Process for producing a biaryl compound having at least two aryl moieties

Abstract

The invention pertains to a process for producing a biaryl compound having at least 2 aryl moieties by cross dehydrogenative coupling (CDC) comprising the step of reacting aryl compounds comprising at least one aryl carbon-hydrogen bond in the presence of an oxidant and a catalyst system comprising a Pd salt and an S,O-ligand, the S,O-ligand comprising at least one oxygen atom and at least one sulfur atom. The process according to the invention makes it possible to manufacture biaryl compounds having at least two aryl moieties in an efficient and cost-effective manner from widely available starting materials. The process can be carried out in under conditions which are attractive for commercial operation while showing attractive yield and selectivity. In one embodiment the synthesis of 3,3',4,4'-tetramethyl-1,1'-biphenyl from o-xylene makes it possible to obtain a 4,4' biphthalic anhydride in two steps rather than in four steps as described above.

Description

[0001] WO40075-HS / mz Process for producing a biaryl compound having at least two aryl moieties 5 The present invention pertains to a process for producing a compound having at least two aryl moieties. Biaryl compounds constitute an important class of compounds with a variety of applications, e.g. in market segments related to pharmaceuticals, agrochemicals, chemicals used in electronic applications. chemicals and polymers. Especially for the producing polymers is it important to produce biaryl compound monomers at low cost. 10 Processes for the production of biaryl compounds have been described. For example, JP2000 / 186063 describes the production of the biaryl compound 3,3',4,4'-biphenyl tetracarboxylic acid tetra-ester. 3,3',4,4'-Biphenyl tetracarboxylic acid tetra-ester is used as monomer for the synthesis of the high performance polyimide Upilex®. The compound is 15 obtained by carrying out the dimerization of an o-phthalic acid diester in the presence of a powdery palladium salt catalyst. However this synthesis requires four steps. An attractive alternative method for the synthesis of biaryl compounds is aerobic cross dehydrogenative coupling. WO 2016 / 008931 describes a process for producing biaryl 20 compounds by CDC of two arene groups in the presence of a catalyst system comprising a palladium salt comprising at least one non-cyclopalladatable carboxylate anion and one or more non-beta-eliminatable, non-cyclopalladatable ligands comprising at least one N-donor atom. Alvarez-Casao et al. ChemCatChem Vol 10, 2620-2626, 2018 describes the cross- 25 dehydrogenative coupling of o-xylene using a palladium carboxylate catalyst in combination with an N-donor ligand. The process described in this reference uses high oxygen pressure to achieve meaningful conversion. Further, the selectivity of the process can be improved. For example, Table S1 for the supporting information for this publication shows that a CDC reaction at 80ºC and 1 bar oxygen pressure in the absence of solvent results in yields of less than 1%, 30 and even at 95ºC and at 11 bar oxygen pressure the maximum yield is 17.6%. There is need for a process to produce biaryl compounds which can provide the desired products in high yield and high chemo- and regio-selectivity using starting materials and conditions which are applicable on an industrial scale. Conditions suitable for applicability on 35 an industrial scale include the use of low oxygen pressure (e.g., of the order of 1 atm), with minimum amounts of solvent (if any), while providing high yield and selectivity at acceptable temperature. 1

[0002] The present invention provides such a process. The invention pertains to a process for producing a biaryl compound having at least 2 aryl 5 moieties by cross dehydrogenative coupling (CDC) comprising the step of reacting aryl compounds comprising at least one aryl carbon-hydrogen bond in the presence of an oxidant and a catalyst system comprising a Pd salt and an S,O-ligand, the S,O-ligand comprising at least one oxygen atom and at least one sulfur atom. 10 It has been found that the process according to the invention makes it possible to manufacture biaryl compounds having at least two aryl moieties in an efficient and cost-effective manner from widely available starting materials. It has also been found that under mild reactions conditions suitable for industrial application the process shows good regioselectivity, excellent chemoselectivity and synthetically useful yields. 15 In one embodiment the synthesis of 3,3′,4,4′-tetramethyl-1,1′-biphenyl from o-xylene makes it possible to obtain a 4,4’ biphthalic anhydride in two steps rather than in four steps as described above. Further advantages of the present invention and specific embodiments will become apparent from the further specification. 20 The invention will be discussed in more detail below. The invention pertains to a process for manufacturing a biaryl compound having at least 2 aryl moieties by cross dehydrogenative coupling (CDC) of two aryl compounds. The process of the invention involves the oxidative dehydrogenative homocoupling of two identical aryl C-H bonds 25 in two identical molecules. The reaction may also be referred to as “oxidative homocoupling” or “homocoupling” for short. The aryl compounds used in the present invention comprise at least one aryl carbon-hydrogen bond. Otherwise they may be selected from a variety of compounds. 30 In the context of the present specification the following definitions are used. A monoaryl compound is a compound having a single aromatic ring. A polycyclic aryl compound comprises at least one polycyclic aryl moiety formed by two or more aromatic rings fused together. 35 A multicyclic aryl compound comprises at least two aryl moieties which may be monocyclic or polycyclic. 2

[0003] A biaryl compound is an organic aromatic compound whose structure contains two aromatic rings or ring systems joined to each other by a single bond. In the present specification the term “aryl” also encompasses “heteroaryl”, unless it is clear from the context that this is not intended. 5 In one embodiment the starting material for the process of the invention is a monoaryl compound optionally substituted with at least one group selected from C1-C8 alkyl, C1-C8 alkylether, or ester C1-C8 alkyl, wherein any of these groups may be substituted with one or more C1-C8 alkyl, halogen, oxirane, amido C1-C8 alkyl or O, wherein the aryl moiety may be 10 homocyclic or heterocyclic with the aryl moiety optionally being substituted with halogen or hydroxy. Preferably, the monoaryl compound is substituted with at least one group selected from C1-C4 alkyl, C1-C4 alkylether, or ester C1-C4 alkyl, wherein any of these groups may be substituted with one or more C1-C4 alkyl, halogen, oxirane, amido C1-C4 alkyl or O, with the aryl ring 15 optionally being substituted with halogen, wherein at least two neighboring substituents on the aromatic ring are H. More preferably, the monoaryl compounds are substituted with at least one group selected from C1 alkyl, C1 alkylether, ester C1 alkyl, wherein the any of these groups may be substituted with one or more C1 alkyl, halogen, oxirane, amido C1 alkyl or O, with the aryl ring optionally 20 being substituted with halogen, wherein at least two neighboring substituents are H. It is particularly preferred for the monoaryl moiety to be substituted with methyl or methoxy. Where the aryl moiety is a 6-membered ring it will generally be a homocyclic ring. Where the aryl moiety is a 5-membered ring it may be a homocyclic ring or a heterocyclic ring. It is preferred for the aryl moiety to be based on a 6-membered homocyclic ring, i.e. a benzene 25 ring, or on a 5-membered ring containing a sulfur atom, i.e., a thiophene ring. In one embodiment the aryl compound used as starting material in the present invention is a compound in which the aryl moiety is based on a 6-membered homocyclic ring, i.e. a benzene ring, or on a 5-membered ring containing a sulfur atom, i.e., a thiophene ring, wherein the aryl 30 moiety is substituted on one or two locations with at least one of C1-C4alkyl, in particular methyl, and C1-C4alkylether, in particular methoxy, wherein the aromatic ring has at least two neighboring H-atoms, in particular three neighboring H-atoms. The use of methylanisole (2- methoxytoluene) of formula 4, o-xylene of formula 5, or 2-methylthophene of formula 6 is particularly preferred, as these compounds yield products which find particular application in 35 chemical industry. These compounds are as follows: 3

[0004] formula 4 formula 5 formula 6 In one embodiment, the aryl compound used as starting material in the process according to 5 the invention is selected from the group of anisole compounds, including anisole, C1-C4 alkylanisoles, in particular 2-methylanisole, 3-methylanisole, 4-methylanisole, and 2-tert.butyl anisole, halogen anisoles such as 2-chloroanisole, 2-bromoanisole, xylenes, in particular o- xylene and m-xylene, alkoxybenzenes such as 1,3-dimethoxybenzene, 1,4- dimethoxybenzene, 1,3-di-tert-butyl-2-methoxybenzene, 1,2-dimethoxy-4-methylbenzene, 1-10 ((benzyloxy)methyl)-4-methoxybenzene, 1-fluoro-2,4-dimethoxybenzene, 1-(3-chloro- propoxy)-2-methylbenzene, 1-(methoxymethoxy)-2-methylbenzene, 1-(tert-butoxy)-2- methylbenzene, 1,2-dimethoxybenzene, methyl 2-methoxybenzoate, guaifenesin dimethyl ether, N-(3-methoxyphenethyl)acetamide. 2-((2,6-dimethylphenoxy)methyl)oxirane is also a preferred compound within the claimed invention, as are 2,6-di-tert-butylphenol, 2,6-di-iso- 15 propylphenol, 2-(o-tolyloxy)acetate. The use of 2-((phenoxy)methyl)oxirane is also preferred. In another embodiment starting materials are selected from toluene, naphthalene, halogenated arenes such as 1,3- and 1,2-dichlorobenzene, and ethylbenzoate. Within the group of thiophene compounds methylthiophenes, in particular 2-methylthiophene, halogen-substituted thiophenenes such as 2-chlorothiophene and 2-bromothiophene, and 20 compounds including 2-methoxythiophene and 2-phenyl thiophene have been found to be preferred. In another embodiment, the aryl compound used as starting material in the present invention is polycyclic compound according to Formula 1 25 Formula 1 wherein A is C, a C-C chain, or O, S, or N, 30 wherein X is C or O, S, or N, 4

[0005] wherein the ring comprising A and X may be aliphatic or aromatic, wherein the aryl ring and ring comprising A and X are optionally substituted with at least one group selected from C1-C8alkyl, C1-C8alkylether, or ester C1-C8alkyl, and optionally with halogen or hydroxy, wherein any of these groups may be substituted with one or 5 more C1-C8 alkyl, halogen, oxirane, amido C1-C8 alkyl or O. Within this group it is preferred for the substituents to be selected from C1-C4 alkyl, C1-C4 alkylether, or ester C1-C4 alkyl, and optionally halogen or hydroxy, in particular C1 alkyl, C1 alkylether, ester C1 alkyl, and halogen, wherein any of these groups may be substituted with one or more C1 alkyl, halogen, oxirane, amido C1 alkyl or O, wherein at least two neighboring 10 substituents are H. In one embodiment, the starting compound is selected from methyl chromane-3-carboxylate, 4-methoxy-2,3-dihydro-1H-indene, 6-methoxy-3,4-dihydronaphthalen-1(2H)-one, 5- methoxybenzo[d][1,3]dioxole, 6-methoxy-2,3-dihydrobenzo[b][1,4]dioxine, 7-methyl-2,3- dihydrobenzofuran, 1-methoxynaphthalene, Nabumetone, and 1,1,4,4-tetramethyl-1,2,3,4- 15 tetrahydronaphthalene. In a further embodiment the aryl compound used as starting material is an aryl compound selected from compounds according to formula 2 or 3: 20 The reaction is carried out in the presence of an S,O-ligand which comprises at least one oxygen atom and at least one sulfur atom. The sulfur atom and the oxygen atom will be in relatively close proximity, generally separated by less than 8 carbon atoms, in particular less 25 than 6 carbon atoms. The oxygen atom is preferably present in the form of a carboxyl group or a derivative thereof such as a carboxylic acid ester, a C(O) group or a hydroxyl group. Its presence as a carboxyl group is considered particularly preferred. The sulphur atom is preferably present in the form of a -S- group. 5

[0006] It is noted that the use of Pd-S,O ligands in organic synthesis has already been described for other types of reactions. For example Naksomboon et al., ACS Catal., 2017, 6342-6346 describes the C-H functionalisation reaction on non-directed arenes using Pd-S,O ligands. Naksomboon et al., J. Am. Chem. Soc. 2019, 6719-6725 describes para-selective C-H 5 olefination of aniline derivatives via Pd / S,O ligand catalysis. Naksomboon et al., Tetrahedron Letters 59 (2018) 379-382 describes the C-H olefination of arenes with allylic substrates in the presence of palladium acetate and an S,O ligand. Alvarez-Casao et al, Eur. J. Org. Chem., 2019, 1842-1845 describes the C-H olefination of thiophenes with allylic substrates in the presence of palladium acetate and an S,O ligand.10 Ke-Zuan Deng et al., Angew. Chem. Int. Ed 2024, 63 e202400689, describes non-directed C- H arylation of anisole derivatives via Pd / S,O-ligand catalysis. Sukowski et al. Angew. Chem. Int. Ed.2022, 61 e202201750 describes S,O-ligand promoted meta-C-H arylation of anisole derivatives via palladium / norbornene catalysis with an S,O ligand. The reaction starts out from an aryl iodide or aryl bromide. 15 Naksomboon et al, Chem. Sci., 2023, 14, 2943 describes mechanistic studies of C-H olefination of aromatic compounds with a palladium catalyst and an S,O ligand. As will be evident to the skilled person, aerobic CDC of arenes takes place through a different reaction mechanism, and the efficacy of the Pd / S,O ligand system in other reactions is not in 20 any way predictive for its efficacy in aerobic CDC of arenes. In addition, the excellent chemoselectivity and attractive regioselectivity observed for the present invention, e.g., for o- xylene, could not be predicted in advance, nor could the mild reaction conditions and the possibility of using air as oxidant. 25 In one embodiment, the S,O ligand is a compound of the formula 7 - a ligand of formula 7 30 formula 7 wherein R1 is selected from the group of halogen, hydroxy, carboxy, amine, C1-C10 alkyl, C4- C10 aryl or C4-C10 heteroaryl, wherein the alkyl or aryl groups may in turn be substituted with, halogen, hydroxy, carboxy, amine, and 6

[0007] R2, R3 are independently selected from the group of H, halogen, hydroxy, carboxy, amine, C1- C10alkyl, C4-C10aryl or C4-C10heteroaryl, wherein the alkyl or aryl groups may in turn be substituted with, halogen, hydroxy, carboxy, amine, and n = 1 to 6, 5 It is preferred that n is in the range of 1-4, in particular 1 or 2. It is preferred that R1 is selected from C4-C10 aryl, in particular C4-C10 aryl substituted with halogen. It is preferred that R2 and R3 are independently selected from H or C1-C10 alkyl, in particular C1-C4 alkyl. 10 In one embodiment n is 1, R1 is perfluorofenyl, and R2 and R3 are selected from H and methyl or isopropyl. In one embodiment, the ligand is selected from 15 In one embodiment, the ligand is of the formula 8 formula 8 20 wherein R1, R2, R3 and n have the meaning stipulated above, and X is selected from the group of C=O; P=O; S=O, SO2, P(O)OH, and P(O)OR, wherein R is selected from C1-C10 alkyl, C4-C10 aryl or C4-C10 heteroaryl, wherein the alkyl or aryl groups may In turn be substituted with halogen, halogen, hydroxy, carboxy, amine. 25 In a further embodiment, the ligand is selected from compounds of the formula 9 or 10, in which R1 is selected from C1-C10 alkyl, C4-C10 aryl or C4-C10 heteroaryl, wherein the alkyl or aryl groups may in turn be substituted with halogen, hydroxy, carboxy, amine, and R2 is selected from H, halogen, hydroxy, carboxy, amine, C1-C10alkyl, C4-C10aryl or C4-C10heteroaryl, wherein the alkyl or aryl groups may In turn be substituted with halogen, hydroxy, carboxy, 30 amine. 7

[0008] formula 9 formula 10 5 The ligand is generally provided in an amount of 0.01-20 mol%, calculated on the amount of starting aryl compound, in particular in an amount of 0.01-10 mol%, more in particular in an amount of 0.01-5 mol%, e.g., in an amount of 0.01 to 1 mol%. If the amount of ligand that is used is too low, the catalytic effect of the reaction may not be obtained. On the other hand, the addition of a too large amount of ligand will not contribute to the efficacy of the reaction while 10 it will contribute to the costs. The reaction is carried out in the presence of a Pd salt. The Pd salt works together with the S,O-ligand to catalyse the reaction. Suitable Pd salts include palladium carboxylate salts and palladium carbonate salts., e.g. palladium acetate. 15 The Pd salt is generally used in an amount of 0.01-20 mol%, calculated on the amount of starting aryl compound, in particular in an amount of 0.01-10 mol%, more in particular in an amount of 0.01-5 mol%, e.g., in an amount of 0.01 to 1 mol%. If the amount of Pd salt that is used is too low, the catalytic effect of the reaction may not be obtained. On the other hand, the addition of a too large amount of Pd salts will not contribute to the efficacy of the reaction while 20 it will contribute to the costs. The reaction is generally carried out in the liquid phase. Where the reactants themselves are liquid as is the case for, e.g., o-xylene and 2-methylanisole, the addition of a further solvent may not be required. Nevertheless, it has been found that even in those cases the presence 25 of a further solvent may sometimes be useful to increase the reaction yield. Where the reactants themselves are not in the liquid phase at reaction conditions, the presence of a solvent will generally be required. In one embodiment, the reaction is carried out in the presence of a solvent. It has been found 30 that the addition of a minor amount of solvent may result in an increase in yield of the reaction. Therefore, in one embodiment solvent is used in an amount of at least 1 mol% of solvent calculated on the amount of the aryl compound to be converted, in particular at least 2 mol%. Within this embodiment it may be preferred to add at most 30 mol%, in particular at most 20 mol%. 8

[0009] Depending on the aryl compound and the nature of the solvent it may be preferred to use more solvent, e.g., in an amount which is such that the concentration of the aryl compound in the solvent is in the range of 0.05 to 4 M, in particular in the range of 0.1 to 2 M. The nature of the solvent is not critical in the present invention, as long as the solvent itself 5 does not react. Examples of suitable solvents include conventional organic solvents such as alcohols (methanol, ethanol, propanol, isopropanol, butanol, pentanol, hexanol, heptanol. octanol, decanol, etc.), aldehydes, ketones such as acetone, methylethylketone, methylbutylketone, 10 esters such as ethylacetate, ethers such as MTBE is methyl-tert-butylether, solvents such as acetic acid, tetrahydrofuran (THF), 1,4-dioxane, dichloromethane (DCM), 1,2-dichloroethane (DCE), tert-amylalcohol, acetonitrile, propylene carbonate (PC), dimethylacetamide (DMA) or N-methyl-2-pyrrolidone (NMP), and fluorine containing solvents such as such as hexafluoro-2- propanol (HFIP), (CF3)3COH, trifluoroacetic acid (TFA), and trifluorethanolacid (TFE). 15 Combinations of solvents may also be used, as may combinations of solvent and water in particular combinations of solvent and water which are miscible, e.g., combinations of water and one or more of THF, HFIP and ethylacetate. The use of fluorine-containing solvents has been found to give good results, with the use of 20 hexafluoro-2-propanol (HFIP), trifluoroacetic acid (TFA), and trifluorethanolacid (TFE) being preferred, with the use of trifluoroacetic acid (TFA) and trifluorethanolacid (TFE) being particularly preferred. For thiophene compounds ethylacetate was found to be particularly preferred as solvent. 25 In one embodiment, a combination of an organic solvent and water is used. This may be particularly attractive for fluorine-containing solvents as discussed above. It has been found that the presence of water may improve the yield of the reaction. If a combination of solvent and water is used, it is preferred for the amount of water to be relatively limited, e.g., in an amount of 2-40 wt.%, calculated on the total of solvent and water, in particular 4-35 wt.%. The 30 combination of THF and water in an amount of 2-30 wt.%, calculated on the total of solvent and water, in particular 2-25 wt.% has been found particularly attractive, specifically for thiophene starting materials. The process according to the invention is carried out in the presence of an oxidant. The oxidant 35 preferably is selected from the group of oxygen or H2O2, wherein oxygen is preferably provided in the form of an oxygen-containing gas, e.g., in the form of air. Other oxidants may also be used, e.g., organic peroxides, metal carboxylate salts and metal carbonate salts. Examples of 9

[0010] suitable metal carboxylate salts and metal carbonate salts are Cu(OAc)2, Ag(OAc)2, AgOAc, AgCO3, AgTFA, Ag2CO3, AcOH, PhCO3tBu, and combinations thereof. Combinations of various types of oxidants, e.g. an oxygen containing gas and a metal carboxylate salt or metal carbonate salt may also be used. 5 Where the oxidant is a solid oxidant, e.g., an organic peroxide, a metal carboxylate salt or a metal carbonate salt, the oxidant generally provided in an amount of 0.01 to 3.0 equivalent, calculated on the starting aryl compound, in particular in an amount of 0.01 to 2.5 equivalent, more in particular in an amount of 0.01 to 2 equivalent. Where a solid oxidant is used in combination with oxygen, lower amounts may be attractive, e.g., at most 1.5 equivalent, in 10 particular at most 1.0 equivalent. Where an oxygen-containing gas is used, it is preferably provided at a total pressure of 0.5-5 bar (0.5 – 5 atm), preferably at a total pressure of 0.9-2 bar (0.9 - 2 atm). The amount of oxygen in the oxygen-containing gas is not critical. It may vary between 100 vol.% (pure oxygen), and say, 1 vol.%. Very low percentages may not be attractive as they will entail the use of large 15 gas streams. Air has been found to be a suitable gas, but other oxygen-containing gases may also be used, as long as they do not contain components which will interfere with the reaction. In general, the pressure at which the reaction is carried out is not critical. Atmospheric pressure is generally suitable, taking the above into account. 20 The reaction is generally carried out at a temperature in the range of 0-120ºC, in particular in the range of 5-100ºC, more in particular in the range of 10-80ºC. In a preferred embodiment of the present invention o-xylene is reacted to form 3,3’,4,4’- tetramethyl-1,1’-biphenyl in the presence of 2-methyl-2-[(perfluorophenyl)thio]propanoic acid 25 (L1 as specified above) and Pd-acetate as palladium salt. This reaction is particularly attractive because it provides an effective manner to obtain 3,3’,4,4’-tetramethyl-1,1’-biphenyl in good yield and selectivity. 3,3’,4,4’-tetramethyl-1,1’-biphenyl is an attractive starting material to obtain 4,4’biphthalic anhydride, which in turn is an attractive starting material for many industrial applications, including the synthesis of polyimides. The use of a fluorine-containing 30 solvent is preferred in this context, in particular a solvent selected from the group consisting of hexafluoro-2-propanol (HFIP), trifluoroacetic acid (TFA), and trifluorethanolacid (TFE), in particular TFA or TFE. The use of oxygen, in particular provided in the form of an oxygen- containing gas, e.g., in the form of air is the preferred oxidant. It has been found that where an oxygen-containing gas is used, it can be provided at a total pressure of 0.5-5 bar (0.5 – 5 atm), 35 preferably at a total pressure of 0.9-2 bar (0.9 - 2 atm) while still obtaining good yields. These ranges are attractive for commercial operation. The reaction is preferably carried out at a 10

[0011] temperature in the range of 0-120ºC, in particular in the range of 5-100ºC, more in particular in the range of 10-80ºC. In another preferred embodiment of the present invention 2-((phenoxy)methyl)oxirane is 5 reacted to form biphenyl-based epoxy monomer (4,4′-Bis(2,3-epoxypropoxy)biphenyl, BP) in the presence of 2-methyl-2-[(perfluorophenyl)thio]propanoic acid (L1 as specified above) and Pd-acetate as palladium salt. This reaction is particularly attractive because 4,4′-Bis(2,3- epoxypropoxy)biphenyl is extensively used to produce liquid crystalline epoxy networks (LCENs). LCENs have been among the most investigated liquid crystal thermosets (LCTs) 10 because of their unique range of properties and potential applications [Carfagna C, Amendola E, Giamberini M. Liquid crystalline epoxy based thermosetting polymers. Prog Polym Sci. 1997;22(8):1607–1647.] The use of a fluorine-containing solvent is preferred in this context, in particular a solvent selected from the group consisting of hexafluoro-2-propanol (HFIP), trifluoroacetic acid (TFA), 15 and trifluorethanolacid (TFE), in particular TFA or TFE. The use of AgOAc as oxidant is considered preferred in this context. It has been found that where an oxygen-containing gas is used, it can be provided at a total pressure of 0.5-5 bar (0.5 – 5 atm), preferably at a total pressure of 0.9-2 bar (0.9 - 2 atm) while still obtaining good yields. These ranges are attractive for commercial operation. The 20 reaction is preferably carried out at a temperature in the range of 0-120ºC, in particular in the range of 5-100ºC, more in particular in the range of 10-80ºC. As will be evident to the skilled person, different embodiments of the present invention can be combined unless they are mutually exclusive. 25 All percentages used herein are weight percentages, unless specified otherwise. When amounts, concentrations, dimensions and other parameters are expressed in the form of a range, a preferable range, an upper limit value, a lower limit value or preferable upper and limit values, it should be understood that any ranges obtainable by combining any upper limit or preferable value with any lower limit or preferable value are also specifically disclosed, 30 irrespective of whether the obtained ranges are clearly mentioned in the context. The following examples will illustrate the practice of the present invention in some of the preferred embodiments. The invention is not limited thereto or thereby. 35 EXAMPLES Example 1: Optimization results of the C‒H homocoupling of 2-methylanisole 11

[0012] In a pressure tube containing a suitable stirring bar Pd(OAc)2, S,O-ligand, solvent(s) and 2- methylanisole (12.6 μL, 0.1 mmol, 1.0 equiv.) were added. Unless otherwise specified, the reaction was conducted at a 0.1 mmol scale. The tube was put in a pre-heated oil bath at an appropriate temperature (in case that 1 bar (1 atm) O2 was utilized, the tube was firstly charged 5 with an O2 balloon before heating) and was stirred for the time indicated below. After cooling to room temperature, the resulting mixture was diluted with DCM, filtered through a plug of Celite® and concentrated under reduced pressure. The NMR yield was the total yield of p-p and o-p product. The 1H NMR yield was determined by adding CH2Br2 as internal standard and CDCl3 as deuterated solvent. 10 Catalyst loading screening Catalyst loading was screened in a reaction of 2-methylanisole. The results of the screening are given below. 15 Ligands Ligands were screened in a reaction of 2-methylanisole. The results of the screening are given 20 below. 12

[0013] The following ligands were tested: 5 13

[0014] [a] 1H NMR yield was determined by using CH2Br2 as the internal standard. [b] ratio for p-p / other isomers. Product composition: 11% p-p product, 3% o-p product and 5% unidentified isomer. [c] ratio for p-p / other isomers. Product composition: 12% p-p product, 5% o-p product and 6% 5 unidentified isomer. [d] ratio for p-p / other isomers. Product composition: 15% p-p product, 7% o-p product and 6% unidentified isomer. As can be seen from the Table the use of Ligand L1 results on a high yield in combination with 10 excellent regioselectivity. L2 also gives high yield and good selectivity. The results for L3, L4 and L5 are less attractive, but the yield and selectivity data are such that that optimizing of the process conditions is expected to give improved results. Oxidants 15 Oxidants were screened in a reaction of 2-methylanisole. The results of the screening are given below. 20 14

[0015] Green oxidants Green oxidants were screened in a reaction of 2-methylanisole. The results of the screening are given below. 5 Solvents Solvents were screened in a reaction of 2-methylanisole using 1.5 equiv. AgOAc. The results of the screening are given below. 10 15

[0016] Ratio of hybrid solvents Ratio of hybrid solvents were screened in a reaction of 2-methylanisole. The results of the screening are given below. 5 Solvent concentration Solvent concentrations were screened in a reaction of 2-methylanisole. The results of the 10 screening are given below. 16

[0017] a) Conducted at 0.2 mmol scale to reduce the influence of solvent evaporation at 0.1 mmole It can be seen that the yield and regioselectivity can be influenced by selecting the 5 concentration of the reactant in the solvent. In the above table an optimum can be detected. This is, however, dependent on the way in which the example is carried out. Oxidant loading screening Oxidant loading was screened in a reaction of 2-methylanisole. The results of the screening 10 are given below. Case 1 is the base case with only oxygen as oxidant. 15 17

[0018] Temperature Temperature was screened in a reaction of 2-methylanisole using 1.5 equiv. AgOAc. The results of the screening are given below. 5 Example 2: Optimization results of the C‒H homocoupling of o-xylene 10 The same experimental set-up was used as described in example 1 replacing 2-methylanisole with o-xylene. Unless otherwise specified, the reaction was conducted at a 0.1 mmol scale. Sometimes small modifications were tested as described below. The NMR yield was the total yield of p-p and o-p product. The 1H NMR yield was determined by adding CH2Br2as internal standard and CDCl3as deuterated solvent. The GC yield was determined by adding dodecane 15 (20 μL, 15 mg) as internal standard. Concentration o-xylene screening Concentrations of o-xylene were screened in a reaction of o-xylene using O2 / 20 mol% Cu(OAc)2. The results of the screening are given below. 20 18

[0019] X mmol a) Determined by GC analysis, internal standard = n-dodecane. b) Collective dimer yield. c) % of p-p product vs all dimers. d) % of dimers vs side products (trimers), no other oxidation 5 side reactions were detected by GCMS. e) solvent would be gone if the screening of higher concentration was tested at 0.1 mmol scale with an oxygen balloon Catalyst loading screening Catalyst loading was screened in a reaction of o-xylene. The results of the screening are given 10 below. 19

[0020] a) Determined by GC analysis, internal standard = n-dodecane. b) Collective dimer yield. c) % of p-p product vs all dimers. d) % of dimers vs side products (trimers), no other oxidation side reactions were detected by GCMS. 5 Neat reaction conditions screening Neat reaction conditions, using o-xylene as reactant and HFIP as a co-solvent, were screened in a reaction of o-xylene with 12 mol% HFIP. The results of the screening are given below. 10 a) Determined by GC analysis, internal standard = n-dodecane. b) Collective dimer yield. c) % of p-p product vs all dimers. d) % of dimers vs side products (trimers), no other oxidation side reactions were detected by GCMS. e) Cu(OAC)2is used in an amount which is twice 15 as high as the amount of Pd / ligand. 20

[0021] Ligand screening Ligands were screened in a reaction of o-xylene using 1.5 equiv. Cu(OAc)2. The results of the screening are given below. L1 L2 L3 L4 5 a) Determined by HNMR, internal standard = CH2Br2. p-p product HNMR yields. It is noted that experimental conditions in this example may have been compromised, resulting in a yield which is lower than expected. The experimental conditions were the same for all 10 ligands tested. Solvent screening Solvents were screened in a reaction of o-xylene using 1.5 equiv. Cu(OAc)2. The results of the screening are given below. 15 21

[0022] a) Determined by HNMR, internal standard = CH2Br2. p-p product HNMR yields. Solvent concentration screening Solvent concentrations were screened in a reaction of o-xylene using 1.5 equiv. Cu(OAc)2. 5 The results of the screening are given below. a) Determined by HNMR, internal standard = CH2Br2. p-p product HNMR yields. 10 Temperature screening Temperature was screened in a reaction of o-xylene using 1.5 equiv. Cu(OAc)2. The results of the screening are given below. 22

[0023] a) Determined by HNMR, internal standard = CH2Br2. p-p product HNMR yields. 5 Additive screening Additives were screened in a reaction of o-xylene using 1.5 equiv. Cu(OAc)2. The results of the screening are given below. 10 23

[0024] a) Determined by HNMR, internal standard = CH2Br2. p-p product HNMR yields. Oxidant loading screening Oxidant loading was screened in a reaction of o-xylene. The results of the screening are given 5 below. Only 3,3‘,4,4‘-tetramethylbiphenyl (p-p) and 2,3,3',4'-tetramethylbiphenyl (o-p) dimer products were obtained. No other oxidation side reactions were detected by GCMS. 10 a) Determined by GC analysis, internal standard = n-dodecane. b) Collective biaryl yield. c) % of 3,3‘,4,4‘-tetramethylbiphenyl vs all dimers. d) % of dimers vs side products (trimers), no other oxidation side reactions were detected by GCMS. Neat reaction conditions solvent screening 15 Neat reaction conditions, using o-xylene as reactant in combination with a co-solvent, were screened with different co-solvents. The results of the screening are given below. Solvent free conditions are relevant for industry as the starting material can be recovered afterwards. 24

[0025] Co-solvent (x mol%) a) Determined by GC analysis, internal standard = n-dodecane. b) Collective biaryl yield. c) % of 3,3‘,4,4‘-tetramethylbiphenyl vs all dimers. d) % of dimers vs side products (trimers), 5 no other oxidation side reactions were detected by GCMS. Example 3: Optimization results of C–H Homocoupling of 2-methyl thiophene The same experimental set-up was used as described in example 1, replacing 2-methylanisole with 2-methyl thiophene. Unless otherwise specified, the reaction was conducted at a 0.1 mmol 10 scale. Sometimes small modifications were tested as described below. The 1H NMR yield was determined by adding CH2Br2 as internal standard and CDCl3 as deuterated solvent. Oxidant screening Oxidants were screened in a reaction of 2-methyl thiophene in solvent EtOAc. The results of 15 the screening are given below. 25

[0026] Oxidant concentration screening 5 Oxidant concentrations were screened in a reaction of 2-methyl thiophene with O2. The results of the screening are given below. 10 *the reaction proceeded at 0.1 mmol, solvent is partially gone after the reaction. 26

[0027] Solvent screening - AgOAc Solvents were screened in a reaction of 2-methyl thiophene with AgOAc. The results of the screening are given below. 5 Solvent screening - Cu(OAc)2 Solvents were screened in a reaction of 2-methyl thiophene with Cu(OAc)2. The results of the 10 screening are given below. DCM stands for dichloromethane. THF stands for tetrafudrofurane. t-AmOH is tert-amylalcohol or 2-methylbutan-2-ol. EtOAc is ethylacetate. MTBE is methyl-tert- butylether. 15 27

[0028] Hybrid solvent screening – mixture of THF and water Hybrid solvents were screened in a reaction of 2-methyl thiophene with Cu(OAc)2. The results of the screening are given below. 5 28

[0029] Hybrid solvent concentration screening Solvent concentrations were screened in a reaction of 2-methyl thiophene using 1 equiv. Cu(OAc)2 and O2. The results of the screening are given below. 5 Temperature screening 10 Temperature was screened in a reaction of 2-methyl thiophene using 1.5 equiv. Cu(OAc)2. The results of the screening are given below. 15 29

[0030] Example 4: C–H Homocoupling of anisole derivatives Reaction conditions were based on the optimization above using 2-methylanisole as the model substrate. The same experimental set-up was used as described in example 1 replacing 2- 5 methylanisole with different anisole derivatives. Unless otherwise specified, the reaction was conducted at a 3 mmol scale. Sometimes small modifications were tested as described below. The NMR yield was the total yield of p-p and o-p product. The 1H NMR yield was determined by adding CH2Br2 as internal standard and CDCl3 as deuterated solvent. If regio-selectivity was not given: it was not determined or pure single product was obtained. 10 The following anisole derivatives were reacted in a CDC reaction: a) Anisole 15 b) 2-Methylanisole 30

[0031] c) 2-tert-Butylanisole d) 1-(3-Chloropropoxy)-2-methylbenzene 5 e) 2-(o-Tolyloxy)acetate 10 31

[0032] f) 1-(Methoxymethoxy)-2-methylbenzene g) 1-(tert-Butoxy)-2-methylbenzene 5 10 i) Guaifenesin dimethyl ether 32

[0033] j) 2-Chloroanisole k) 2-Bromoanisole 5 l) methyl 2-methoxybenzoate 10 33

[0034] n) 3-Methylanisole o) 1,3-Dimethoxybenzene 5 p) N-(3-Methoxyphenethyl)acetamide 41% isolated yield (o-o / other isomers 6.2:1) 10 34

[0035] q) 4-Methylanisole r) 1,4-Dimethoxybenzene 5 s) 1-((benzyloxy)methyl)-4-methoxybenzene 10 35

[0036] t) 4-Methoxy-2,3-dihydro-1H-indene u) 1,3-Di-tert-butyl-2-methoxybenzene 5 v) 1,2-Dimethoxy-4-methylbenzene 10 36

[0037] x) 2-((2,6-Dimethylphenoxy)methyl)oxirane 5 y) 5-Methoxybenzo[d][1,3]dioxole z) 6-methoxy-2,3-dihydrobenzo[b][1,4]dioxine 10 aa) 7-Methyl-2,3-dihydrobenzofuran 37

[0038] bb) Estrone methyl ether 5 dd) 1-Fluoro-2,4-dimethoxybenzene 10 ee) 1-Methoxynaphthalene 38

[0039] ff) Nabumetone gg) 2,6-Di-tert-butylphenol 5 hh) 2,6-Di-iso-propylphenol 10 Example 5: C–H Homocoupling of xylene derivatives Reaction conditions were based on the optimization above using 2-methylanisole as the model substrate. The same experimental set-up was used as described in example 1 replacing 2- methylanisole with xylene derivatives. Unless otherwise specified, the reaction was conducted 15 at a 0.1 mmol scale. Sometimes small modifications were tested as described below. The NMR yield was the total yield of p-p and o-p product. The 1H NMR yield was determined by adding CH2Br2as internal standard and CDCl3as deuterated solvent. 39

[0040] The following xylene derivatives were reacted in a CDC reaction: a) o-Xylene 5 b) 1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene c) m-Xylene 10 Example 6: C–H Homocoupling of thiophenes derivatives Reaction conditions were based on the optimization above using 2-methylanisole as the model substrate. The same experimental set-up was used as described in example 1 replacing 2- 15 methylanisole with thiophenes derivatives. Unless otherwise specified, the reaction was conducted at a 0.1 mmol scale. Sometimes small modifications were tested as described below. The NMR yield was the total yield of p-p and o-p product. The 1H NMR yield was determined by adding CH2Br2as internal standard and CDCl3as deuterated solvent. 20 40

[0041] In the following results reaction conditions have not been optimized and it may be possible to achieve higher yields. The following thiophenes were reacted in a CDC reaction: a) 2-Cl thiophene 5 b) 2-Br thiophene 10 c) 2-OMe thiophene 41

Claims

1. CLAIMS 1. Process for producing a biaryl compound having at least 2 aryl moieties by cross dehydrogenative coupling (CDC) comprising the step of reacting aryl compounds 5 comprising at least one aryl carbon-hydrogen bond in the presence of an oxidant and a catalyst system comprising a Pd salt and an S,O-ligand, the S,O-ligand comprising at least one oxygen atom and at least one sulfur atom.

2. Process according to claim 1, wherein the aryl compounds are selected from the group 10 of a) monoaryl compounds optionally substituted with at least one group selected from C1- C8 alkyl, C1-C8 alkylether, or ester C1-C8 alkyl, wherein any of these groups may be substituted with one or more C1-C8 alkyl, halogen, oxirane, amido C1-C8 alkyl or O, wherein the aryl moiety may be homocyclic or heterocyclic, with the aryl moiety optionally 15 being substituted with halogen or hydroxy b) polycyclic compounds according to Formula IFormula 1 wherein A is C, a C-C chain, or O, S, or N, wherein X is C or O, S, or N, 20 wherein the ring comprising A and X is aliphatic or aromatic, wherein the aryl ring and ring comprising A and X are optionally substituted with at least one group selected from C1-C8 alkyl, C1-C8 alkylether, or ester C1-C8 alkyl, and optionally with halogen or hydroxy, wherein any of these groups may be substituted with one or more C1-C8 alkyl, halogen, oxirane, amido C1-C8 alkyl or O, 25 c) aryl compounds according to Formula II or IIIformula 2 formula 3 3. Process according to claim 2, wherein monoaryl compounds are substituted with at least one group selected from C1-C4alkyl, C1-C4alkylether, ester C1-C4alkyl, and halogen, 43wherein any of these groups may be substituted with one or more C1-C4alkyl, halogen, oxirane, amido C1-C4alkyl or O, wherein at least one group is H.

4. Process according to claim 3, wherein monoaryl compounds are substituted with at least 5 one group selected from C1 alkyl, C1 alkylether, ester C1 alkyl, and halogen, wherein the any of these groups may be substituted with one or more C1 alkyl, halogen, oxirane, amido C1 alkyl or O, wherein at least two neighboring groups are H.

5. Process according to claim 4, wherein the monoaryl compound is selected from10 methylanisole (2-methoxytoluene) of formula 4, o-xylene of formula 5, or 2- methylthophene of formula 6formula 4 formula 5 formula 6 15 6. Process according to any one of the preceding claims, wherein the S,O-ligand is selected from the group of - a ligand of formula 720 formula 7 wherein R1 is selected from the group of halogen, hydroxy, carboxy, amine, C1-C10 alkyl, C4-C10 aryl or C4-C10 heteroaryl, wherein the alkyl or aryl groups may in turn be 25 substituted with halogen, halogen, hydroxy, carboxy, amine, and R2, R3 are independently selected from the group of H, halogen, hydroxy, carboxy, amine, C1-C10 alkyl, C4-C10 aryl or C4-C10 heteroaryl, wherein the alkyl or aryl groups may in turn be substituted with, halogen, hydroxy, carboxy, amine, and n = 1 to 6, 30 - a ligand of formula 8 44formula 8 5 wherein R1, R2, R3 and n have the meaning stipulated above, and X is selected from the group of C=O; P=O; S=O, SO2, P(O)OH, and P(O)OR, wherein R is selected from C1-C10 alkyl, C4-C10 aryl or C4-C10 heteroaryl, wherein the alkyl or aryl groups may In turn be substituted with halogen, halogen, hydroxy, carboxy, amine. 10 7. Process according to claim 6, wherein n is in the range of 1-4, in particular 1 or 2, R1 is selected from C4-C10aryl, in particular C4-C10aryl substituted with halogen, and that R2 and R3 are selected from H or C1-C10alkyl, in particular C1-C4alkyl.

8. Process according to claim 7, wherein the ligand is selected from L1 or L2 below.

159. Process according to any one of the preceding claims, wherein the reaction is carried out in the presence of a solvent, e.g., an organic solvent selected from the group of alcohols, 20 aldehydes, ketones such as acetone, methylethylketone, methylbutylketone, esters such as ethylacetate, ethers such as MTBE is methyl-tert-butylether, solvents such as acetic acid, tetrahydrofuran (THF), 1,4-dioxane, dichloromethane (DCM), 1,2-dichloroethane (DCE), tert-amylalcohol, acetonitrile, propylene carbonate (PC), dimethylacetamide (DMA) or N-methyl-2-pyrrolidone (NMP), and fluorine containing solvents such as 25 hexafluoro-2-propanol (HFIP), (CF3)3COH, trifluoroacetic acid (TFA), and trifluorethanolacid (TFE), wherein combinations of solvents, and combinations of solvents and water may also be used. 4510. Process according to claim 9, wherein a fluorine-containing solvent is used selected from the group consisting of hexafluoro-2-propanol (HFIP), trifluoroacetic acid (TFA), and trifluorethanolacid (TFE), in particular TFA or TFE, wherein the solvent is optionally used in combination with water. 5 11. Process according to any one of the preceding claims, wherein at least 1 mol% of solvent is used, calculated on the amount of the aryl compound to be converted, in particular at least 2 mol%, and / or wherein at most 30 mol% solvent is used, in particular at most 20 mol%. 10 12. Process according to any one of the preceding claims, wherein the oxidant is selected from one or more oxidants selected from the group consisting of oxygen, preferably provided in the form of an oxygen-containing gas, e.g., in the form of air, H2O2, or metal carboxylate salts and metal carbonate salts, wherein when an oxygen-containing gas is 15 used as an oxidant, e.g. at a pressure of 0.5-5 bar (0.5 – 5 atm), preferably at a pressure of 0.9-2 bar (0.9 - 2 atm).

13. Process according to any one of the preceding claims, wherein the reaction is carried out at a temperature out at a temperature in the range of 0-120ºC, in particular in the 20 range of 5-100ºC, more in particular in the range of 10-80ºC.

14. Process according to any one of the preceding claims, wherein the Pd salt is selected from the group of palladium carboxylate salts and palladium carbonate salts, and is used in an amount of 0.01-20 mol%, calculated on the amount of starting aryl compound, in 25 particular in an amount of 0.01-10 mol%, more in particular in an amount of 0.01-5 mol%, e.g., in an amount of 0.01 to 1 mol%.

15. Process according to any one of the preceding claims, wherein o-xylene is reacted to form 3,3’,4,4’-tetramethyl-1,1’-biphenyl in the presence of 30 2-methyl-2-[(perfluorophenyl)thio]propanoic acid as ligand and Pd-acetate as palladium salt, or wherein 2-((phenoxy)methyl)oxirane is reacted to form biphenyl-based epoxy monomer (4,4′-Bis(2,3-epoxypropoxy)biphenyl) in the presence of 2-methyl-2- [(perfluorophenyl)thio]propanoic acid as ligand and Pd-acetate as palladium salt. 35 46

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