MX2008009034A - Process for preparing substituted biphenyls - Google Patents

Abstract

A process for preparing substituted biphenyls of the formula (I), in which the substituents are defined as follows:X is fluorine or chlorine;R1is nitro, amino or NHR3;R2is cyano, nitro, halogen, C1-C6-alkyl, C1-C6-alkenyl, C1-C6-alkynyl, C1-C6-alkoxy, C1-C6-haloalkyl, C1-C6-alkylcarbonyl or phenyl;R3is C1-C4-alkyl, C1-C4-alkenyl or C1-C4-alkynyl;n is 1, 2 or 3, where in case that n is 2 or 3, the R2radicals may also be different, which comprises reacting the compound of the formula (II), in which Hal is halogen and X and R1are as defined above, in the presence of a base and of a palladium catalyst selected from the group of:a) palladium-triarylphosphine or -trialkylphosphine complex with palladium in the zero oxidation state, b) salt of palladium in the presence of triarylphospine or trialkylphosphine as a complex ligand or c) metallic palladium, optionally applied to support, in the presence of triarylphosphine or trialkylphosphine, in a solvent, with a diphenylborinic acid (III), in which R2and n are as defined above, where the triarylphosphines or trialkylphosphines used may be substituted.

Description

PROCESS FOR PREPARING SUBSTITUTE BIPHENYL Description The present invention relates to a process for preparing substituted biphenyls of the formula I wherein the substituents are defined as detailed below: X is fluorine or chlorine; R1 is nitro, amino or NHR3; R 2 is cyano, nitro, halogen, C 1 -C 6 alkyl, CrC 6 alkenyl C 1 Cs alkenyl, C 1 alkoxy, C 1 -C 6 haloalkyl (C 6 -C alkyl) carbonyl or phenyl; R 3 is C 1 -C 4 alkyl C 4 alkenyl or CrC alkynyl; n is 1, 2 or 3, wherein in the case where n is 2 or 3, the radicals R 2 may also be different, which comprises reacting a compound of the formula II wherein Hal is halogen and X and R1 as defined above, in the presence of a base and a palladium catalyst selected from the group of: a) palladium-triarylphosphine or -trialkylphosphine complex with palladium in the oxidation state zero; b) palladium salt in the presence of triarylphosphine or trialkylphosphine as a complex ligand or c) palladium metal, optionally applicator to support, in the presence of triarylphosphine or trialkylphosphine, in a solvent, with diphenylborinic acid (III) wherein R1 and n are as defined above, wherein the triarylphosphines The trialkylphosphines used can be substituted. Tetrahedron Lett. 32, page 2277 (1991) discloses that the coupling reaction between phenylboronic acid and chlorobenzene with the use of the catalyst of [1,4-bis (diphenylphosphine) butane] palatal dichloride (II) proceeds with a yield of only 28 %. EP-A 0 888 261 discloses a process for preparing nitrobiphenyls by reacting chloronitrobenzene with a phenylboronic acid in the presence of a palladium catalyst and a base. In this process, a very high catalyst concentration is necessary. It was therefore an object of the present invention to provide an economically viable process that can be implemented on the industrial scale in order to regioselectively prepare substituted biphenyls, which is carried out with a reduced palladium catalyst concentration. Therefore, the process that is defined at the beginning has been found. Diphenylborinic acid (III) is obtained by the reaction of phenylmagnesium chloride V optionally substituted with trialkyl borate, preferably trimethyl borate, in tetrahydrofuran as a solvent according to the scheme 1 which is detailed below: Scheme 1: R is C1-C4-alkyl, preferably methyl. Essential for a high yield of diphenylborinic acid (III) is the use of only 0.7 eq. of trialkyl borate based on the substituted chlorobenzene (IV) used. The use of 1, 1 eq. of trialkyl borate provides phenylboronic acid as described in EP-A 0 888 261.

This reduction in the use of trialkyl borate has several surprising advantages with respect to the preparation of nitrobiphenyls (I). The space-time performance is increased. The costs of the basic materials decrease as a result of the reduction in the amount of high cost trimethyl borate. Unlike the phenylboronic acids used in EP-A 0 888 261, diphenylborinic acids (III) are soluble in tetrahydrofuran, which leads to an improvement in heat extraction during the reaction, which is accompanied by lower consumption of the cooling capacity. This in turn leads to greater process security. The reaction temperature in this stage of the process ranges from 10 to 30 ° C, preferably from 15 to 25 ° C. The substituted biphenyls prepared by the present process have the following preferred substituents, in each case both individually and in combination: R1 nitro, amino, methylamino, propylamino, butylamino, allylamino or propargyl-amino, more preferably nitro, amino or methylamino, furthermore preferably nitro or amino; R2 cyano, nitro, fluorine, chlorine, bromine, methyl, ethyl, propyl, butyl, allyl, propargyl, methoxy, ethoxy, trifluoromethyl or phenyl, more preferably fluorine, chlorine, methyl or methoxy, even more preferably fluorine or chlorine; R3 methyl, ethyl, propyl, butyl, allyl or propargyl, more preferably methyl, ethyl, or allyl, even more preferably methyl; n 1 or 2, preferably 2. The subsequent homozygously catalyzed bicaryl cross-coupling Suzuki is carried out according to scheme 2. Scheme 2: Preference is given at the beginning from the diphenylborinic acids of the formula (III) wherein R2 and n are as defined above. Additional preferred starting materials are the diphenylborinic acids (III) wherein n is 1 or 2, in particular 2. Particularly preferred are the diphenylborinic acids (III) which are substituted in the 3- and 4- position. A very particular preference is given to di (2,3-difluorophenyl) borinic acid, to di (3,4-di-fluorophenyl) borinic acid, to di (2,3-dichlorophenyl) borinic acid and in particular to di ( 3,4-dichlorophenyl) borinic acid as the starting compound (III). . Preference is given to the start of the following compounds (II): 2-bromo-4-fluoroaniline, 2-chloro-4-fluoroaniline and in particular 2-c] gold-4-fluoro-1-nitrobenzene or 2-bromo-4 -fluoro-1-nitrobenzene. Compound (II) is used, based on diphenylborinic acids (III) (equivalents of diphenylborinic acid), usually in an equimolar amount, preferably with an excess of 20 percent, in particular with an excess of 50 percent. The bases used can be organic bases, for example tertiary amines. Preference is given to the use of triethylamine or dimethylcyclohexylamine. The bases used are preferably alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydrogencarbonates, alkali metal acetates, alkaline earth metal acetates, alkali metal alkoxides and alkaline earth metal alkoxides, in a mixture and in particular individually. Particularly preferred bases are the alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates and alkali metal hydrogen carbonates. Especially preferred bases are the alkali metal hydroxides, for example, sodium hydroxide and potassium hydroxide, as well as alkali metal carbonates and alkali metal hydrogen carbonates, for example, lithium carbonate, sodium carbonate and potassium carbonate. The base is used in the process according to the invention preferably with a fraction from 100 to 500 mol%, more preferably from 150 to 400 mol%, based on the amount of diphenylborinic acid (III). Suitable palladium catalysts are palladium-ligand complexes with palladium in the zero oxidation state, palladium salts in the presence of complex ligands, or metallic palladium optionally applied to support, preferably in the presence of complex ligands. Suitable complex ligands are uncharged ligands such as triarylphosphines and trialkylphosphines, which may be optionally substituted on the aryl rings, such as triphenylphosphine (TPP), di-1-adamantyl-p-butylphosphine, tri-fery-butylphosphine (TtBP) or 2- (dicyclohexylphosphino) biphenyl. In addition, the literature has also described additional particularly reactive complex ligands of other structural classes, including 1,3-bis (2,6-diisopropylphenyl) -4,5-H2-imidazolium chloride (cf., for example, GA Fat et al. Organometallics 2002, 21, 2866) and tris (2,4-di-feri-butylphenol) phosphite (see A. Zapf et al., Chem. Eur. J. 2000, 6, 1830). The reactivity of the complex ligands can be increased by adding a quaternary ammonium salt such as tetra-rβ-butylammonium bromide (TBAB) (see, for example, D. Zim et al., Tetrahedron Lett 2000, 41, 8199 ). If so required, the water solubility of the palladium complexes can be improved by various substituents such as sulfonic acid or sulfonate salt groups, carboxylic acid or carboxylate salt groups, phosphonic acid, phosphonium or phosphonate salt, peralkylammonium, hydroxyl and polyether groups. Among the palladium-ligand complexes with palladium in the oxidation state 0, preference is given to the use of tetrakis (triphenylphosphine) palladium and additionally tetrakis [tr, (o-tolyl) phosphine] palladium. In palladium salts which are used in the presence of complex ligands, palladium is normally present in the positive oxidation state two. Preference is given to the use of palladium chloride, palladium acetate or bisacetonitrile palladium chloride. Particular preference is given to the use of palladium chloride. In general, from 6 to 60, preferably from 15 to 25, equivalents of the aforementioned complex ligands, in particular triphenylphosphine and tri-tert-butylphosphine, are combined with one equivalent of the palladium salt. EP-A 0 888 261 discloses the use of from 2 to 6 equivalents of triphenylphosphine per equivalent of the palladium catalyst. The use of high excess ligands is generally seen as disadvantageous in the literature, since this is expected to result in the inactivation of the catalytically active complex (cf., for example, J.

Hassan et al., Chem. Rev. 2002, 102, 1359). In this way it was surprising that this low use of triphenylphosphine in combination with the use of low catalyst led to an increase in the yield of the process of the present invention and consequently to an improvement in economic viability. Metal palladium is prably used in pulverized form or on a support material, for example in the form of palladium on activated carbon, palladium on alumina, palladium on barium carbonate, palladium on barium sulfate, palladium on calcium carbonate, aluminosilicates of palladium such as montmorillonite, palladium on Si02 and palladium on calcium carbonate, in each case with a palladium content of 0.5 to 12% by weight. In addition to palladium and support material, these catalysts may comprise additional dopants, for example lead. When metallic palladium optionally applied to the support is used, particular prence is also given to the use of the above-mentioned complex ligands, in particular to the use of palladium on activated carbon in the presence of triphenylphosphine as a complex ligand, where the phenyl groups in the triphenylphosphine they are prably substituted by a total of one to three sulfonate groups. In the process according to the invention, the palladium catalyst is used with a low fraction from 0.001 to 1.0 mol%, prably from 0.005 to 0.5 mol% or from 0.01 to 0.5 mol% and in particular from 0.005 to 0.05 mol%, based on the amount of compound (II). The low use of a palladium salt in combination with a high use of a complex ligand constitutes a significant cost advantage of this process over the processes of the prior art. The process according to the invention can be carried out in a two-phase system composed of an aqueous phase and a solid phase, ie the catalyst. In that case, the aqueous phase may also comprise an organic solvent soluble in water in addition to water. Suitable organic solvents for the process according to the invention are the ethers such as dimethoxyethane, diethylene glycol dimethyl ether, tetrahydrofuran, dioxane and tert.-butyl methyl ether, hydrocarbons such as n-hexane, n-heptane, cyclohexane, benzene, toluene and xylene, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, ethylene glycol, 1-butanol, 2-butanol and tert.-butanol, ketones such as acetone, ethyl methyl ketone and isobutyl methyl ketone, amides such as dimethylformamide, dimethylacetamide and? / - methylpyrrolidone, in each case individually or in a mixture.

The prred solvents are the ethers such as dimethoxyethane, tetrahydrofuran and dioxane, hydrocarbons such as cyclohexane, toluene and xylene, alcohols such as ethanol, 1-propanol, 2-propanol, 1-butanol and tert.-butanol, in each case individually or in a mixture. In a particularly prred variant of the process according to the invention, water, one or more water-insoluble solvents and one or more water-soluble solvents are used, for example mixtures of water and dioxane, or water and tetrahydrofuran, or water, dioxane and ethanol, or water, tetrahydrofuran and methanol, or water, toluene and tetrahydrofuran, prably water and tetrahydrofuran, or water, tetrahydrofuran and methanol. The total amount of solvent is usually from 3000 to 500 g and prably from 2000 to 700 g, per mole of the compound (II). Suitably, the process is carried out by adding the compound (II), the diphenylborinic acids (III), the base and the catalytic amount of the palladium catalyst to a mixture of water and one or more inert organic solvents, and stirring at a temperature from 50 ° C to 120 ° C, prably from 70 ° C to 110 ° C, more prably from 90 ° C to 100 ° C, for a period of 1 to 50 hours, prably from 2 to 24 hours. Depending on the solvent and the temperature used, a pressure is established from 1 bar to 6 bar, prably from 1 bar to 4 bar. Prence is given to carry out the reaction in water and in tetrahydrofuran.

The reaction can be carried out in a usual apparatus suitable for such processes. After completion of the reaction, the palladium catalyst obtained as a solid is removed, for example by filtration, and the crude product is freed from the solvent or the solvents. In the case of products that are not completely soluble in water, complex ligands or water-soluble palladium catalysts are completely removed from the crude product in the separation of the water phase. Subsequently, further purification can be carried out by methods known to those skilled in the art and suitable for the particular product, for example by re-crystallization, distillation, sublimation, zone fusion process, melt crystallization or chromatography By the process according to the invention, it is possible to prepare, for example: 3 ', 4'-dichloro-5-fluoro-biphenyl-2-ylamine, 2', 3'-dichloro-5-fluoro-biphenyl-2- ilamine, 3 ', 4'-dichloro-3-fluoro-biphenyl-2-ylamine, 2', 3'-dichloro-3-fluoro-biphenyl-2-ylamine, S'''-dichloro-fluoro-biphenyl -amine, 2 ', 3'-dichloro-4-fluoro-b-phenyl-2-ylamine, 3', 4'-dichloro-6-fluoro-biphenyl-2-ylamine, 2 ', 3'-dichloro-6 -fluoro-biphenyl-2-amlamine, 3 ', 4'-d-fluoro-5-fluoro-biphenyl-2-ylamine, 2', 3'-difluoro-5-fluoro-b-phenyl-2- Ilamine, 3 ', 4'-difluoro-3-fluoro-biphenyl-2-ylamine, 2', 3'-difluoro-3-fluoro-biphenyl-2-ylamine, S '^' - difluoro ^ -fluoro-biphenyl -alkylamine, 2 ', 3'-difluoro-4-fluoro-biphenyl-2-ylamine, 3', 4'-d-fluoro-6-fluoro-biphen-2-ylamine, 2 ', 3'-dichlor 6-fluoro-biphenyl-2-ylamine, 3 ', 4'-dichloro-5-chloro-biphenyl-2-amlamine, 2', 3'-dichloro-5-chloro-biphenyl-2-ylamine, 3 ', 4'-dichloro-3-chloro-biphenyl-2-ylamine, 2', 3'-dichloro-3-chloro-biphenyl-2-alamine, 3 ', 4'-d-chloro-4-chloro -biphenyl-2-ylamine, 2 ', 3'-dichloro-4-chloro-biphenyl-2-ylamine, 3', 4'-dichloro-6-chloro-biphenyl-2-ylamine, 2 ', 3'-dichloro-6-chloro-biphenyl- 2-ylamine, 3 ', 4'-difluoro-5-chloro-biphenyl-2-ylamine, 2', 3'-difluoro-5-chloro-biphenyl-2-ylamine, S '^' - difluoro-S-chloro -biphenyl ^ -ylamine, 2 ', 3'-difluoro-3-chloro-biphenyl-2-ylamine, 3', 4'-difluoro-4-chloro-2-phenyl-2-ylamine, 2 ', 3'- difluoro-4-chloro-biphenyl-2-ylamine, S '^' - difluoro-d-chloro-biphenyl-amine, 2 ', 3'-dichloro-6-chloro-biphenyl-2-ylamine, 3', 4 '-d? chloro-5-fluoro-2-nitrobiphenyl, 2 ', 3'-dichloro-5-fluoro-2-nitrobiphenyl, S' ^ '- dichloro-S-fluoro ^ -nitrobiphenyl, 2', 3'-dichloro-3-fluoro-2-nitrobiphenyl, 3 ', 4 '-dichloro-4-fluoro-2-nitrobiphenyl, 2', 3'-dichloro-4-fluoro-2-nitrobiphenyl, 3 ', 4'-dichloro-6-fluoro-2-nitrobiphenyl, 2' , 3'-dichloro-6-fluoro-2-nitrobiphenyl, 3 ', 4'-difluoro-5-fluoro-2-nitrobiphenyl, 2', 3'-difluoro-5-fluoro-2-nitrobiphenyl, 3 ' , 4'-d-fluoro-3-fluoro-2-n-trobifenl, 2 ', 3'-difluoro-3-fluoro-2-nitrobiphenyl, 3', 4'-difluoro-4-fluoro-2- nitrobiphenyl, 2 ', 3'-difluoro-4-fluoro-2-nitrobiphenyl, 3', 4'-difluoro-6-fluoro-2-nitrobiphen, S'.S'-dichloro-e-fluoro ^ -nitrobiphenyl, 3 ', 4'-dichloro-5-chloro-2-nitrobiphenyl, 2', 3'-dichloro-5-chloro-2-nitrobiphenyl, 3 ', 4'-dichloro-3-chloro-2-nitrobiphenyl , 2 ', 3'-dichloro-3-chloro-2-n-trobophenyl, 3', 4'-dichloro-4-chloro-2-nitrobiphen, 2 ', 3'-dichloro-4 -chloro-2-nitrobiphenyl, 3 ', 4'-dichloro-6-chloro-2-nitrobiphenyl, 2,, 3'-dichloro-6-chloro-2-nitrobiphenyl, 3', 4'-difluoro-5-chloro -2-nitrobiphenyl, 2 ', 3, -difluoro-5-chloro-2-nitrob ifenyl, 3 ', 4'-difluoro-3-chloro-2-nitrobiphenyl, 2,, 3'-difluoro-3-chloro-2-nitrobiphenyl, 3', 4'-difluoro-4-chloro-2-nitrobiphenyl, 2 ', 3'-difluoro-4-chloro-2-nitrobiphenyl-3', 4'-difluoro-6-chloro-2-nitrobiphenyl, 2 ', 3'-dichloro-6-chloro-2-n-thiobiphenyl. The process according to the invention provides the compounds I in very high to quantitative yields at a very good purity. The substituted biphenyls that can be obtained by the process according to the invention are suitable as precursors of active ingredients for the fungicide protection of crops (see WO 03/070705). Synthesis of 3 ', 4'-dichloro-5-fluoro-2-nitro-biphenyl Example 1: Di- (3,4-dichlorophenyl) borinic acid A solution of 1281 g of trimethyl borate (123 mM) and 30 mL of tetrahydrofuran are heated to reflux. To this is added 245 g of 18% by weight of a solution of 3,4-dichlorophenylmagnesium bromide (177 mM) in tetrahydrofuran in the space of 1 hour. After complete addition, the reaction solution is stirred at reflux for an additional hour. Subsequently, the reaction solution is treated with 110 mL of 10% aqueous hydrochloric acid and stirred at 40 ° C for 30 minutes. After phase separation, a solution of di (3,4-dichlorophenyl) boronic acid in tetrahydrofuran is obtained. 32.1 g of di (4-chlorophenyl) borinic acid are isolated by crystallization from 200 mL of hexane (57% yield). MS: m / z = 320 [m + Hf, 1 H-NMR (DMSO, 500 MHz): P [ppm] = 7.51 (s, 1H), 7.38 (d, 1 H, 7 Hz), 7 , 27 (d, 1 H, 7 Hz). Example 2: Reaction of di (3,4-dichlorophenyl) borinic acid and 2-bromo-4-fluoroaniline. A reaction vessel is initially charged with 0.55 g of sodium hydroxide (13.7 mM) and 50 mL of water at 15-20 ° C. To this 2.5 g of di (3,4-dichlorophenyl) borinic acid (7.8 mM) and 0.199 g of triphenylphosphine (0.76 mM) in 50 mL of dioxane are metered in. After complete addition, the reaction solution is stirred at 18-22 ° C for 40 minutes. After deoxygenation, 27 mg of palladium (II) chloride (0.15 mM) and 1.4 g of 2-bromo-4-fluoroaniline (7.4 mM) are added to the reaction solution. The reaction solution is heated to 85 ° C for 6 hours. The reaction mixture is cooled, acidified with 2 M hydrochloric acid and the dioxane is evaporated. The residue is extracted with dichloromethane and after evaporation of the solvent 3 ', 4'-dichloro-5-fluoro-biphenol-2-ylamine is isolated by column chromatography (0.63 g, 33% yield) . HPLC-MS: m / z = 256.0 [m + H] + Example 3: Reaction of di (3,4-dichlorophenyl) boric acid and 2-chloro-4-fluoro-1-nitro-benzene A reaction vessel It is initially charged with 0.55 g of sodium hydroxide (13.7 mM) and 50 mL of water at 15-20 ° C.

To this 2.5 g of di (3,4-dichlorophenyl) borinic acid (7.8 mM) and 0.199 g of triphenylphosphine (0.76 mM) in 50 mL of dioxane are metered in. After complete addition, the reaction solution is stirred at 18-22 ° C for 40 minutes. After deoxygenation, 27 mg of palladium (II) chloride (0.15 mM) and 1.3 g of 2-chloro-4-fluoro-1-nitro-benzene (7) are added to the reaction solution. 4 mM). The reaction solution is heated to 85 ° C for 6 hours. The reaction mixture is cooled, acidified with 2 M hydrochloric acid and the dioxane is evaporated. The residue is extracted with dichloromethane and after evaporation of the solvent 3 ', 4'-dichloro-5-fluoro-2-n-th-biphenyl is isolated by column chromatography (0.76 g, 36% yield). GC-MS: m / z = 285.9 [m-H] "

Claims (16)

1. CLAIMS A process to prepare substituted biphenyls of the formula wherein the substituents are as detailed below: X is fluorine or chlorine; R1 is nitro, amino or NHR3; R 2 is cyano, nitro, halogen, CrC 6 alkyl, CrCd alkenyl, C 1 -C alkynyl, alkoxy. d-Cβ, haloalkyl C ^ Ce, (C? -C6-alkyl) carbonyl or phenyl; R3 is CrC4 alkyl, C4 alkenyl or C1-C4 alkynyl; n is 1, 2 or 3, wherein in the case where n is 2 or 3, the radicals R 2 may also be different, which comprises reacting a compound of the formula II wherein Hal is halogen and X and R1 are as defined above, in the presence of a base and a palladium catalyst selected from the group of: a) palladium-triarylphosphine or -trialkylphosphine complex with palladium in the state of zero oxidation; b) palladium salt in the presence of triarylphosphine or trialkylphosphine as a complex ligand or c) palladium metal, optionally applied to support, in the presence of triarylphosphine or trialkylphosphine, in a solvent, with a diphenylborinic acid (III) wherein R2 and n are as defined above, wherein the triarylphosphines or the trialkylphosphines used can be substituted.
2. The process according to claim 1, wherein the compound II used is 2-nitro-3-fluoro-chlorobenzene or 2-amino-3-fluoro-bromobenzene.
3. The process according to claim 1 or 2, wherein the starting compound III is a diphenylborinic acid which is substituted in the 3- and 4- position.
4. The process according to claim 1 or 2, wherein a diphenylborinic acid III carrying fluorine or chlorine in the 3- and 4- positions is used.
5. The process according to claim 1 or 2, wherein the starting compound III is di (3,4-dichlorophenyl) boric acid.
6. The process according to claims 1 to 5, wherein the palladium catalyst a) according to claim 1 used is tetrakis (triphenylphosphine) palladium or tetrakis (tri-tert.-butylphosphine) palladium.
7. The process according to claims 1 to 5, wherein a palladium catalyst b) is used according to claim 1.
8. The process according to claims 1 to 5, wherein the palladium catalyst c) according to claim 1 used is palladium metal on activated carbon in the presence of triphenylphosphine whose phenyl groups are replaced by a total of 1 to 3 sulfonate groups.
9. The process as claimed in claim 7, wherein the salt of the palladium catalyst b) used is palladium chloride, palladium acetate or bisacetonitrile palladium chloride.
10. 10. The process according to claim 7, wherein a palladium catalyst b) is used for which from 6 to 60 equivalents of triphenylphosphine are used per equivalent of the palladium salt.
11. 11. The process according to claim 1, wherein from 0.001 to 1.0 mol% of the palladium catalyst is used, based on the amount of the compound II.
12. 12. The process according to claim 1, wherein the reaction is carried out at a temperature from 50 to 120 ° C.
13. 13. The process according to claim 1, wherein the reaction is carried out in a mixture of water and an organic solvent.
14. 14. The process according to claim 13, wherein the organic solvent used is an ether.
15. 15. The process according to claim 1, wherein the reactions are carried out at a pressure of from 1 to 6 bar.
16. 16. 3 ', 4'-dichloro-5-fluoro-2-nitro-biphenyl.