Method for producing biphenylamines from azobenzenes by ruthenium catalysis

The present invention relates to a novel method for preparing substituted biphenylamines.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Stage entry of International Application No. PCT/EP2015/075386, filed Nov. 2, 2015, which claims priority to European Patent Application No. 14191403.6, filed Nov. 3, 2014.

BACKGROUND

Field

The present invention relates to a novel method for preparing substituted biphenylamines by ruthenium-catalysed arylation of azobenzenes.

Description of Related Art

Biaryl compounds, especially biphenyl compounds, are of industrial significance as fine chemicals, intermediates for pharmaceuticals, optical brighteners and agrochemicals.

Basic methods for the preparation of biaryl compounds and also the disadvantages associated therewith have already been disclosed and discussed in the European patent application EP 14166058.9.

Disadvantages of these methods include the high production costs. Transition metal-catalysed cross-couplings (for example according to Suzuki) require relatively large amounts of costly palladium catalysts or else (Bull. Korean Chem. Soc. 2000, 21, 165-166) the use of virtually equivalent amounts of zinc which has to be disposed of as waste. Moreover, activation of the zinc requires carcinogenic dibromomethane.

It has already been described as well that azobenzenes halogenated in the ortho position can be arylated with boronic acids catalysed by palladium in a Suzuki-Miyaura reaction (see, for example: K. Suwa et al., Tetrahedron Letters 50 (2009) 2106-8). This method has the disadvantages of using expensive palladium catalysts and the necessity of preparing the halogenated azobenzenes.

It has also been described already that azobenzenes can be arylated with boronic acids in the presence of rhodium catalysts (S. Miyamura et al., J. Organomet. Chem. 693 (2008) 2438-42). However, rhodium catalysts are exceptionally expensive. In addition, there exists the additional requirement to prepare the boronic acids, typically from the corresponding iodo- or bromoaromatic compounds. Finally, the yields are unsatisfactory (maximum 50%) and only the ortho,ortho′ double-arylated compounds are obtained as products.

SUMMARY

The problem addressed by the present invention was thus that of providing a novel method by which biphenylamines can be obtained with a high overall yield and high purity without the use of costly palladium or rhodium catalysts and under industrially preferred reaction conditions.

Accordingly, the present invention provides a method for preparing biphenylamines of the general formula (I)

in whichR1is as defined above,
are reacted with an aromatic compound of the formula (III)

in whichX1, X2and X3are as defined above,andHal is iodine, bromine or chlorine
in the presence of a catalyst system consisting of a ruthenium catalyst, an activator, and a base,
and (2) in a second stage the azobenzenes of the formula (IV) thus obtained

in which R1, X1, X2and X3are as defined aboveand the numbers 1 to 6 and 1′ to 6′ define the positions of the residue R1in the compounds specified in Table 1 and also in reference to the positions in formula (IV) in the description,
are hydrogenated to give the biphenylamines of the formula (I).

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT

By means of this reaction sequence, surprisingly, the biphenylamines of the formula (I) may be prepared in good yields without using halogenated azobenzenes, without using expensive palladium or rhodium catalysts, without the necessity of preparing boronic acids and under industrially advantageous reaction conditions.

If azobenzene and bromobenzene are used as starting materials, the method according to the invention can be illustrated by way of example by the following formula scheme:

Preference is given to the performance of the method according to the invention using starting materials in which the residues specified are each defined as follows. The preferred, particularly preferred and especially preferred definitions apply to all the compounds in which the respective residues occur:R1is preferably hydrogen, fluorine, chlorine, C1-C4-alkyl or C1-C4-alkoxy.R1is further preferably fluorine, C1-C4-alkyl and C1-C4-alkoxy, where the substituent is preferably in the 3′, 4′ or 5′ position, further preferably in the 4′ or 5′ position and more preferably in the 5′ position [cf., for example, formula (IV)].R1is particularly preferably C1-C4-alkyl and C1-C4-alkoxy, where the substituent is in the 4′ or 5′ position and particularly preferably in the 5′ position [cf., for example, formula (IV)].

In the definitions above for R1, C1-C4-alkyl is preferably selected from the group comprising methyl, ethyl and isopropyl, and C1-C4-alkoxy is preferably selected from the group comprising methoxy and ethoxy.

In an alternative embodiment,R1is preferably trifluoromethyl, where trifluoromethyl is preferably in the 4′ or 5′ position, further preferably in the 5′ position, of the respective compound.

In a further alternative embodiment,R1is preferably methoxy or methylthio, preferably in the 4′, 5′ or 6′ position, further preferably in the 5′ position, of the respective compound.X1is preferably alkoxy, alkanoyl, alkyl carboxylate or chlorine.X1is particularly preferably alkoxy, alkanoyl or alkyl carboxylate and especially preferably alkyl carboxylate.X2is preferably alkoxy, alkanoyl, alkyl carboxylate or chlorine.X2is particularly preferably alkoxy, alkanoyl or alkyl carboxylate and especially preferably alkyl carboxylate.X3is preferably alkoxy, alkanoyl, alkyl carboxylate or chlorine.X3is particularly preferably alkoxy, alkanoyl or alkyl carboxylate and especially preferably alkyl carboxylate.

In the definitions above, alkyl carboxylate is especially preferably selected from the group comprising methyl, ethyl and isopropyl carboxylate. In the above definitions, alkanoyl is especially preferably selected from the group comprising —COMe, —COEt, —COiPr, —COPr, —CObutyl, —COisobutyl and —COtert-butyl, where Me, Et, and Pr have the customary meanings of methyl, ethyl and propyl.

The azobenzenes of the formula (II) for use as starting materials in the first stage in the performance of the method according to the invention are known or can be obtained by known methods.

The first stage of the method according to the invention is performed in the presence of a ruthenium catalyst. Ruthenium catalysts used are, for example, ruthenium complexes such as [{RuCl2(p-cymene)}2], [{RuCl2(cumene)}2], [{RuCl2(benzene)}2], [{RuCl2(C6Me6)}2], [Cp*Ru(PPh3)2Cl] (Cp*=pentamethylcyclopentadienyl). Preference is given to using [{RuCl2(p-cymene)}2].

The amount of ruthenium catalyst can be varied within wide limits Typically, amounts of 0.1 to 30 mole percent of the relevant complex are used, based on the aromatic compound of the formula (III). Preferably, 1 to 20 mole percent of the relevant complex is used, further preferably 1 to 10 mole percent.

The first stage of the method according to the invention is performed in the presence of an activator.

The activator is preferably an acid, further preferably a carboxylic acid.

Preference is given to using 2,4,6-trimethylbenzoic acid (MesCO2H).

The activator is used in amounts of 0.1 to 100 mole percent, based on the aromatic compound of the formula (III). Preferably 1 to 50 mole percent is used, more preferably 10 to 40 mole percent.

Particular preference is given to using potassium carbonate.

The first stage of the method according to the invention is performed in solvents or solvent mixtures. Examples include:

ketones such as acetone, diethyl ketone, methyl ethyl ketone and methyl isobutyl ketone;

nitriles such as acetonitrile and butyronitrile;

The solvent is preferably selected from the group comprising ethers, aromatic hydrocarbons, chlorinated aromatic hydrocarbons and branched alcohols, or mixtures of these solvents.

Branched alcohols in the context of the present invention are preferably isopropanol, tertiary butanol, isoamyl alcohol and tertiary amyl alcohol.

The solvent is particularly preferably selected from the group comprising 1,4-dioxane, THF, 2-Me-THF, DME, toluene, ortho-xylene, meta-xylene, para-xylene, mesitylene or tertiary amyl alcohol, or mixtures of these solvents.

Very particular preference is given to the solvents 1,4-dioxane, toluene, ortho-xylene, meta-xylene, para-xylene or mixtures of these solvents.

Solvents which have proven to be unsuitable are methanol, N,N-dialkylalkanamides such as N-methylpyrrolidone, lactones such as γ-valerolactone, water, dimethyl sulphoxide (DMSO) and carboxylic acids such as acetic acid.

The first stage of the method according to the invention is generally performed at temperatures in the range of 20° C. to 220° C., preferably in the range of 50° C. to 180° C., more preferably in the range of 80° C. to 150° C.

In the performance of the first stage of the method according to the invention, generally a substoichiometric amount up to equimolar amounts of haloaromatic compounds of the formula (III) are used per 1 mol of azobenzene of the formula (II). The molar ratio of azobenzene of the formula (II) to haloaromatic compound of the formula (III) is generally 1:0.4 to 1, preferably 1:0.45 to 0.9.

The first stage of the method according to the invention is, unless stated otherwise, generally conducted under atmospheric pressure. However, it is also possible to work under elevated or reduced pressure. The reaction is preferably carried out under atmospheric pressure.

The second stage of the method according to the invention, i.e. the reduction of the azobenzene of the formula (IV) to give a biphenylamine of the formula (I), may be carried out by methods known in principle, for example, by means of zinc and ammonium formate (S. Gowda et al., Tetrahedron Letters 43 (2002) 1329-31); iron and calcium chloride (S. Chandrappa et al., Synlett 2010, 3019-22); ruthenium-catalysed transfer hydrogenation (M. Beller et al., Chem. Eur. J. 2011, 17, 14375-79); ruthenium-catalysed reduction with zinc and KOH (T. Schabel et al., Org. Lett. 15 (2013) 2858-61):

Ruthenium-catalysed methods are preferably used.

The reduction is particularly preferably carried out in the presence of the ruthenium catalyst which was already used for the first stage of the method according to the invention.

The second stage of the method according to the invention is especially preferably carried out here in such a way that it takes place directly after the first stage of the method according to the invention in a one-pot reaction without isolating the azobenzene of the formula (IV).

In a particularly preferred embodiment, the solvent is selected from the group comprising 1,4-dioxane, toluene, ortho-xylene, meta-xylene, para-xylene or mixtures of these solvents and the activator is 2,4,6-trimethylbenzoic acid, the aromatic compound of the formula (III) is a brominated aromatic compound, the base is potassium carbonate and the catalyst is [{RuCl2(p-cymene)}2].

The biphenylamines of the formula (I) are valuable intermediates for preparation of active fungicidal ingredients (cf. WO 03/070705).

Preferred embodiments of compounds of the formula (IV) in the context of the present invention are (the numbers for R1each indicate the position and HAL the halogen of the starting compound III):

PREPARATION EXAMPLES

In an oven-dried reaction vessel, a suspension consisting of (E)-bis(3-methylphenyl)diazene (210 mg, 1.0 mmol), [{RuCl2(p-cymene)}2] (15.3 mg, 5.0 mol %), MesCO2H (24.6 mg, 30 mol %), K2CO3(138 mg, 1.0 mmol) and methyl 4-bromobenzoate (108 mg, 0.5 mmol) was stirred in dry 1,4-dioxane (2.0 ml) at 120° C. for 18 h in a nitrogen atmosphere. The reaction mixture was then diluted at room temperature with dichloromethane (DCM) (75 ml) and filtered through Celite and silica gel, and the filtrate was concentrated. The crude product thus obtained was purified by chromatography on silica gel (n-hexane/DCM: 7/3). 150 mg of methyl 4′-methyl-2′-[(E)-(3-methylphenyl)diazenyl]biphenyl-4-carboxylate were obtained as an orange solid (87% of theory).

The experiment was carried out as described for Example 1, with the difference that toluene was used as solvent in place of 1,4-dioxane. The yield was 83% of theory.

The experiment was carried out as described for Example 1, with the difference that ortho-xylene was used as solvent in place of 1,4-dioxane. The yield was 84% of theory.

The experiment was carried out as described for Example 1, with the difference that tertiary amyl alcohol was used as solvent in place of 1,4-dioxane. The yield was 75% of theory.

The experiment was carried out as described for Example 1, with the difference that sodium carbonate was used as base in place of potassium carbonate. The yield was 75% of theory.

The experiment was carried out as described for Example 1, with the difference that potassium acetate was used as additive in place of MesCO2H. The yield was 79% of theory.

The experiment was carried out as described for Example 1, with the difference that pivalic acid was used as additive in place of MesCO2H. The yield was 76% of theory.

In an oven-dried reaction vessel, a suspension consisting of (E)-1,2-di-m-tolyldiazene (210 mg, 1.0 mmol), [{RuCl2(p-cymene)}2] (15.3 mg, 5.0 mol %), MesCO2H (24.6 mg, 30 mol %), K2CO3(138 mg, 1.0 mmol) and 4-bromoacetophenone (99.5 mg, 0.5 mmol) was stirred in dry 1,4-dioxane (2.0 ml) at 120° C. for 18 h in a nitrogen atmosphere. The reaction mixture was then diluted at room temperature with dichloromethane (DCM) (75 ml) and filtered through Celite and silica gel, and the filtrate was concentrated. The crude product thus obtained was purified by chromatography on silica gel (n-hexane/DCM: 7/3). 106 mg of 1-{4′-methyl-2′-[(E)-(3-methylphenyl)diazenyl]biphenyl-4-yl}ethanone were obtained (65% of theory).

In an oven-dried reaction vessel, a suspension consisting of (E)-bis(3-methoxyphenyl)diazene (242 mg, 1.0 mmol), [{RuCl2(p-cymene)}2] (15.3 mg, 5.0 mol %), MesCO2H (24.6 mg, 30 mol %), K2CO3(138 mg, 1.0 mmol) and 4-bromoacetophenone (99.5 mg, 0.5 mmol) was stirred in dry 1,4-dioxane (2.0 ml) at 120° C. for 18 h in a nitrogen atmosphere. The reaction mixture was then diluted at room temperature with dichloromethane (DCM) (75 ml) and filtered through Celite and silica gel, and the filtrate was concentrated. The crude product thus obtained was purified by chromatography on silica gel (n-hexane/DCM: 7/3). 96 mg of 1-{4′-methoxy-2′-[(E)-(3-methoxyphenyl)diazenyl]biphenyl-4-yl}ethanone were obtained (53% of theory).

In an oven-dried reaction vessel, a suspension consisting of (E)-bis(2-methylphenyl)diazene (210 mg, 1.0 mmol), [{RuCl2(p-cymene)}2] (15.3 mg, 5.0 mol %), MesCO2H (24.6 mg, 30 mol %), K2CO3(138 mg, 1.0 mmol) and 4-bromoacetophenone (99.5 mg, 0.5 mmol) was stirred in dry 1,4-dioxane (2.0 ml) at 120° C. for 18 h in a nitrogen atmosphere. The reaction mixture was then diluted at room temperature with dichloromethane (DCM) (75 ml) and filtered through Celite and silica gel, and the filtrate was concentrated. The crude product thus obtained was purified by chromatography on silica gel (n-hexane/DCM: 7/3). 87 mg of 1-{3′-methyl-2′-[(E)-(2-methylphenyl)diazenyl]biphenyl-4-yl}ethanone were obtained (53% of theory).

In an oven-dried reaction vessel, a suspension consisting of (E)-bis(3-methylphenyl)diazene (210 mg, 1.0 mmol), [{RuCl2(p-cymene)}2] (15.3 mg, 5.0 mol %), MesCO2H (24.6 mg, 30 mol %), K2CO3(138 mg, 1.0 mmol) and ethyl 4-bromobenzoate (107 mg, 0.5 mmol) was stirred in dry 1,4-dioxane (2.0 ml) at 120° C. for 18 h in a nitrogen atmosphere. The reaction mixture was then diluted at room temperature with dichloromethane (DCM) (75 ml) and filtered through Celite and silica gel, and the filtrate was concentrated. The crude product thus obtained was purified by chromatography on silica gel (n-hexane/DCM: 7/3). 113 mg of ethyl 4′-methyl-2′-[(E)-(3-methylphenyl)diazenyl]biphenyl-4-carboxylate were obtained (63% of theory).

In an oven-dried reaction vessel, a suspension consisting of (E)-bis(3-methylphenyl)diazene (210 mg, 1.0 mmol), [{RuCl2(p-cymene)}2] (15.3 mg, 5.0 mol %), MesCO2H (24.6 mg, 30 mol %), K2CO3(138 mg, 1.0 mmol) and 4-bromoanisole (93.5 mg, 0.5 mmol) was stirred in dry 1,4-dioxane (2.0 ml) at 120° C. for 18 h in a nitrogen atmosphere. The reaction mixture was then diluted at room temperature with dichloromethane (DCM) (75 ml) and filtered through Celite and silica gel, and the filtrate was concentrated. The crude product thus obtained was purified by chromatography on silica gel (n-hexane/DCM: 7/3). 106 mg of (E)-1-(4′-methoxy-4-methylbiphenyl-2-yl)-2-(3-methylphenyl)diazene were obtained (67% of theory).

In an oven-dried reaction vessel, a suspension consisting of (E)-1,2-diphenyldiazene (182 mg, 1.0 mmol), [{RuCl2(p-cymene)}2] (15.3 mg, 5.0 mol %), MesCO2H (24.6 mg, 30 mol %), K2CO3(138 mg, 1.0 mmol) and bromobenzene (79 mg, 0.5 mmol) was stirred in dry 1,4-dioxane (2.0 ml) at 120° C. for 18 h in a nitrogen atmosphere. The reaction mixture was then diluted at 23° C. with CH2Cl2(75 ml) and filtered through Celite and silica gel, and the filtrate was concentrated. The crude product thus obtained was purified by chromatography on silica gel (n-hexane/EtOAc/NEt3: 88/6/6). (E)-1-(Biphenyl-2-yl)-2-phenyldiazene (68 mg, 53%) was obtained as an orange viscous oil.

In an oven-dried reaction vessel, a suspension consisting of (E)-1,2-diphenyldiazene (182 mg, 1.0 mmol), [{RuCl2(p-cymene)}2] (15.3 mg, 5.0 mol %), MesCO2H (24.6 mg, 30 mol %), K2CO3(138 mg, 1.0 mmol) and methyl 4-bromobenzoate (108 mg, 0.5 mmol) was stirred in dry 1,4-dioxane (2.0 ml) at 120° C. for 18 h in a nitrogen atmosphere. The reaction mixture was then diluted at 23° C. with CH2Cl2(75 ml) and filtered through Celite and silica gel, and the filtrate was concentrated. The crude product thus obtained was purified by chromatography on silica gel (n-hexane/CH2Cl2: 7/3). Methyl 2′-[(E)-phenyldiazenyl]biphenyl-4-carboxylate (93 mg, 59%) was obtained as an orange solid.

In an oven-dried reaction vessel, a suspension consisting of (E)-1,2-di-o-tolyldiazene (210 mg, 1.0 mmol), [{RuCl2(p-cymene)}2] (15.3 mg, 5.0 mol %), MesCO2H (24.6 mg, 30 mol %), K2CO3(138 mg, 1.0 mmol) and methyl 4-bromobenzoate (108 mg, 0.5 mmol) was stirred in dry 1,4-dioxane (2.0 ml) at 120° C. for 18 h in a nitrogen atmosphere. The reaction mixture was then diluted at 23° C. with CH2Cl2(75 ml) and filtered through Celite and silica gel, and the filtrate was concentrated. The crude product thus obtained was purified by chromatography on silica gel (n-hexane/CH2Cl2: 7/3). Methyl 3′-methyl-2′-[(E)-(2-methylphenyl)diazenyl]biphenyl-4-carboxylate (103 mg, 60%) was obtained as an orange solid.

In an oven-dried reaction vessel, a suspension consisting of (E)-1,2-di-p-tolyldiazene (210 mg, 1.0 mmol), [{RuCl2(p-cymene)}2] (15.3 mg, 5.0 mol %), MesCO2H (24.6 mg, 30 mol %), K2CO3(138 mg, 1.0 mmol) and methyl 4-bromobenzoate (108 mg, 0.5 mmol) was stirred in dry 1,4-dioxane (2.0 ml) at 120° C. for 18 h in a nitrogen atmosphere. The reaction mixture was then diluted at 23° C. with CH2Cl2(75 ml) and filtered through Celite and silica gel, and the filtrate was concentrated. The crude product thus obtained was purified by chromatography on silica gel (n-hexane/CH2Cl2: 7/3). Methyl 5′-methyl-2′-[(E)-(4-methylphenyl)diazenyl]biphenyl-4-carboxylate (112 mg, 65%) was obtained as an orange solid.

In an oven-dried reaction vessel, a suspension consisting of (E)-1,2-diphenyldiazene (182 mg, 1.0 mmol), [{RuCl2(p-cymene)}2] (15.3 mg, 5.0 mol %), MesCO2H (24.6 mg, 30 mol %), K2CO3(138 mg, 1.0 mmol) and 4-bromo-1,2-dichlorobenzene (113 mg, 0.5 mmol) was stirred in dry 1,4-dioxane (2.0 ml) at 120° C. for 18 h in a nitrogen atmosphere. The reaction mixture was then diluted at 23° C. with CH2Cl2(75 ml) and filtered through Celite and silica gel, and the filtrate was concentrated. The crude product thus obtained was purified by chromatography on silica gel (n-hexane/EtOAc/NEt3: 88/6/6). (E)-1-(3′,4′-Dichlorobiphenyl-2-yl)-2-phenyldiazene (79 mg, 48%) was obtained as an orange solid.

In an oven-dried reaction vessel, a suspension consisting of (E)-1,2-di-m-tolyldiazene (210 mg, 1.0 mmol), [{RuCl2(p-cymene)}2] (15.3 mg, 5.0 mol %), MesCO2H (24.6 mg, 30 mol %), K2CO3(138 mg, 1.0 mmol) and 1-bromo-4-chlorobenzene (96 mg, 0.5 mmol) was stirred in dry 1,4-dioxane (2.0 ml) at 120° C. for 18 h in a nitrogen atmosphere. The reaction mixture was then diluted at 23° C. with CH2Cl2(75 ml) and filtered through Celite and silica gel, and the filtrate was concentrated. The crude product thus obtained was purified by chromatography on silica gel (n-hexane/EtOAc/NEt3: 88/6/6). (E)-1-(4′-Chloro-4-methylbiphenyl-2-yl)-2-(3-methylphenyl)diazene (93 mg, 58%) was obtained as an orange solid.

The experiment was carried out as described for Example 1, with the difference that N,N-dimethylformamide was used as solvent in place of 1,4-dioxane. No target product was obtained.

The experiment was carried out as described for Example 1, with the difference that N,N-dimethylacetamide was used as solvent in place of 1,4-dioxane. No target product was obtained.

The experiment was carried out as described for Example 1, with the difference that methanol was used as solvent in place of 1,4-dioxane. No target product was obtained.

The experiment was carried out as described for Example 1, with the difference that N-methylpyrrolidone was used as solvent in place of 1,4-dioxane. No target product was obtained.

The experiment was carried out as described for Example 1, with the difference that γ-valerolactone was used as solvent in place of 1,4-dioxane. No target product was obtained.

The experiment was carried out as described for Example 1, with the difference that dimethyl sulphoxide was used as solvent in place of 1,4-dioxane. No target product was obtained.

The experiment was carried out as described for Example 1, with the difference that water was used as solvent in place of 1,4-dioxane. No target product was obtained.

The experiment was carried out as described for Example 1, with the difference that acetic acid was used as solvent in place of 1,4-dioxane. No target product was obtained.