Patent Application
20080039633
Equation 1 below illustrates the course of the synthesis in the process of the invention:
In equation 1 Hal is fluorine, chlorine, bromine, iodine, alkoxy or a sulfonate leaving group such as trifluoromethanesulfonate (triflate), nonafluorobutanesulfonate (nonaflate), methanesulfonate, benzenesulfonate, para-toluenesulfonate.
The atoms X1-5 are each, independently of one another, carbon or the moieties XiRi (i=1-5) are nitrogen or two adjacent moieties XiRi which are bound to one another by a formal double bond are together 0 (furans), S (thiophenes), NH or NRi (i=1-5) (pyrroles).
Preferred compounds of the formula (I) which can be reacted by the process of the invention are, for example, benzenes, pyridines, pyrimidines, pyrazines, pyridazines, furans, thiophenes, pyrroles, any N-substituted pyrroles or naphthalenes, quinolines, indoles, benzofurans, etc.
The radicals R15 are substituents selected from the group consisting of hydrogen, methyl, ethyl, primary, secondary or tertiary, cyclic or acyclic alkyl radicals which have from 3 to 20 carbon atoms and in which one or more hydrogen atoms may have been replaced by fluorine or chlorine or bromine, e.g. CF3, hydroxy, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, pentafluorosulfuranyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, thio, alkylthio, arylthio, diarylphosphino, dialkylphosphino, alkylarylphosphino, substituted or unsubstituted aminocarbonyl, COO−, alkyl, or aryloxycarbonyl, hydroxyalkyl, alkoxyalkyl, fluorine or chlorine, nitro, cyano, arylsulfone or alkylsulfone, arylsulfonyl or alkylsulfonyl, or two adjacent radicals R15 can together correspond to an aromatic, heteroaromatic or aliphatic fused-on ring.
R′ and R″ can be identical or different and can each be, independently of one another, an alkyl radical selected from the group consisting of hydrogen, C1-, C2-alkyl, straight-chain, branched or cyclic C3-C20-alkyl, substituted or unsubstituted aryl or heteroaryl or an acyl radical selected from the group consisting of formyl, acetyl, linear or branched C3-C20-acetyl and substituted or unsubstituted aroyl or heteroaroyl or together form a ring. R′ and R″ are preferably not simultaneously hydrogen.
Typical examples of compounds II are thus methylamine, ethylamine, 1-methylethylamine, propylamine, 1-methylpropylamine, 2-methylpropylamine, 1,1-dimethylethylamine, butylamine and pentylamine, cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine, phenylamine, benzylamine, morpholin from the group of amines or acetamide, benzamide, 2,2-dimethylpropionamide from the group of amides.
According to the invention, a transition metal or a salt, a complex or a metal-organic compound of a transition metal selected from the group consisting of Ni, Pd, preferably on a support such as carbon, together with a bidentate bis(phosphino)alkanediyl ligand is used as catalyst. The catalyst can be added in finished form or can form in situ, e.g. from a precatalyst by reduction or hydrolysis or from a transition metal salt and an added ligand by complex formation. The catalyst is used in combination with one or more but at least one bidentate bis(phosphino)alkanediyl ligand. The transition metal can be used in any oxidation state. According to the invention, it is used in a molar ratio to the reactant I of from 0.0001 to 100, preferably from 0.01 to 10, particularly preferably from 0.01 to 2.
Preference is given to ligands having the structure shown below
in combination with palladium or nickel as catalyst, where the radicals Ar1-4 are each, independently of one another, an aryl or heteroaryl substituent selected from the group consisting of phenyl, naphthyl, pyridyl, biphenyl and the like in which hydrogen may have been replaced by other radicals such as lower alkyl substituents, halogen atoms, sulfonic acid groups, carboxylic acid groups, lower alkyloxy substituents or the like.
L has the meanings indicated above for the structure depicted.
The addition of Brønsted bases to the reaction mixture is necessary to achieve acceptable reaction rates. Well-suited bases are, for example, hydroxides, alkoxides and fluorides of the alkali metals and alkaline earth metals, carbonates, hydrogencarbonates and phosphates of the alkali metals and mixtures thereof. Particularly useful bases are the bases of the group potassium tert-butoxide, sodium tert-butoxide, cesium tert-butoxide, lithium tert-butoxide and the corresponding isopropoxides for the coupling of amides and the bases of the groups sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate for the coupling of amides. It is usual to use at least the molar amount of base which corresponds to the molar amount of the amine or amide to be coupled, mostly from 1.0 to 6 equivalents, preferably from 1.2 to 3 equivalents, of base based on the compound (II).
The reaction is carried out in a suitable solvent or a single-phase or multiphase solvent mixture which has a sufficient solvent capability for all participating reactants, with heterogeneous reactions also being possible (e.g. use of virtually insoluble bases). The reaction is preferably carried out in polar, aprotic or protic solvents. Well-suited solvents are open-chain and cyclic ethers and diethers, oligoethers and polyethers and also substituted simple or multiple alcohols and substituted or unsubstituted aromatics. Particular preference is given to using a solvent or mixture of a plurality of solvents selected from the group consisting of diglyme, substituted glymes, 1,4-dioxane, isopropanol, tert-butanol, 2,2-dimethyl-1-propanol, toluene, xylene.
The reaction can be carried out at temperatures in the range from room temperature to the boiling point of the solvent used and the pressure used. To achieve a more rapid reaction, preference is given to carrying it out at elevated temperatures in the range from 0 to 240° C. Particular preference is given to the temperature range from 20 to 200° C., in particular from 50 to 150° C.
The concentration of the reactants can be varied within a wide range. The reaction is advantageously carried out at a very high concentration, with the solubilities of the reactants and reagents in the respective reaction medium having to be taken into account. The reaction is preferably carried out in the range from 0.05 to 5 mol/l based on the reactants present in a substoichiometric amount (depending on the relative prices of the reactants).
Amine or amide and aromatic or heteroaromatic reactant (I) can be used in a molar ratio of from 10:1 to 1:10, preferably from 3:1 to 1:3 and particularly preferably from 1.2:1 to 1:1.2.
In a preferred embodiment, all materials are placed in the reaction vessel and the mixture is heated to the reaction temperature while stirring. In a further preferred embodiment, which is particularly suitable for use on a large scale, the compound (II) and, if appropriate, further reactants, e.g. base and catalyst or precatalyst, are metered into the reaction mixture during the reaction. As an alternative, the reaction can also be carried out in an addition-controlled fashion by slow addition of the base. The selectivities are, according to the invention, very high and it is usually possible to find conditions under which no further by-products apart from very small amounts of dehalogenation product can be detected.
The work-up is usually carried out, after removal of inorganic salts by means of water, by customary methods, i.e. in the laboratory by chromatography and in industry by distillation or recrystallization.
The process of the invention is illustrated by the following examples without the invention being restricted thereto:
5.8 g of sodium t-butoxide (60.1 mmol), 5.2 g of 3-methylpiperidine (52.6 mmol) and 8.5 g of 4-bromobenzotrifluoride (37.6 mmol) are dissolved or suspended in 50 ml of dioxane and admixed at 80° C. with a suspension of 0.167 g of palladium(II) acetate (2 mol %) and 0.43 g of 2,2-dimethyl-1,3-bis(diphenylphosphino)propane (2.5 mol %). The mixture is subsequently refluxed and the conversion is monitored by HPLC. After about 4 hours, the conversion is >98%. The work-up is carried out by addition of water to dissolve the precipitated salts, addition of toluene and phase separation. The upper, product-containing phase is evaporated on a rotary evaporator and the product is purified by chromatography. This gives 7.5 g (82%) of coupling product (3-methyl-1-(4-trifluoromethylphenyl)piperidine).
As example 1 but using 0.40 g of bis(dibenzylideneacetone)palladium(0) instead of 0.167 g of palladium(II) acetate. As in example 1, the reaction was concluded after a short reaction time (in this case boiling overnight). Yield: 7.8 g (84%)
As example 1 but using 6.7 g of 4-chlorobenzotrifluoride (37.6 mmol) instead of 8.5 g of 4-bromobenzotrifluoride (37.6 mmol). To achieve complete conversion (>95%), boiling had to be continued for a somewhat long time (60 h) when using the less reactive chloro compound. However, the yield was comparable with that in the two previous examples (7.1 g, 78%).
5.9 g of sodium t-butoxide (61.3 mmol), 6.7 g of 2-chloroaniline (52.6 mmol) and 7.0 g of 4-bromoanisole (37.6 mmol) are dissolved or suspended in 50 ml of dioxane and admixed at 80° C. with a suspension of 0.167 g of palladium(II) acetate (2 mol %) and 0.43 g of 2,2-dimethyl-1,3-bis(diphenylphosphino)propane (2.5 mol %). The mixture is subsequently refluxed and the conversion is monitored by HPLC. The conversion is quantitative (>95%) after 72 hours. The work-up is carried out by addition of water to dissolve the precipitated salts, addition of toluene and phase separation. The upper, product-containing phase is evaporated on a rotary evaporator and the product is purified by chromatography. This gave 6.4 g (73%) of coupling product (2-chlorophenyl)(4-methoxyphenyl)amine.
4.8 g of sodium t-butoxide (48.4 mmol), 4.1 g of 2-chloroaniline (33.2 mmol) and 7.0 g of 4-bromobenzotrifluoride (30.2 mmol) are dissolved or suspended in 50 ml of dioxane and admixed at 80° C. with a suspension of 0.14 g of palladium(1) acetate (2 mol %) and 0.33 g of 2,2-dimethyl-1,3-bis(diphenylphosphino)propane (2.5 mol %). The mixture is subsequently refluxed and the conversion is monitored by HPLC. The conversion is quantitative (>95%) after 72 hours. The work-up is carried out by addition of water to dissolve the precipitated salts, addition of toluene and phase separation. The upper, product-containing phase is evaporated on a rotary evaporator and the product is purified by chromatography. This gave 5.3 g (64%) of coupling product (2-chloro-phenyl)(4-trifluoromethylphenyl)amine.
2.9 g of sodium t-butoxide (30.1 mmol), 2.6 g of 3-methylpiperidine (26.3 mmol) and 4.2 g of 4-bromobenzotrifluoride (18.8 mmol) are dissolved or suspended in 25 ml of dioxane and admixed at 80° C. with a suspension of 0.088 g of palladium(II) acetate (2 mol %) and 0.201 g of 1,4-bis(diphenylphosphino)butane (2.5 mol %). The mixture is subsequently refluxed and the conversion is monitored by HPLC. After about 5 hours, the conversion is >98%. The work-up is carried out by addition of water to dissolve the precipitated salts, addition of toluene and phase separation. The upper, product-containing phase is evaporated on a rotary evaporator and the product is purified by chromatography. This gave 3.1 g (87%) of coupling product (3-methyl-1-(4-trifluoromethylphenyl)piperidine).
2.9 g of sodium t-butoxide (30.1 mmol), 2.6 g of 3-methylpiperidine (26.3 mmol) and 4.2 g of 4-bromobenzotrifluoride (18.8 mmol) are dissolved or suspended in 25 ml of dioxane and admixed at 80° C. with a suspension of 0.088 g of palladium(II) acetate (2 mol %) and 0.194 g of 1,3-bis(diphenylphosphino)propane (2.5 mol %). The mixture is subsequently refluxed and the conversion is monitored by HPLC. After about 5 hours, the conversion is >98%. The work-up is carried out by addition of water to dissolve the precipitated salts, addition of toluene and phase separation. The upper, product-containing phase is evaporated on a rotary evaporator and the product is purified by chromatography. This gave 3.2 g (90%) of coupling product (3-methyl-1-(4-trifluoromethylphenyl)piperidine).
2.9 g of sodium t-butoxide (30.1 mmol), 2.6 g of 3-methylpiperidine (26.3 mmol) and 4.2 g of 4-bromobenzotrifluoride (18.8 mmol) are dissolved or suspended in 25 ml of dioxane and admixed at 80° C. with a suspension of 0.088 g of palladium(1) acetate (2 mol %) and 0.187 g of 1,2-bis(diphenylphosphino)ethane (2.5 mol %). The mixture is subsequently refluxed and the conversion is monitored by HPLC. After about 5 hours, the conversion is >98%. The work-up is carried out by addition of water to dissolve the precipitated salts, addition of toluene and phase separation. The upper, product-containing phase is evaporated on a rotary evaporator and the product is purified by chromatography. This gave 2.9 g (82%) of coupling product (3-methyl-1-(4-trifluoromethylphenyl)piperidine).
Apart from the couplings of amines, the systems described are also especially active in the coupling of amides with aromatics, i.e. in particular in the coupling with heteroaromatics such as pyridines. In these couplings, potassium carbonate can advantageously be used as base.
4.0 g of potassium carbonate (28.9 mmol), 3.5 g of 4-fluorobenzamide (25.3 mmol) and 2.1 g of 2-chloropyridine (18.1 mmol) are dissolved or suspended in 25 ml of dioxane and admixed at 80° C. with a suspension of 0.036 g of palladium(II) acetate (0.9 mol %) and 0.200 g of 1,3-bis(diphenylphosphino)propane (2.5 mol %). The mixture is subsequently refluxed and the conversion is monitored by HPLC. After boiling overnight, the conversion is >98%. The work-up is carried out by addition of water to dissolve the precipitated salts, addition of toluene and phase separation. The upper, product-containing phase is evaporated on a rotary evaporator and the product is purified by chromatography. This gave 3.5 g (89%) of coupling product (4-fluoro-N-pyridin-2-yl-benzamide).
3.1 g of potassium carbonate (22.7 mmol), 2.0 g of 2,2-dimethylpropionamide (20.0 mmol) and 1.7 g of 2-chloropyridine (14.2 mmol) are dissolved or suspended in 40 ml of dioxane and admixed at 80° C. with a suspension of 0.027 g of palladium(II) acetate (0.9 mol %) and 0.156 g of 2,2-dimethyl-1,3-bis(diphenylphosphino)propane (2.5 mol %). The mixture is subsequently refluxed and the conversion is monitored by HPLC. After boiling overnight, the conversion is >98%. The work-up is carried out by addition of water to dissolve the precipitated salts, addition of toluene and phase separation. The upper, product-containing phase is evaporated on a rotary evaporator and the product is purified by chromatography. This gave 2.6 g (88%) of coupling product (2,2-dimethyl-N-pyridin-2-yl-propionamide)
As example 10, but 0.151 g of 1,4-bis(diphenylphosphino)butane (2.5 mol %) was used instead of 0.156 g of 2,2-dimethyl-1,3-bis(diphenylphosphino)propane (2.5 mol %). Yield: 2.4 g (81%).
As example 10, but 0.151 g of 1,4-bis(diphenylphosphino)ethane (2.5 mol %) is used instead of 0.141 g of 2,2-dimethyl-1,3-bis(diphenylphosphino)propane (2.5 mol %). Yield: 2.5 g (85%).
As example 10, but 0.187 g of triphenylphosphine (5 mol %) is used instead of 0.141 g of 2,2-dimethyl-1,3-bis(diphenylphosphino)propane (2.5 mol %). However, no conversion was able to be achieved using this ligand.
| Number | Date | Country | Kind |
|---|---|---|---|
| 10 2006 037 399.5 | Aug 2006 | DE | national |
