Nitrogen-containing monodentate phosphines and their use in catalysis

The present invention relates to novel ligands for transition metals, to their preparation and to their use in catalytic reactions, especially for the improvement of haloaromatic compounds.

Haloaromatic compounds, including especially chloroaromatic compounds, are intermediates which can be used variously in the chemical industry and which serve as preliminary products for the production of agricultural intermediates, pharmaceuticals, colourings, materials, etc. Vinyl halides are also important intermediates which are used as starting materials for polymers and in the production of the above-mentioned products.

Catalysts which are frequently employed for the functionalisation of haloaromatic compounds or vinyl halides to aromatic olefins or dienes (Heck reaction, Stille reaction), biaryls (Suzuki reaction), alkynes (Sonogashira reaction), carboxylic acid derivatives (Heck carbonylation), amines (Buchwald-Hartwig reaction) are palladium catalysts and nickel catalysts. Palladium catalysts are generally advantageous, owing to the wide applicability of coupling substrates with in some cases good catalytic activities, while nickel catalysts have advantages in the field of the reaction of chloroaromatic compounds and vinyl chlorides. Moreover, nickel is more readily available than palladium.

Palladium and nickel catalysts used within the scope of the activation and further improvement of haloaromatic compounds are both palladium(II) and/or nickel(II) complexes as well as palladium(0) and/or nickel(0) complexes, although it is known that palladium(0) and nickel(0) compounds are the actual catalysts of the reaction. In particular, according to information in the literature, coordinatively-unsaturated 14- and 16-electron palladium(0) and nickel(0) complexes stabilised with donor ligands such as phosphanes are formulated as the active species.

When iodides are used as starting materials in coupling reactions it is also possible to dispense with phosphane ligands. However, aryl iodides and vinyl iodides are starting materials which are scarcely available and therefore very expensive, and their reaction additionally yields stoichiometric amounts of iodine salt waste products. If other starting materials are used in the Heck reaction, such as aryl bromides or aryl chlorides, the addition of stabilising and activating ligands is necessary if catalytically effective reaction of the starting materials is to be possible.

The catalyst systems described for olefinations, alkynylations, carbonylations, arylations, aminations and similar reactions frequently have satisfactory catalytic turnover numbers (TON) only with uneconomical starting materials such as iodoaromatic compounds and activated bromoaromatic compounds. Otherwise, in the case of deactivated bromoaromatic compounds and, especially, in the case of chloroaromatic compounds, large amounts of catalyst—usually more than 1 mol. %—must generally be added in order to achieve industrially usable yields (>90%). Moreover, owing to the complexity of the reaction mixtures, simple recycling of the catalyst is not possible, so that recovery of the catalyst also gives rise to high costs, which generally stand in the way of industrial implementation. Furthermore, it is undesirable to work with large amounts of catalyst, especially when preparing active ingredients or preliminary products for active ingredients, because catalyst residues otherwise remain in the product in this case.

More recent active catalyst systems are based on cyclopalladated phosphanes (W. A. Herrmann, C. BroBmer, K. Öfele, C.-P. Reisinger, T. Priermeier, M. Beller, H. Fischer, Angew. Chem. 1995, 107, 1989; Angew. Chem. Int. Ed. Engl. 1995, 34, 1844) or mixtures of sterically demanding arylphosphanes (J. P. Wolfe, S. L. Buchwald, Angew. Chem. 1999, 111, 2570; Angew. Chem. Int. Ed. Engl. 1999, 38, 2413) or tri-tert.-butylphosphane (A. F. Littke, G. C. Fu, Angew. Chem. 1998, 110, 3586; Angew. Chem. Int. Ed. Engl. 1998, 37, 3387) with palladium salts or palladium. complexes.

However, chloroaromatic compounds can generally not be activated in an industrially satisfactory manner even using these catalysts. Accordingly, in order to achieve high yields, comparatively large, amounts of catalyst must be used. Therefore, despite all the further developments which have been made to catalysts in recent years, only a small number of industrial reactions of the arylation, carbonylation, olefination, etc. of chloroaromatic compounds have hitherto become known.

For the mentioned reasons, the object underlying the present invention was to provide novel ligands and catalysts which are suitable for large-scale applications, are readily accessible and convert chloro- and bromo-aromatic compounds as well as corresponding vinyl compounds to the respective coupling products in high yield and with high purity, with high catalyst productivity.

This object is achieved according to the invention by novel phosphane ligands of formula (I)

wherein

X independently of Y represents a nitrogen atom or a C—R 2 group and Y independently of X represents a nitrogen atom or a C—R 9 group, R 1 for each of the two R 1 groups independently of the other represents a radical selected from the group C 1 -C 24 -alkyl,

C 3 -C 20 -cycloalkyl, which includes especially both monocyclic and also bi- and tri-cyclic cycloalkyl radicals, C 5 -C 14 -aryl, which includes especially the phenyl, naphthyl, fluorenyl radical, C 2 -C 13 -heteroaryl, wherein the number of hetero atoms, selected from the group N, O, S, may be from 1 to 2, wherein the two radicals R 1 may also be linked to one another, there preferably being formed a 4- to 8-membered saturated, unsaturated or aromatic ring. The above-mentioned radicals R 1 may themselves each be mono- or poly-substituted. These substituents, independently of one another, may be hydrogen, C 1 -C 20 -alkyl, C 2 -C 20 -alkenyl, C 3 -C 8 -cycloalkyl, C 2 -C 9 -hetero-alkyl C 5 -C 10 -aryl, C 2 -C 9 -heteroaryl, wherein the number of hetero atoms, especially from the group N, O, S, may be from 1 to 4, C 1 -C 20 -alkoxy, preferably C 1 -C 10 -alkoxy, particularly preferably OMe, C 1 -C 10 -halo-alkyl, preferably trifluoromethyl, hydroxy, secondary, tertiary amino groups of the forms NH—(C 1 -C 20 -alkyl), NH—(C 5 -C 10 -aryl), N(C 1 -C 20 -alkyl) 2 , N(C 1 -C 20 -alkyl) (C 5 -C 10 -aryl), N(C 5 -C 10 -aryl) 2 , N(C 1 -C 20 -alkyl/C 5 -C 10 -aryl 3 ) 3 + , NH—CO—C 1 -C 20 -alkyl, NH—CO—C 5 -C 10 -aryl, carboxylato of the forms COOH and COOQ (wherein Q represents either a monovalent cation or C 1 -C 8 -alkyl), C 1 -C 6 -acyloxy, sulfinato, sulfonato of the forms SO 3 H and SO 3 Q (wherein Q represents either a monovalent cation, C 1 -C 20 -alkyl or C 5 -C 10 -aryl) tri-C 1 -C 6 -alkylsilyl, especially SiMe 3 , wherein two of the mentioned substituents may also be bridged with one another, there preferably being formed a 4- to 8-membered ring which can be further substituted preferably by linear or branched C 1 -C 10 -alkyl, C 6 -aryl, benzyl, C 1 -C 10 -alkoxy, hydroxy or benzyloxy groups.

R 2 -R 9 represent a hydrogen, alkyl, alkenyl, cycloalkyl, aromatic or heteroaromatic aryl, O-alkyl, NH-alkyl, N-(alkyl) 2 , O-(aryl), NH-(aryl), N-(alkyl) (aryl), O—CO -alkyl, O—CO-aryl, F, Si(alkyl) 3 , CF 3 , CN, CO 2 H, COH, SO 3 H, CONH 2 , CONH(alkyl), CON(alkyl) 2 , SO 2 (alkyl), SO(alkyl), SO(aryl), SO 2 (aryl), SO 3 (alkyl), SO 3 (aryl), S-alkyl, S-aryl, NH—CO(alkyl), CO 2 (alkyl), CONH 2 , CO(alkyl), NHCOH, NHCO 2 (alkyl), CO(aryl), CO 2 (aryl) radical,

wherein two or more adjacent radicals, each independently of the other(s), may also be linked to one another so that a condensed ring system is present and wherein in R 2 to R 9 alkyl represents a hydrocarbon radical having from 1 to 20 carbon atoms which may in each case be linear or branched, alkenyl represents a mono- or poly-unsaturated hydrocarbon radical having from 2 to 20 carbon atoms which may in each case be linear or branched, and cycloalkyl represents a hydrocarbon having from 3 to 20 carbon atoms, wherein the alkyl, alkenyl and cycloalkyl groups may also carry further substituents as defined for R 1 . Preferred substituents in this connection are selected from the group Br, Cl, F, (C 1 -C 12 )-alkyl, O—(C 1 -C 12 )-alkyl, phenyl, O-phenyl, NH((C 1 -C 12 )-alkyl), N((C 1 -C 12 )-alkyl) 2 , and aryl represents a 5- to 14-membered aromatic radical in which from one to four carbon atoms may also be replaced by hetero atoms from the group nitrogen, oxygen and sulfur so that a 5- to 14-membered hetero-aromatic radical is present and wherein the aryl or heteroaryl radical may carry further substituents as defined for R 1 , preferred substituents being selected from the group Br, Cl, F, (C 1 -C 12 )-alkyl, O—(C 1 -C 12 ) -alkyl, phenyl, O-phenyl, NH 2 , NH((C 1 -C 12 )-alkyl), N((C 1 -C 12 )-alkyl) 2 .

The mentioned alkyl radicals have preferably from 1 to 10 carbon atoms, particularly preferably from 1 to 5. The alkenyl radicals have preferably from 2 to 10 carbon atoms, particularly preferably from 2 to 5. The cycloalkyl radicals have preferably from 3 to 8 carbon atoms. The aryl radicals have preferably from 6 to 10 carbon atoms, the heteroaryl radicals from 4 to 9.

Preference is given to ligands wherein X is CR 2 and Y is CR 9 , yielding compounds of formula (II)

wherein the radicals R 1 to R 9 are as defined above. In a further preferred embodiment, X is nitrogen and Y is a CR 9 group.

Preferred ligands of formula (I) or (II) carry at least one radical R 1 selected from the group consisting of phenyl, C 1 -C 10 -alkyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-adamantyl, 2-adamantyl, 5H-dibenzophospholyl, 9-phospha-bicyclo[3.3.1]nonanyl, 9-phosphabicyclo[4.2.1]nonanyl radicals. Examples of preferred C 1 -C 10 -alkyl- radicals are methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methyl-propyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethyl-propyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methyl-pentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethyl-butyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethyl-butyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, n-heptyl, n-octyl, n-nonyl, n-decyl, particular preference being given especially to the isopropyl radical and the tert-butyl radical.

Preferred radicals R 2 to R 9 are selected from the group hydrogen, C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 1 -C 10 -haloalkyl, C 3 -C 8 -cycloalkyl, C 6 -C 10 -aryl, which includes especially also phenyl, naphthyl, fluorenyl, and C 2 -C 6 -heteroaryl, wherein from 1 to 3 nitrogen atoms or an oxygen or sulfur atom may be present as hetero atom, and wherein two adjacent radicals R 2 to R 9 may be bridged with one another, there preferably being formed a 4- to 8-membered, preferably aromatic ring.

The ligands according to the invention can be prepared by reacting the corresponding phenylpyrrole derivative in the presence of a strong base, such as, for example, an alkyl-lithium compound, and subsequently adding a halophosphane, in accordance with the following reaction scheme, which is given by way of example

According to the invention, the novel phosphane ligands are used as catalysts in combination with transition metal complexes or transition metal salts of sub-group VIII of the periodic system of the elements, such as, for example, palladium, nickel, platinum, rhodium, iridium, ruthenium, cobalt. The ligands according to the invention can generally be added in situ to corresponding transition metal precursor compounds and accordingly used for catalytic applications. However, it may occasionally be advantageous for specific mono-, di-, tri- or tetra-phosphane complexes of the mentioned transition metals to be prepared first and subsequently used for catalysis reactions. The catalytic activity can thereby be increased further in some catalyst systems.

As transition metal compounds there are preferably used palladium or nickel compounds and particularly preferably palladium compounds.

The ligands according to the invention are generally added in situ preferably to nickel(II) or palladium(II) salts or to nickel(II), palladium(II) or nickel(0) or palladium(0) complexes. Preferred palladium complexes are, for example, palladium(II) acetate, palladium(II) chloride, palladium(II) bromide, lithium tetrachloropalladate(II), palladium(II) acetylacetonate, palladium(0) -dibenzylidene-acetone complexes, palladium(0) tetrakis(triphenyl-phosphane), palladium(0) bis(tri-o-tolylphosphane), palladium(II) propionate, palladium (II) bis(triphenyl-phosphane) dichloride, palladium(0) diallyl ether complexes, palladium(II) nitrate, palladium(II) chloride bis(acetonitrile), palladium(II) chloride bis(benzo-nitrile).

In catalytic applications, the phosphane ligand is generally used in excess relative to the transition metal. The ratio of transition metal to ligand is preferably from 1:1 to 1;1000. Ratios of transition metal to ligand of from 1:1 to 1:100 are particularly preferred. The exact transition metal/ligand ratio to be used depends on the concrete application, but also on the amount of catalyst used. Accordingly, it is generally customary to use low transition metal/ligand ratios at very low transition metal concentrations (<0.01 mol. %) than at transition metal concentrations of from 0.5 to 0.01 mol. % transition metal.

The catalysts are preferably used at temperatures of from 20 to 200° C.; in many cases, it has proved advantageous to work at temperatures of from 30 to 180° C., preferably from 40 to 160° C. The ligands can also be used without any loss of activity in reactions under pressure, reactions usually being carried out only up to a pressure of 100 bar, but preferably in the range of from normal pressure to 60 bar.

When carrying out catalytic reactions using ligands of formula (I), high turnover rates (TON) can be achieved with a low catalyst concentration. The transition metal is preferably used in a ratio of from 5 mol. % to 0.001 mol. %, particularly preferably from 0.5 mol. % to 0.01 mol. %, relative to the substrate.

The phosphane ligands prepared in accordance with the invention have proved suitable especially as the ligand component for the catalytic preparation of arylated olefins (Heck reactions), biaryls (Suzuki reactions), α-aryl ketones and amines from aryl halides or vinyl halides. However, it is obvious to the person skilled in the art that the novel catalyst systems can also be used to catalyse other transition-metal-catalysed reactions, such as metathesis or hydrogenations of double bonds or carbonyl compounds, but especially palladium- and nickel-catalysed carbonylations of aryl halides, alkynylations using alkynes (Sonogashira couplings), cross-couplings using organometallic reagents, such as, for example, zinc reagents or tin reagents.

A particular advantage of the ligands according to the invention is the high degree of activity induced by the ligands in the activation of readily available but inert chloroaromatic compounds. The described catalyst and ligand systems can accordingly be used for large-scale purposes.

The phosphanes prepared in accordance with the invention can be used in the preparation of aryl olefins, dienes, diaryls, benzoic acid derivatives, acrylic acid derivatives, arylalkanes, alkynes, amines. The compounds so prepared are used, for example, as UV absorbers, as intermediates for pharmaceuticals and agrochemicals, as ligand precursors for metallocene catalysts, as perfumes, as active ingredients having biological activity and as structural units for polymers.

General

Reactions of compounds sensitive to air were carried out in an argon-filled glove-box or in standard Schlenk tubes. The solvents tetrahydrofuran (THF), diethyl ether and dichloromethane were degassed and rendered absolute by means of a solvent-drying installation (Innovative Technologies) by filtration through a column packed with activated aluminium oxide. Toluene and pentane were additionally freed of oxygen using a column packed with a copper catalyst.

The Examples which follow serve to explain the invention without limiting it thereto.

Preparation of Ligands 1 to 3 (L1 to L3):

10 mmol. of phenylpyrrole are dissolved under argon in 20 ml of absolute hexane. 10 mmol. of TMEDA and 10 mmol. of n-BuLi (1.6 M in hexane) are added at room temperature. After three hours' heating under reflux, a yellow suspension is obtained. It is cooled to room temperature, and 10 mmol. of C1-PR 1 2 are slowly added thereto. After reacting for one hour under reflux, hydrolysis is carried out at room temperature using 15 ml of degassed water. The organic phase is transferred to a separating funnel, under argon, with the aid of a cannula. The aqueous phase is extracted twice using 15 ml of hexane each time. The hexane fractions are likewise transferred to the separating funnel. The combined organic phases are washed with 15 ml of degassed water and dried over degassed sodium sulfate. The solvents are distilled off and the viscous residue is dissolved in methanol with heating. After one day at room temperature, the mixture is cooled for four hours at 0° C. The resulting white solid is filtered off and dried in vacuo (purity 90-95%).

Yields:

PR 1 2 =PCy 2 72% ( 31 P—NMR: −28.0 ppm) (L1; N—PHOS-Cy):

PR 1 2 =PPh 2 64% ( 31 P—NMR: −29.8 ppm) (L2; N—PHOS-Ph)

PR 1 2 =P t Bu 2 40% ( 31 P—NMR: 3.6 ppm) (L3; N—PHOS- t Bu)

CATALYSIS EXAMPLES 1 to 32

Suzuki Couplings

1.25 mmol. of phenylboronic acid and 2.00 mmol. of base are weighed into 2.5 ml glass bottles. These bottles are purged with argon and sealed. All further stock solutions are prepared under argon.

Solution S-1: 147 mmol. of 2-chlorotoluene, 58 mmol. of tetradecane, 155 ml of abs. toluene Solution S-2: 150 mmol. of 4-chloroanisole, 57 mmol. of tetradecane, 154 ml of abs. toluene Solution M-1: 0.073 mmol. pd of palladium(II) acetate, 49 ml of abs. toluene Solution M-2: 0.065 mmol. pd of tris-(dibenzylideneacetone)-dipalladium(0), 49 ml of abs. toluene Solution L-1: 0.04 mmol. of N—PHOS-Cy (L1), 10 abs. toluene Solution L-2: 0.08 mmol. of N—PHOS-tBu (L3), 21 abs. toluene

The following solutions are mixed under Ar and stirred for about 1 hour at room temperature (reaction metal precursor with ligand):

A Vantage synthesizer is used to pipette the following amounts of the resulting solutions into the Vantage vials:

1. 1.25 ml of S-1 (No. 1-8), (No. 17-24) 1.25 ml of S-2 (No. 9-16), (No. 25-32) 2. 1.25 ml of M-L-1 (No. 1-16) or 1.25 ml of M-L-2 (No. 17-32).

Using the Vantage mixing/heating unit, the Vantage vials so filled are heated for 4.0 hours at 110° C. (Vantage setting) with shaking (1000 rpm) (heating phase 0.5 h/internal temperature about 120° C.).

After the reaction, 1.0 ml of each reaction solution is filtered over silica gel. The solution so obtained is analysed by means of GC. The yields of the individual conversions are summarised in Table 1.

CATALYSIS EXAMPLES 33 to 59

Suzuki Reaction of Aryl Chlorides with Phenylboronic Acid/-pyrrolylphosphanes

R—Ar—Cl+PhB(OH) 2 →R—Ar—Ph

Reagents: 3 nmol. of ArCl, 4.5 mmol. of PhB(OH) 2 , 6 mmol. of K 3 PO 4 , Pd(OAc) 2 , Pd/L=1:2, 6 ml of toluene, 20 hours. The reaction is carried out as a one-pot reaction under protecting gas. Working-up is carried out with 10 ml of each of methylene chloride and 1N sodium hydroxide solution. The reaction is monitored by means of GC, internal GC standard: hexadecane.

The starting materials used and the results of the conversions are summarised in Table 2.

EXAMPLES 60 to 64

Examples of Ligand Syntheses