WO2017102944A1

WO2017102944A1 - Process for the production of biaryl compounds

Info

Publication number: WO2017102944A1
Application number: PCT/EP2016/081190
Authority: WO
Inventors: Paulus Lambertus Alsters; Laurent Lefort; Christian Albert Michiel Raymond VAN SLAGMAAT; Ruben Petrus VAN SUMMEREN; Gerardus Karel Maria Verzijl
Original assignee: Dsm Ip Assets B.V.
Priority date: 2015-12-15
Filing date: 2016-12-15
Publication date: 2017-06-22

Abstract

A process for producing biaryl compounds by aerobic cross dehydrogenative coupling (CDC) of two arene groups comprising at least one aryl carbon-hydrogen bond, in the presence of a catalyst system, wherein the catalyst system comprises as phosphor containing acid a non-cyclopalladatable phosphinate and/or a non-cyclopalladatable phosphate monoester and/or a non-cyclopalladatable phosphate diester and/or a non-cyclopalladatable phosphonate and/or a non-cyclopalladatable phosphonate monoester as well as a palladium cation.

Description

PROCESS FOR THE PRODUCTION OF BIARYL COMPOUNDS.

The invention relates to a process for the production of biaryl compounds.

Biaryl compounds constitute an important class of compounds with a variety of applications, e.g. in market segments related to pharmaceuticals, agrochemicals, electronic chemicals and polymers.

Especially for bulk applications, for example as monomer units in polymers, it is important to produce the biaryl compounds at low costs.

Known processes for the production of biaryl compounds based on the coupling of two substituted arene units with prior activation of the arene units are in general not commercially viable. This is because the process requires many steps and expensive reagents, and it also generates large amounts of salt water.

An improvement was provided by a process for the production of biaryl compounds by cross dehydrogenative coupling (CDC) of two arene units, as recently reviewed in Chem. Asian J. 2014, 9, 26. As is illustrated in this paper, such a process does not require prior activation of the arene units and it is economic, especially if oxygen is used as oxidant. Such a process is called aerobic CDC.

Palladium (Pd) catalyzed aerobic CDC is already used commercially for coupling of dimethyl phthalate to produce tetramethyl [1 ,1 '-biphenyl]-3,3',4,4'-tetracarboxylate, an intermediate for polyimide resins. However, such a process, as for example described in WO2008/067443, also has serious disadvantageous. In the process of

WO2008/067443, the CDC is carried out in a solvent in the presence of a catalyst, such as palladium acetate [Pd(OAc)2], optionally with an oxidant such as copper acetate [Cu(OAc)2] or phosphomolybdovanate [HMPV]. Herein the amount of catalyst was 100 mole%, or in the presence of an oxidant in the range of in the range from 10 to 25 mole% with the HMPV oxidant being present in an amount of 10 to 25 mole%. Thus apart from the solvent, very high amounts of catalyst and oxidants are needed.

As explained in Adv. Synth. Catal. 2010, 352, 3223, this process could be significantly streamlined by carrying out the CDC of ortho-xylene, followed by aerobic oxidation of the benzylic methyl groups of the coupling product 3, 3', 4,4'- tetramethyl-1 ,1 '-biphenyl (3344). This paper discloses an aerobic CDC catalyst system comprising a palladium dicarboxylate salt and 2-fluoropyridine as ligand, used in a 2/1 molar ratio relative to Pd. This catalyst system is preferably applied in acetic acid as solvent while using copper(ll) triflate as cocatalyst. In high volume, low cost applications such as those for the manufacture of bulk monomers, minimizing process costs is essential to meet the strict cost price requirements. It is therefore desirable to obtain a CDC process that operates efficiently with only a small amount of solvent or preferably no solvent at all. Such essentially or completely solvent-free conditions reduce process costs because little or no solvent needs to be separated from the reaction mixture after completion of the reaction. Essentially or completely solvent-free conditions are also beneficial for increasing the productivity per unit of reactor volume (higher space time yield). This is especially important in the case of CDC of arenes to biaryl compounds, since under the low conversion conditions typically employed to suppress further arene CDC to triaryl compounds, reactor productivity erodes to unacceptably low values in the presence of a substantial amount of solvent. To reduce process costs, it is also desirable to obtain a CDC process that operates efficiently with only a small amount of catalyst, i.e. with a catalyst that has a high activity. Surprisingly these aims are achieved by a process for producing biaryl compounds by aerobic CDC of two arene groups comprising at least one aryl carbon-hydrogen bond, in the presence of a catalyst system comprising as phosphor containing acid a non- cyclopalladatable phosphinate and/or non-cyclopalladatable phosphate monoester and/or non-cyclopalladatable phosphate diester and/or non-cyclopalladatable phosphonate and/or non-cyclopalladatable phosphonate monoester as well as a palladium cation. Preferably the catalyst system comprises as phosphor containing acid a non-cyclopalladatable phosphinate and/or a non-cyclopalladatable phosphate diester and/or a non-cyclopalladatable phosphonate and/or a non-cyclopalladatable phosphonate monoester. Phosphor containing acid is also referred to as P-acid.

With non-cyclopalladatable phosphinate or non-cyclopalladatable phosphate monoester or non-cyclopalladatable phosphate diester or non-cyclopalladatable phosphonate or non-cyclopalladatable phosphonate monoester are meant a phosphinate or phosphate monoester or phosphate diester or phosphonate or phosphonate monoester devoid of C-H bonds prone to cleavage by palladium, typically leading to 5 or 6 membered rings with a C,0-donor set linked to the Pd center, with the C-atom originating from the C-H bond that is cleaved. A phosphinate prone to cyclopalladation via C-H cleavage is known, and can be found in Chemical

Communications 2011 , 47, 2333. A review on cyclopalladation and cyclopalladated compounds can be found in Chem. Rev. 2005, 105, 2527. The phosphinate or phosphate monoester or phosphate diester or phosphonate or phosphonate monoester may be non-cyclic or cyclic, with cyclic meaning that the phosphorus atom is part of a ring system. The phosphinate may be in the form of a phosphinate salt, or preferably in the form of a phosphinic acid. The phosphate monoester may be in the form of a phosphate monoester salt, or preferably in the form of a dihydrogen phosphate. The phosphate diester may be in the form of a phosphate diester salt, or preferably in the form of a monohydrogen phosphate. The phosphonate may be in the form of a phosphonate salt, or preferably in the form of a phosphonic acid. The phosphonate monoester may be in the form of a phosphonate monoester salt, or preferably in the form of a monohydrogen phosphonate.

Preferably the P-acid is a phosphinic acid or a monohydrogen phosphate. More preferably, the P-acid is a phosphinic acid with a pK_a that is smaller than the pK_a of dimethyl hydrogen phosphate. Most preferably, the P-acid is a bis(perfluoroaryl)phosphinic acid or bis(perfluoroalkyl)phosphinic acid with a pK_a that is smaller than the pK_a of dimethyl hydrogen phosphate. The palladium cation may be in the form of a hydrogen palladate, or preferably in the form of a palladium salt. The palladium salt may be derived from a P-acid. Preferably the catalyst system comprises at least one P-acid as well as a palladium cation in the form of a palladium salt derived from an acid with a pK_a that is larger than the pK_a of the P-acids comprised in the catalyst system. Most preferably the palladium salt is a palladium dicarboxylate derived from a carboxylic acid with a pK_a that is larger than the pK_a of the P-acids comprised in the catalyst system. When the catalyst system comprises a P-acid and a palladium salt, preferably the molar ratio of P-acid/palladium is 0.8/1 - 20/1. When the P-acid is devoid of an additional functional group that may coordinate to the palladium center, most preferably the molar ratio of P-acid/palladium is 1.8/1 - 10/1 . When the P-acid contains an additional functional group that may coordinate to the palladium center, it may be advantageous that the molar ratio of P-acid/palladium is 0.8/1 - 1 .2/1.

Even with low concentrations of catalysts in the reaction mixture high arene conversion rates are obtained. Surprisingly also a high selectivity towards formation of the desired biaryl compound may be obtained. Especially surprising is the high selectivity towards formation of the desired biaryl compound derived from arenes that may also undergo competitive benzylic oxidation, such as methylbenzenes including ortho-xylene.

With the process of the invention improved results in terms of catalyst activity and/or selectivity are obtained, resulting in lower costs. Preferably the amount of palladium cations comprised in the catalyst system is equal or less than 1 mol% relative to the arene coupling partner or to the limiting arene coupling partner, with the limiting arene coupling partner being the arene with the lowest molarity in the reaction mixture in case more than one arene coupling partner is used. More preferably the amount of palladium cations comprised in the catalyst system is equal or less than 0.5 mol% relative to the arene coupling partner or to the limiting arene coupling partner. Most preferably the amount of palladium cations comprised in the catalyst system is equal or less than 0.1 mol% relative to the arene coupling partner or to the limiting arene coupling partner.

With the process according to the invention good results in terms of activity and selectivity are obtained if the process is carried out with a low amount of solvent or even without a solvent, provided the arene is in the liquid phase at the reaction temperature. Preferably at most 50 wt% of solvent is used, based on the total reaction mass, more preferably at most 25 wt%, even more preferably at most 10 wt%, even more preferably at most 5 wt%, even more preferably at most 2 wt%. Most preferably no solvent at all is used.

Optionally additives may be added. These additives may improve the activity, stability, or selectivity of the catalyst. Examples of such additives are Lewis acids, such as metal triflates, or Bransted acids. Other examples of potentially beneficial additives are redox active compounds that inhibit catalyst deactivation by formation of metallic palladium. Such redox active compounds include copper(ll) salts, vanadium-containing polyoxometalates, or organic electron acceptors such as benzoquinones. In case CDC of two arene groups may lead to a mixture of biaryl regioisomers of which only one is a desired product, a particularly useful class of additives comprises non-beta-eliminatable, non-cyclopalladatable organic ligands that improve the regioselectivity of the catalyst. With a non-beta-eliminatable nitrogen donor ligand is meant a nitrogen donor ligand that does not induce reduction of palladium(ll) to palladium(O) via beta-hydride elimination from a Pd-N-C-H fragment, with the N-C-H fragment being part of the nitrogen donor ligand that is bound to palladium. Nitrogen donor ligands prone to beta-hydride elimination include trialkylamines containing a N- C-H fragment, such as found in for example tributylamine as described in Chemistry 2011 , 77, 3091 . With a non-cyclopalladatable nitrogen donor ligand is meant a nitrogen donor ligand devoid of C-H bonds prone to cleavage by palladium, typically leading to 5 or 6 membered rings with a C,N-donor set linked to the Pd center, with the C-atom originating from the C-H bond that is cleaved. Nitrogen donor ligands prone to cyclopalladation via C-H cleavage are well known, and examples can, among others, be found in Chem. Rev. 2005, 105, 2527 and in Palladacycles 2008, 13, which also clarify rules for their formation.

Good results may be obtained when aliphatic cyclic or non-cyclic primary, secondary or tertiary amines, aromatic N-heterocycles and/or benzofused derivatives thereof are used as the one or more ligands. Preferably N-heterocycles and benzofused derivatives thereof are used that contain a sp² hybridized nitrogen atom with the lone electron pair on the nitrogen atom positioned in-plane with respect to the plane formed by the X-N-Y group, where X and Y denote the atoms directly bound to the sp² nitrogen atom. Even more preferably N-heterocyclic compounds are used that contain a sp² hybridized nitrogen atom with the lone electron pair on the nitrogen atom positioned in-plane with respect to the plane formed by the X-N-Y group, where X and Y denote the atoms directly bound to the sp² nitrogen atom and either X or Y being a carbon atom. From above defined preferred group even more preferably pyridines, pyridazines, pyrimidines, pyrazines, triazines, imidazoles, triazoles, oxazoles, 4,5- dihydrooxazoles, isoxazoles, 4,5-dihydroisoxazoles, and 5,6-dihydro-4/-/-1 ,3-oxazines or quinolines, isoquinolines, cinnolines, phthalazines, quinazoline, quinoxalines, 1 H- benzo[d]imidazoles, 1 /-/-benzo[d][1 ,2,3]triazoles, benzo[d]oxazoles, benzo[d]isoxazoles and 4/-/-benzo[e][1 ,3]oxazines and/or benzofused derivatives thereof are used as ligand.

Even more preferably aromatic 6 membered ring N-heterocycles or benzofused derivatives thereof are used as the one or more ligands. Preferably in this group pyridines, pyridazines, pyrimidines, pyrazines, triazines, quinolines,

isoquinolines, cinnolines, phthalazine, quinazoline and quinoxalines and/or benzofused derivatives thereof are used as the one or more ligands.

The nitrogen donor ligand may be further substituted to control the activity and/or the selectivity of the catalyst. The optimum choice of the substituent depends among others on the nature of the catalyst and on the required regioselectivity of the arene CDC process, which is determined by the final application. When the final application requires the CDC of ortho-xylene to be directed towards symmetrical 3344 instead of the asymmetrical 2,3,3',4'-tetramethyl-1 ,1 '-biphenyl (2334) regioisomer, it is advantageous to add a suitably substituted pyridine as ligand.

Preferably the molar ratio of ligand/palladium is 0.5/1 - 1.5/1. Most preferably the molar ratio of ligand/palladium is 0.8/1 - 1.2/1. When a ligand is present and the catalyst system comprises at least one P-acid as well as a palladium cation in the form of a palladium salt derived from an acid with a pK_a that is larger than the pK_a of the P-acids comprised in the catalyst system, preferably the molar ratio of P- acid/palladium is 2/1 - 2.2/1.

The CDC process according to this invention is preferably carried out at temperatures above room temperature. The optimum temperature depends on the nature of the arene coupling partner(s) and the required selectivity, in particular the required regioselectivity. Preferably, the reaction temperature is between 70 and 200°C, most preferably between 90 and 180°C. The preferred oxygen pressure depends on the available infrastructure and the nature of the CDC reaction. Preferably, the CDC process according to the invention is carried out in such a way that either the explosion risk is eliminated (e.g. by operating a semi-batch reactor via continuous supply of an oxygen/nitrogen mixture with a composition below the oxygen limit concentration), or the impact of an unintended explosion is minimized to an acceptable level (e.g. by operating a continuous flow tube reactor with oxygen or a minimum- headspace semi-batch reactor via continuous supply of oxygen).

The CDC process according to this invention may involve a homocoupling (i.e. with a single arene that is coupled to form a biaryl product) or a heterocoupling (i.e. with two different arene coupling partners). CDC processes of these types according to this invention may be either intermolecular or intramolecular.

Examples of suitable arenes in homo- or heterocoupling processes according to this invention are arenes (such as benzene, naphthalene, anthracene, phenanthrene), alkylarenes (such as toluene, 1 -methylnaphthalene, 2- methylnapthalene, ortho-xylene, meta-xylene, para-xylene, ethylbenzene, cumene, tert.-butylbenzene, diphenylmethane, propane-2,2-diyldibenzene), aryl carboxylic acid esters (such as methyl benzoate, methyl 1 -naphthoate, methyl 2-naphthoate, dimethyl phthalate, methyl ortho-toluate, methyl meta-toluate, methyl para-toluate, dimethyl isophthalate, dimethyl terephthalate), halogenated arenes (such as fluorobenzene, 1 - fluoronaphthalene, 2-fluoronaphthalene, (trifluoromethyl)benzene, chlorobenzene, 1 - chloronaphthalene, 2-chloronaphthalene, 1 -(trifluoromethyl)naphthalene, 2- (trifluoromethyl)naphthalene), aryl ethers (such as anisole, 1 -methoxynaphthalene, 2- methoxynaphthalene, diphenylether), and diaryl amines (such as N,N- diphenylacetamide). The arene in a homocoupling process according to this invention may also be a heteroarene, as long as the heteroarene does not have a heteroatom that interferes negatively in the CDC process, e.g. by competing with a nitrogen donor ligand in its coordination to the palladium salt. Examples of suitable heteroarenes can be found in Chem. Asian J. 2014, 9, 26 (such as furans, thiophenes, pyrroles, pyridine- /V-oxides, and benzofused derivatives thereof).

Examples

In the examples below dealing with the CDC of ortho-xylene, yields refer to the percentages of ortho-xylene that are converted into biaryl products, benzylic oxidation products, or triaryl isomers. Benzylic oxidation products refer to 2- methylbenzaldehyde, 2-methylbenzyl alcohol, and 2-methylbenzoic acid. Triaryl isomers refer to products with a molecular weight that equals that of a compound with the formula C24H26. The turnover number is defined as the combined 2334+3344 yield (in %) per palladium cation amount unit (in mol%). The space time yield of 3344+2334 biaryls is defined as the combined 2334+3344 yield (in milligrams) per added ortho- xylene and solvent volume unit (in milliliters) per reaction time unit (in hours). P refers to the molar amount of P-acid comprised in the catalyst system, Pd refers to the molar amount of Pd cations comprised in the catalyst system.

Gas Chromatography (GC) measurements were carried out on an Agilent 6890 instrument equipped with an Agilent HP-5 column (length, 30 m; diameter, 0.32 mm; film, 0.25 μηη). Settings: initial temperature, 80°C (1 min); ramp rate,

20°C/min; final temperature, 300°C (3 min). Retention times (min): Bald, 4.04;

hexadecane internal standard, 7.45; 2334, 8.45; 3344, 9.04. In the examples below dealing with the CDC of substrates other than ortho-xylene, GC area percentages of biaryl isomers refer to the sum of peak areas ascribed to biaryl isomers, as percentage of the total peak area excluding the peak of the solvent used for sample dilution.

Example 1 : CDC of ortho-xylene without solvent at 85°C/1 1 bar O2 with a catalyst system comprising a non-cyclopalladatable phosphinate in the form of a phosphinic acid as well as a palladium cation in the form of a palladium salt; 0.1 mol% Pd; P/Pd = 4,

A mixture of ortho-xylene (1 .0 ml_), palladium(ll) pivalate (0.1 mol% relative to ortho- xylene), and bis(perfluorophenyl)phosphinic acid (0.4 mol% relative to ortho-xylene) was stirred for -17 hrs at 85°C (external temperature) in an autoclave under 1 1 bar O2. The reaction mixture was diluted and a sample was subsequently analyzed by GC, using hexadecane as internal standard.

Yield of 3344+2334 biaryls: 8.9% Turnover number:

Space time yield of 3344+2334 biaryl

Yield of benzylic oxidation products:

Yield of triaryl isomers:

Molar 3344/2334 biaryl ratio:

Comparative experiment A: CDC of ortho-xylene carried out with the catalyst system as described in Adv. Synth. Catal. 2010, 352, 3223.

A mixture of ortho-xylene (0.4 g; 0.46 ml_), acetic acid (solvent; 0.4 g; 0.38 ml_;

solvent), palladium(ll) acetate (0.1 mol% relative to ortho-xylene), copper(ll) triflate (0.1 mol% relative to ortho-xylene), trifluoroacetic acid (0.13 mol% relative to ortho-xylene), and 2-fluoropyridine (0.2 mol% relative to ortho-xylene) was stirred for 17 hrs at 85°C (external temperature) in a glass vial under 1 bar O2. The reaction mixture was diluted and a sample was subsequently analyzed by GC, using hexadecane as internal standard. In various separate experiments, the color of the reaction mixture ranged from bright green to dark brown, and the yield of 3344+2334 biaryls ranged from 0.7- 5.2% (corresponds to space time yields ranging from 0.2-1.4 mg-mL^"1 -h^"1, respectively). Comparison of example 1 with comparative experiment A shows that both the

3344+2334 biaryl yield and the space time yield are significantly higher in example 1 than in comparative experiment A.

Example 2: CDC of ortho-xylene without solvent at 135°C/1 1 bar O2 with a catalyst system comprising a non-cyclopalladatable phosphinate in the form of a phosphinic acid as well as a palladium cation in the form of a palladium salt; 0.03 mol% Pd; P/Pd =

A mixture of ortho-xylene (1 .0 ml_), palladium(ll) pivalate (0.03 mol% relative to ortho- xylene), and bis(perfluorophenyl)phosphinic acid (0.06 mol% relative to ortho-xylene) was stirred for ~8 hrs at 135°C (external temperature) in an autoclave under 1 1 bar O2. The reaction mixture was diluted and a sample was subsequently analyzed by GC, using hexadecane as internal standard.

Yield of 3344+2334 biaryls:

Turnover number:

Space time yield of 3344+2334 biaryl

Yield of benzylic oxidation products:

Yield of triaryl isomers: Molar 3344/2334 biaryl ratio: 1 .1

Example 3: CDC of ortho-xylene without solvent at 85°C/1 1 bar O2 with a catalyst system comprising a non-cvclopalladatable phosphinate in the form of a phosphinic acid as well as a palladium cation in the form of a palladium salt; 0.1 mol% Pd; P/Pd

A mixture of ortho-xylene (1 .0 ml_), palladium(ll) pivalate (0.1 mol% relative to ortho- xylene), and bis(perfluorophenyl)phosphinic acid (0.2 mol% relative to ortho-xylene) was stirred for -17 hrs at 85°C (external temperature) in an autoclave under 1 1 bar O2. The reaction mixture was diluted and a sample was subsequently analyzed by GC, using hexadecane as internal standard.

Yield of 3344+2334 biaryls:

Turnover number:

Space time yield of 3344+2334 biaryl

Yield of benzylic oxidation products:

Yield of triaryl isomers:

Molar 3344/2334 biaryl ratio:

Example 4: CDC of ortho-xylene without solvent at 1 10°C/1 1 bar O2 with a catalyst system comprising a non-cvclopalladatable phosphinate in the form of a phosphinic acid as well as a palladium cation in the form of a palladium salt; 0.1 mol% Pd; P/Pd

A mixture of ortho-xylene (1 .0 ml_), palladium(ll) pivalate (0.1 mol% relative to ortho- xylene), and bis(perfluorophenyl)phosphinic acid (0.2 mol% relative to ortho-xylene) was stirred for -17 hrs at 1 10°C (external temperature) in an autoclave under 1 1 bar O2. The reaction mixture was diluted and a sample was subsequently analyzed by GC, using hexadecane as internal standard.

Yield of 3344+2334 biaryls:

Turnover number:

Space time yield of 3344+2334 biaryl

Yield of benzylic oxidation products:

Yield of triaryl isomers:

Molar 3344/2334 biaryl ratio: Example 5: CDC of ortho-xylene without solvent at 1 10°C/1 1 bar O2 with a catalyst system comprising a non-cyclopalladatable phosphinate in the form of a phosphinic acid, a palladium cation in the form of a palladium salt, as well as a ligand; 0.1 mol% Pd; P/Pd =2.

A mixture of ortho-xylene (1 .0 ml_), palladium(ll) pivalate (0.1 mol% relative to ortho- xylene), bis(perfluorophenyl)phosphinic acid (0.2 mol% relative to ortho-xylene), and 2- (difluoromethyl)pyridine (ligand; 0.1 mol% relative to ortho-xylene) was stirred for -17 hrs at 1 10°C (external temperature) in an autoclave under 1 1 bar O2. The reaction mixture was diluted and a sample was subsequently analyzed by GC, using

hexadecane as internal standard.

Yield of 3344+2334 biaryls: 9.9%

Turnover number: 99

Space time yield of 3344+2334 biaryls: 5.1 mg-mL^"1 -h^"1

Yield of benzylic oxidation products: 0.4%

Yield of triaryl isomers: 0.3%

Molar 3344/2334 biaryl ratio: 4.3

From the molar 3344/2334 biaryl ratios of 4.3 in example 6 and 2.2 in example 5, it follows that the addition of a ligand in the form of 2-(difluoromethyl)pyridine improves the regioselectivity of the catalyst towards formation of 3344.

Example 6: CDC of ortho-xylene without solvent at 135°C/1 1 bar O2 with a catalyst system comprising a non-cyclopalladatable phosphinate in the form of a phosphinic acid as well as a palladium cation in the form of a palladium salt; 0.1 mol% Pd; P/Pd = A mixture of ortho-xylene (1 .0 ml_), palladium(ll) pivalate (0.1 mol% relative to ortho- xylene), and bis(perfluorophenyl)phosphinic acid (0.2 mol% relative to ortho-xylene) was stirred for ~8 hrs at 135°C (external temperature) in an autoclave under 1 1 bar O2. The reaction mixture was diluted and a sample was subsequently analyzed by GC, using hexadecane as internal standard.

Yield of 3344+2334 biaryls: 16.2%

Turnover number: 162

Space time yield of 3344+2334 biaryls: 17.6 mg-mL^"1 -h^"1

Yield of benzylic oxidation products: 0.0%

Yield of triaryl isomers: 3.3%

Molar 3344/2334 biaryl ratio: 1 .4 Example 7: CDC of ortho-xylene without solvent at 135°C/1 1 bar O2 with a catalyst system comprising a non-cyclopalladatable phosphinate in the form of a phosphinic acid as well as a palladium cation in the form of a palladium salt; pivalic acid used as Bronsted acid additive; 0.1 mol% Pd; P/Pd = 2.

A mixture of ortho-xylene (1 .0 ml_), palladium(ll) pivalate (0.1 mol% relative to ortho- xylene), bis(perfluorophenyl)phosphinic acid (0.2 mol% relative to ortho-xylene), and pivalic acid (Bransted acid additive; 0.6 mol% relative to ortho-xylene) was stirred for ~8 hrs at 135°C (external temperature) in an autoclave under 1 1 bar O2. The reaction mixture was diluted and a sample was subsequently analyzed by GC, using

hexadecane as internal standard.

Yield of 3344+2334 biaryls:

Turnover number:

Space time yield of 3344+2334 biaryl

Yield of benzylic oxidation products:

Yield of triaryl isomers:

Molar 3344/2334 biaryl ratio:

From both the combined 3344+2334 yield of 16.2% in example 6 and 21 .0% in example 7 and the molar 3344/2334 biaryl ratios of 1.4 in example 6 and 1.8 in example 7, it follows that the addition of a Bransted acid in the form of pivalic acid improves both the activity of the catalyst towards biaryl formation and the

regioselectivity of the catalyst towards formation of 3344.

Example 8: CDC of ortho-xylene without solvent at 85°C/1 1 bar O2 with a catalyst system comprising a non-cyclopalladatable phosphate in the form of a non-cyclic monohydrogen phosphate as well as a palladium cation in the form of a palladium salt; 0.5 mol% Pd; P/Pd = 2.

A mixture of ortho-xylene (1 .0 ml_), palladium(ll) acetate (0.5 mol% relative to ortho- xylene), and dimethyl hydrogen phosphate (1 mol% relative to ortho-xylene) was stirred for -17 hrs at 85°C (external temperature) in an autoclave under 1 1 bar O2. The reaction mixture was diluted and a sample was subsequently analyzed by GC, using hexadecane as internal standard.

Yield of 3344+2334 biaryls: 10.4%

Turnover number: 20.8

Space time yield of 3344+2334 biaryls: 5.3 mg-mL^"1 -h^"1 Yield of benzylic oxidation products: 0.4%

Yield of triaryl isomers: 0.4%

Molar 3344/2334 biaryl ratio: 4.1 Example 9: CDC of ortho-xylene without solvent at 135°C/1 1 bar O2 with a catalyst system comprising a non-cyclopalladatable phosphate in the form of a cyclic monohydrogen phosphate as well as a palladium cation in the form of a palladium salt; 0.5 mol% Pd; P/Pd = 2.

A mixture of ortho-xylene (1 .0 ml_), palladium(ll) acetate (0.5 mol% relative to ortho- xylene), and 2-hydroxy-1 ,3,2-dioxaphosphepane 2-oxide (1 mol% relative to ortho- xylene) was stirred for -17 hrs at 135°C (external temperature) in an autoclave under 1 1 bar O2. The reaction mixture was diluted and a sample was subsequently analyzed by GC, using hexadecane as internal standard.

Yield of 3344+2334 biaryls: 13.9%

Turnover number: 27.8

Space time yield of 3344+2334 biaryls: 7.1 mg-mL^"1 -h^"1

Yield of benzylic oxidation products: 0.2%

Yield of triaryl isomers: 1 .1 %

Molar 3344/2334 biaryl ratio: 3.6

Example 10: CDC of ortho-xylene without solvent at 85°C/1 1 bar O2 with a catalyst system comprising a non-cyclopalladatable phosphate in the form of a monohydrogen phosphonate as well as a palladium cation in the form of a palladium salt; 0.5 mol% Pd;

P/Pd = 2.

A mixture of ortho-xylene (1 .0 ml_), palladium(ll) acetate (0.5 mol% relative to ortho- xylene), and ethyl hydrogen methylphosphonate (1 mol% relative to ortho-xylene) was stirred for -17 hrs at 85°C (external temperature) in an autoclave under 1 1 bar O2. The reaction mixture was diluted and a sample was subsequently analyzed by GC, using hexadecane as internal standard.

Yield of 3344+2334 biaryls: 7.7%

Turnover number: 15.4

Space time yield of 3344+2334 biaryls: 3.9 mg-mL^"1 -h^"1

Yield of benzylic oxidation products: 0.3%

Yield of triaryl isomers: 0.2%

Molar 3344/2334 biaryl ratio: 4.7 Example 1 1 : CDC of ortho-xylene without solvent at 1 10°C/1 1 bar O2 with a catalyst system comprising a non-cyclopalladatable phosphonate in the form of a phosphonic acid with an additional functional group that may coordinate to the palladium center, a palladium cation in the form of a palladium salt, as well as a ligand; 0.1 mol% Pd; P/Pd = 1 .

A mixture of ortho-xylene (1 .0 ml_), palladium(ll) pivalate (0.1 mol% relative to ortho- xylene), (pyridin-2-ylmethyl)phosphonic acid (0.1 mol% relative to ortho-xylene), and 2- (difluoromethyl)pyridine (ligand; 0.1 mol% relative to ortho-xylene) was stirred for -17 hrs at 1 10°C (external temperature) in an autoclave under 1 1 bar O2. The reaction mixture was diluted and a sample was subsequently analyzed by GC, using hexadecane as internal standard.

Yield of 3344+2334 biaryls:

Turnover number:

Space time yield of 3344+2334 biaryl

Yield of benzylic oxidation products:

Yield of triaryl isomers:

Molar 3344/2334 biaryl ratio: Example 12: CDC of ortho-xylene without solvent at 85°C/1 1 bar O2 with a catalyst system comprising a non-cyclopalladatable phosphinate as well as a palladium cation in the form of a palladium phosphinate salt; 0.5 mol% Pd.

The palladium(ll) salt of bis(perfluorophenyl)phosphinic acid was prepared by evaporation of solvent and acetic acid from a dichloromethane solution of

bis(perfluorophenyl)phosphinic acid and palladium(ll) acetate in a 2/1 molar ratio. A mixture of ortho-xylene (1 .0 ml.) and the palladium(ll) salt of

bis(perfluorophenyl)phosphinic acid (0.5 mol% relative to ortho-xylene) was stirred for -17 hrs at 85°C (external temperature) in an autoclave under 1 1 bar O2. The reaction mixture was diluted and a sample was subsequently analyzed by GC, using hexadecane as internal standard.

Yield of 3344+2334 biaryls: 9.8%

Turnover number: 19.6

Space time yield of 3344+2334 biaryls: 5.0 mg-mL^"1 -h^"1

Yield of benzylic oxidation products: 0.0%

Yield of triaryl isomers: 0.7% Molar 3344/2334 biaryl ratio: 3.4

Example 13: CDC of toluene without solvent at 1 10°C/13 bar O2 with a catalyst system comprising a non-cyclopalladatable phosphinate in the form of a phosphinic acid as well as a palladium cation in the form of a palladium salt; 0.1 mol% Pd; P/Pd = 2.

A mixture of toluene (1.0 mL), palladium(ll) pivalate (0.1 mol% relative to toluene), and bis(perfluorophenyl)phosphinic acid (0.2 mol% relative to toluene) was stirred for -17 hrs at 1 10°C (external temperature) in an autoclave under 13 bar O2. The reaction mixture was diluted and a sample was subsequently analyzed by GC.

GC area percentage of biaryl isomers: 15.8%

Example 14: CDC of (trifluoromethyl)benzene without solvent at 1 10°C/13 bar O2 with a catalyst system comprising a non-cyclopalladatable phosphinate in the form of a phosphinic acid as well as a palladium cation in the form of a palladium salt; 0.1 mol% Pd; P/Pd = 2.

A mixture of (trifluoromethyl)benzene (1.0 mL), palladium(ll) pivalate (0.1 mol% relative to (trifluoromethyl)benzene), and bis(perfluorophenyl)phosphinic acid (0.2 mol% relative to (trifluoromethyl)benzene) was stirred for -17 hrs at 1 10°C (external temperature) in an autoclave under 13 bar O2. The reaction mixture was diluted and a sample was subsequently analyzed by GC.

GC area percentage of biaryl isomers: 3.9%

Example 15: CDC of meta-xylene without solvent at 1 10°C/13 bar O2 with a catalyst system comprising a non-cyclopalladatable phosphinate in the form of a phosphinic acid as well as a palladium cation in the form of a palladium salt; 0.1 mol% Pd; P/Pd =

2.

A mixture of meta-xylene (1 .0 mL), palladium(ll) pivalate (0.1 mol% relative to meta- xylene), and bis(perfluorophenyl)phosphinic acid (0.2 mol% relative to meta-xylene) was stirred for -17 hrs at 1 10°C (external temperature) in an autoclave under 13 bar O2. The reaction mixture was diluted and a sample was subsequently analyzed by GC.

GC area percentage of biaryl isomers: 1 1.0%

Example 16: CDC of naphthalene without solvent at 1 10°C/13 bar O2 with a catalyst system comprising a non-cyclopalladatable phosphinate in the form of a phosphinic acid as well as a palladium cation in the form of a palladium salt; 0.1 mol% Pd; P/Pd =

A mixture of naphthalene (1 .0 g), palladium(ll) pivalate (0.1 mol% relative to naphthalene), and bis(perfluorophenyl)phosphinic acid (0.2 mol% relative to naphthalene) was stirred for -17 hrs at 1 10°C (external temperature) in an autoclave under 13 bar O2. The reaction mixture was diluted and a sample was subsequently analyzed by GC.

GC area percentage of biaryl isomers: 18.6% Example 17: CDC of ortho-xylene and meta-xylene; illustration of heterocoupling of two different arenes without solvent at 1 10°C/13 bar O2 with a catalyst system comprising a non-cyclopalladatable phosphinate in the form of a phosphinic acid as well as a palladium cation in the form of a palladium salt; 0.1 mol% Pd; P/Pd = 2.

A mixture of ortho-xylene (0.5 g), meta-xylene (0.5 g), palladium(ll) pivalate (0.1 mol% relative to the combined xylenes), and bis(perfluorophenyl)phosphinic acid (0.2 mol% relative to ortho-xylene) was stirred for -17 hrs at 1 10°C (external temperature) in an autoclave under 13 bar O2. The reaction mixture was diluted and a sample was subsequently analyzed by GC.

GC/MS analysis showed the presence of 3,3',4,5'-tetramethyl-1 ,1 '-biphenyl

(heterocoupling product) besides 3, 3',4, 4'-tetramethyl-1 ,1 '-biphenyl and 3, 3', 5,5'- tetramethyl-1 ,1 '-biphenyl (homocoupling products).

Claims

1 . A process for producing biaryl compounds by aerobic cross dehydrogenative coupling (CDC) of two arene groups comprising at least one aryl carbon- hydrogen bond, in the presence of a catalyst system, characterized in that the catalyst system comprises as phosphor containing acid a non-cyclopalladatable phosphinate and/or a non-cyclopalladatable phosphate monoester and/or a non-cyclopalladatable phosphate diester and/or a non-cyclopalladatable phosphonate and/or a non-cyclopalladatable phosphonate monoester as well as a palladium cation.

2. A process according to claim 1 , wherein the catalyst system comprises as

phosphor containing acid a non-cyclopalladatable phosphinate and/or a non- cyclopalladatable phosphate diester and/or a non-cyclopalladatable

phosphonate and/or a non-cyclopalladatable phosphonate monoester.

3. A process according to claim 1 or 2, wherein the phosphinate is in the form of a phosphinic acid.

4. A process according to any one of claims 1 -3, wherein the phosphate

monoester is in the form of a dihydrogen phosphate.

5. A process according to any one of claims 1 -4, wherein the phosphate diester is in the form of a monohydrogen phosphate.

6. A process according to any one of claims 1 -5, wherein the phosphonate is in the form of a phosphonic acid.

7. A process according to any one of claims 1 -5, wherein the phosphonate

monoester is in the form of a monohydrogen phosphonate.

8. A process according to claim 3, wherein the phosphinic acid has a pK_a that is smaller than the pK_a of dimethyl hydrogen phosphate.

9. A process according to claim 8, wherein the phosphinic acid is a

bis(perfluoroaryl)phosphinic acid or bis(perfluoroalkyl)phosphinic acid.

10. A process according to any one of the preceding claims, wherein the catalyst system comprises a palladium cation in the form of a palladium salt.

1 1 . A process according to claim 10, wherein the palladium salt is derived from an acid with a pK_a that is larger than the pK_a of the P-acid or P-acids.

12. A process according to claim 10, wherein the palladium salt is a palladium

dicarboxylate.

13. A process according to any one of claims 10-12, wherein the molar ratio of phosphor containing acid/palladium is 1 .8/1 - 10/1 and the P-acid is devoid of an additional functional group that may coordinate to the palladium center.

14. A process according to any one of claims 10-12, wherein the molar ratio of phosphor containing acid /palladium is 0.8 /1 - 1.2/1 and the phosphor containing acid contains an additional functional group that may coordinate to the palladium center.

15. A process according to any one of the preceding claims, wherein at most 50 wt% of solvent is used relative to the total reaction mass.

16. A process according to claim 15, wherein at most 25 wt% of solvent is used relative to the total reaction mass.