal compounds are:
[Rh2(μ2-Cl)2(CO)4], [Ir2(μ2—Cl)2(CO)4], [Ir2(μ2—Cl)2(coe)4], [Rh2(μ2-Cl)2(coe)4], [Rh2(μ2-Cl)2(C2H4)4], [Ir2(μ2-Cl)2(C2H4)4] [Rh(cod)Cl]2, [Rh(cod)OH]2, [Rh(cod)2Br], [Rh(cod)2]ClO4, [Rh(cod)2]BF4, [Rh(cod)2]PF6, [Rh(cod)2]OTf, [Rh(cod)2]BAr4 (Ar=3,5-bistrifluoromethylphenyl) [Rh(cod)2]SbF6, [Ir(cod)Cl]2, [Ir(cod)OH]2, [Ir(cod)2Br], [Ir(cod)2]ClO4, [Ir(cod)2]BF4, [Ir(cod)2]PF6, [Ir(cod)2]OTf, [Ir(cod)2]BAr4 (Ar=3,5-bistrifluoromethylphenyl) [Ir(cod)2]SbF6, [Rh(nbd)Cl]2, (nbd=norbornadiene) [Rh(nbd)2Br], [Rh(nbd)2]ClO4, [Rh(nbd)2]BF4, [Rh(nbd)2]PF6, [Rh(nbd)2]OTf, [Rh(nbd)2]BAr4 (Ar=3,5-bistrifluoromethylphenyl) [Rh(nbd)2]SbF6 RuCl2(nbd), [Ir(nbd)2]PF6, [Ir(nbd)2]ClO4, [Ir(nbd)2]SbF6 [Ir(nbd)2]BF4, [Ir(nbd)2]OTf, [Ir(nbd)2]BAr4 (Ar=3,5-bistrifluoromethylphenyl) and Ir(pyridine)2(nbd).
The molar amount of the transition metal in the transition metal compound used can be, for example, from 50 to 300 mol %, based on the compound of the formula (I) used;
when isolated transition metal complexes of the compounds of the formula (I) are used, the ratio of transition metal to compounds of the formula (I) is preferably 1:1 or 1:2.
Particularly preferred isolated complexes are:
S,S- and R,R-[Ir(PhtroppPh)2]OTf, S- and R-[Rh(cod)(PhtroppPh)]OTf, S- and R-[Rh(MeCN)2(PhtroppPh)]PF6 and S- and R-[RhCl(MeCN)(PhtroppPh)].
The catalysts of the invention are particularly suitable for use in processes for preparing stereoisomerically enriched compounds.
Preferred processes for preparing stereoisomerically enriched compounds are asymmetric 1,4-additions such as, in particular, the coupling of arylboronic acids with α,β-unsaturated ketones and α,β-unsaturated carboxylic acid derivatives and also asymmetric hydrogenations, in particular of α,β-unsaturated carboxylic acid derivatives.
The following examples illustrate the advantageous effects of the invention.
In a 250 ml flask, 10-broml-5H-dibenzo[a,d]cyclohepten-5-ol (4.0 g, 13.9 mmol) was admixed with 100 ml of dimethoxyethane. Pd(OAc)2 (93 mg, 0.4 mmol), Ph3P (349 mg, 1.3 mmol), a degassed solution of Na2CO3 (9 ml, 2 M) and PhB(OH)2 (2.0 g, 16.6 mmol) were added and the mixture was refluxed for 18 hours. After addition of 30 ml of H2O, the product was extracted with ethyl acetate (3×30 ml), the combined organic phases were dried over Na2SO4, filtered and freed of volatile compounds. The resulting residue was purified by chromatography (eluent: AcOEt/n-hexane 2/8). Yield: 3.9 g (97%).
13C-NMR (75.5 MHz, CDCl3): δ70.9 (br, CHbenz), 120.9 (br, 2C, CHar), 125.9 (br, CHar), 126.1 (br, 1C, CHar), 127.72 (CHar), 127.9 (br, CHar), 128.34 (CHar), 128.45 (CHar), 128.92 (CHar), 129.1 (br, CHar), 129.97 (br, 2C, CHar), 132.4 (br, Cquat), 133.6 (br, Cquat), 141.8 (br, Cquat), 142.6 (br, Cquat), 143.3 (br, Cquat), 143.57(Cquat).
520 mg of 5-hydroxy-10-phenyl-dibenzo[a,d]cycloheptene (1.8 mmol) in 15 ml of CH2Cl2 were admixed with 0.15 ml of CF3COOH (1.13 mmol). The solution became red and 0.33 ml of chlorodiphenylphosphane (2.26 mmol) was added. Another 0.15 ml of CF3COOH (1.13 mmol) was subsequently added to the reaction mixture. This gave a clear yellow solution which was stirred at room temperature for 2 hours. 20 ml of Na2CO3 (18% in H2O) were subsequently added. The organic phase was separated off and the aqueous phase was extracted with 3×20 ml of CH2Cl2. The combined organic phases were dried over MgSO4 and the solvent was subsequently evaporated. The racemidic product was obtained (660 mg, 80%). The two enantiomers were subsequently separated by means of preparative HPLC (column material OD-H [cellulose triphenylcarbamate] using a mixture of n-hexane/isopropanol 98/2 (% by volume) as eluent:
Retention times: R-isomer: 8.0 min., [α]D=−27.8, S isomer: 10.4 min., [α]D=20.9. Melting point: 95-100° C., 31P NMR: 27.3 ppm-1H NMR: 5.15 (d, 2JPH=13 Hz, 1H, CHP), 6.50 (s, 1H, ═CH), 7.0-7.9 (m, 23H, Harom).
2.0 g of S-(5-diphenyloxophosphoranyl-10-phenyldibenzo[a,d]cycloheptene) (4.3 mmol) were dissolved in 100 ml of toluene and 11.5 g of SiHCl3 (85 mmol) were added. The reaction mixture was heated at 90° C. for 18 hours. After cooling, 70 ml of 20% deoxygenated NaOH were added with cooling. The organic phase was separated off and dried over MgSO4. Taking off all volatile components and recrystallization from methylene chloride gave the product (1.75 g, 90%) in the form of colourless crystals.
31P NMR (CDCl3): −13.1 ppm-1H NMR: 4.99 (d, 2JPH=6 Hz, 1H, CHP), 6.90 (d, JPH=6 Hz, 1H, ═CH), 7.0-7.53 (m, 23H, Harom).
A solution of [Rh(cod)2]OTf (0.08 g, 0.17 mmol) in 2 ml of CH2Cl2 was added dropwise to a solution of S-phtroppph (0.08 g, 0.17 mmol) in 1 ml of CH2Cl2. The red solution was stirred for 30 minutes and the solution was subsequently evaporated to dryness. The red solid was dissolved in a little dichloromethane and the solution was covered with a layer of hexane. After 18 hours, 0.13 g of red crystals were obtained (yield: 90%).
31P-NMR (121.5 MHz, CDCl3): δ=79.1 (d, 1JRhP=163.2)
103Rh-NMR (12.6 MHz, CDCl3): δ=377.1 (d, 1JRhP=163.2).
In a 10 ml Schlenk flask, [Rh2(μ2—Cl)2(CO)4] (40 mg, 0.10 mmol), S-phtroppph (93 mg, 0.20 mmol) and TlPF6 (72 mg, 0.20 mmol) were admixed with 3 ml of CH3CN. The liberation of CO and the precipitation of TlCl were immediately observed. The orange suspension was filtered through Celite and the filtrate was evaporated to dryness under reduced pressure. This gave 156 mg (95% of theory) of the desired product.
31P-NMR (121.5 MHz, CD3CN): δ=−144.4 (sept, 1JPF=706.5, 1 P, PF6) 93.8 (d, 1JRhp=158.2).
103Rh-NMR (12.6 MHz, CD3CN): δ=596.2 (dd, 1JRhP=158.2, 2JRhH=2.9).
A mixture of [Rh2(μ2-Cl)2(C2H4)4] (9 mg, 23 μmol) and S-PhtroppPh (21 mg, 46 μmol) in 1 ml of THF was stirred at room temperature for 1 hour. The solvent was removed and [Rh2(μ2-Cl)2(PhtroppPh)2] was precipitated as an orange powder from methylene chloride and hexane (25 mg, 93%). The NMR spectrum was recorded in CD3CN, which led to the formation of [RhCl(CD3CN)(PhtroppPh)].
31P-NMR (121.5 MHz, CDCl3, 5% CD3CN): δ=99.3 (d, JRhP=197).
A solution of [Ir2(μ2—Cl)2(coe)4] (coe=cyclooctene, 200 mg, 0.22 mmol) in 5 ml of THF was added dropwise to a solution of S-PhtroppPh (403 mg, 0.89 mmol) in 5 ml of THF and the mixture was stirred for one hour. AgOTf (114 mg, 0.45 mmol) was added and the mixture was stirred for another 5 hours. The suspension formed was filtered and the filtrate was evaporated to dryness. Reprecipitation from methylene chloride and hexane gave the product in the form of deep red crystals (540 mg, yield: 97%).
31P-NMR (121.5 MHz, CD2Cl2): δ=52.9 (s)
Catalyst Experiments
A solution of [Rh2(μ2—Cl)2(C2H4)4] (10 mg, 26 μmol) and S-PhtroppPh (24 mg, 53 μmol) in 1,4-dioxane (3 ml) was stirred at room temperature for 15 minutes, subsequently admixed with KOH (0.3 ml of a 1.7 M solution, 0.5 mmol) and the mixture was stirred for another 5 minutes. PhB(OH)2 (370 mg, 3.0 mmol) and, 5 minutes later, cyclohex-2-enone (103 mg, 1.0 mmol) were added to the orange solution. The mixture was maintained at 55° C. for 2 hours and the course of the reaction was followed by GC (capillary HP-5: 90° C. for 3 min, then heating to 180° C. at a heating rate of 3° C. min−1; flow rate: 1.6 ml of H2 min−1; retention times: 2.93 min. and 18.6 min). Under these conditions, the following results were obtained:
5 mol % of catalyst: 86% conversion; 3 mol % of catalyst: 81% conversion; 1 mol % of catalyst: 51% conversion. The enantiomeric excess (92-95%) was determined by means of chiral HPLC (Chiralcel OD-H, n-hexane: iPrOH=98: 2, retention times: R: 26.3 min.; S: 31.3 min. The product formed predominantly had the R configuration.
A solution of [Rh2(μ2-Cl)2(C2H4)4] (5 mg, 13 μmol) and S-PhtroppPh (13 mg, 28 μmol) in 1,4-dioxane (3 ml) was stirred at room temperature for 15 minutes, subsequently admixed with KOH (0.25 ml of a 1.0 M solution, 0.5 mmol) and the mixture was stirred for another 5 minutes.
PhB(OH)2 (185 mg, 1.5 mmol) and, 5 min later, (1-benzylpyrrole-2,5-dione) (97 mg, 0.5 mmol) were added to the orange solution. The mixture was maintained at 55° C. for 2 hours and the course of the reaction was followed by GC (capillary HP-5: 90° C. for 3 min, then heating to 180° C. at heating rate of 4° C. min−1; flow rate: 1.6 ml of H2 min−1; retention times 23.1 min. and 34.1 min.). Under these conditions, the following results were obtained: yield: 93%, the enantiomeric excess (79%) was determined by means of chiral HPLC (Chiralcel OD-H, n-hexane: iPrOH=98:2, retention times: R: 25.3 min.; S: 21.1 min. The product formed predominantly had the R configuration. Complete conversion was observed at a catalyst usage of 0.1%.
| Number | Date | Country | Kind |
|---|---|---|---|
| 10 2005 062 363.8 | Dec 2005 | DE | national |
