CA2094802A1

CA2094802A1 - Process for the production of diaryls

Info

Publication number: CA2094802A1
Application number: CA002094802A
Authority: CA
Inventors: Thomas Schach; Theodor Papenfuhs; Joachim Hackenbruch
Original assignee: Individual
Current assignee: Hoechst AG
Priority date: 1990-10-26
Filing date: 1991-10-16
Publication date: 1992-04-27
Also published as: EP0555260A1; IN172469B; DE59106559D1; DE4034109A1; EP0555260B1; WO1992007809A1

Abstract

Abstract Process for the preparation of biaryls Process for the preparation of biaryls of the formula (1) R1m - Ar - Ar - R1m (1) wherein Ar is a phenylene or naphthylene radical, R1 is a hydrogen, fluorine or chlorine atom or an unbranched or branched alkyl(C1-C6)-, alkyl(C1-C6)-O-, alkyl(C1-C6)-CO- or alkyl(C1-C6)-SO2H radical and m is the number of still unsubstituted =C- positions on the Ar radical, in which a compound of the formula (2) R1m - Ar - X (2) wherein Ar, R1 and m have the meanings cited above and X
is a chlorine or bromine atom, is dehalogenated and dimerized in the presence of a palladium catalyst on a support material, of a reducing agent, a hydrogen halide acceptor, a polyether or polyether mixture and of water at temperatures of about 50 to about 120°C.

Description

2~8~
W092~07809 PCT/EP91/01968 Description Process for the preparation of biaryls The present invention relates to an improved process for the preparation of biaryls by dehalogenation and dimeriz-ation of aryl halides in the presence of a palladiumcatalyst on a support material, of a reducing agent, a hydrogen halide acceptor, a polyether or polyether mixture and of water.

Biaryls have great importance as building blocks for synthesis of pharmaceutical products, but are also required in the ~ields of plant protection and liquid crystal technology, where fluorinated biaryls are par-ticularly important. The targeted introduction o~ a fluorine substituent into a biaryl structure is in many cases only possible by a laborious and thus expensive Balz-Schiemann reaction. The limits of this reaction lie on the one hand in the availability of the starting com-pounds and on the other in the high toxicity of some of them (e.g. benzidine), both being arguments that greatly restrict its potential for synthesis.

For the synthesis of the desired biaryls by synthetic reactions from already fluorinated compounds a number of coupling reactions are available. These either require extensive technical effort (electroreductive coupling, Grignard reactions) or give the desired biaryls in only moderate yields (Ullmann coupling) or with poor selectivity (Gomberg-Bachmann reaction).

A further possibility for the preparation of biaryls is given by a dehalogenation-dimerization reaction in the presence of noble metal catalysts, a reducing agent and a hydrogen halide acceptor (M. Busch and W. Weber;
Journal f. pra~t. Chemie, 146, 1-55, 1936; F. R. Mayo and M.D. Hurwitz, J. Chem. Soc., 71, 776-779, 1949; P.
Bamfield and P. M. Quan, Synthesis 7, 537-538, 1978). The 2~9~8~2 problem with this type of reaction lies in the frequently unfavorable selectivity with which the desired biaryl is obtained. Thus as well as the desired biaryls the dehalo-genated starting compounds always occur, which thereby reduces, sometimes significantly, the yields. A further disadvantage lies in the rapid reduction in selectivity of the catalyst during repeated use, thereby setting firm limits on the technical application of this reaction (see e.g.: F.R. Mayo and M.D. Hurwitz, J. Chem. Soc., 71, 776-779, 1949).

This synthesis method was used with various reducing agents for the preparation of biaryls (EP 206 543), in particular for the synthesis of 3,3',4,4'-diphenyltetra-carboxylic acid (US 4 727 185, EP 318 634). The hitherto known reactions of this type give at most only moderate yields of the desired biaryls.

It has now surprisingly been found that biaryls of the formula (1) R m ~ Ar--Ar--Rlm (1) in which Ar is a phenylene or naphthylene radical, Rl is a hydrogen, fluorine or chlorine atom or an unbranched or branched alkyl(Cl-C6)-, alkyl(Cl-C6)-O-, alkyl(Cl-C6)-CO- or alkyl(C1-C6)-SO2-H radical and m is the number of still unsubstituted =C- positions on the Ar radical, can be prepared advantageously in good yields and with high selectivity, by dehalogenating and dimerizing a compound of the formula (2) R1m - Ar - X

in which Ar, R1 and m have the meanings cited above and X
is a chlorine or bromine atom, in the presence of a palladium catalyst on a support material, of a reducing agent, a hydrogen halide acceptor, a polyether or poly-ether mixt~ure and of water at temperatures from about 2 0 ~q ~

50 to about 120C, preferably from about 70 to about 1~ 0C.

In particular it was found that the dehalogenating dimerization in the presence of a polyether or polyether mixture has a decisive influence on the selectivity of the coupling reaction with the consequence of a signifi-cant increase in yield.

Possible examples of polyether or polyether mixtures are those of the formula (3) R3 - (O - CH2 - CH2 - )p oR4 (3) in which R3 and R4 are the same or different linear or branched alkyl(Cl-C6)- radicals, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, i-propyl or i-butyl groups, and p is a number from 1 to about 20.

The polyether or polyether mixture is used in amounts from about 0.1 to about 500 ~ by weight, preferably from about 1 to about 100 % by weight, related to the aryl halide used.

Through the presence of polyethers or polyether mixtures in the dehalogenating dimerization, a marked increase in selectivity as well as an increase in catalyst activity can be established, with the consequence that in particu-lar during recycling of catalyst already used in the process according to the invention, scarcely any losses in selectivity can be established, which is in marked contrast to the solvent-free reaction variant.

The hydrogen halide acceptor can expediently be an inor-ganic compound of an alXali metal or alkaline earth metal, for example the hydroxide, carbonate or hydrogen carbonate of lithium, sodium, potassium, rubidium, cesium, magnesium, calcium, barium or strontium or mixtures t;hereof. Preferably, sodium compounds, in 2 ~ 2 particular sodium hydroxide, are used. However, for example, sodium methylate can also be used as acceptor.

It is expedient to use the hydrogen halide acceptor in the form of an aqueous solution, containing abaut 50 to about 500 mol%, preferably about 100 to about 350 mol%, more preferably about 150 to about 200 mol%, per mole of aryl halide used. The concentration of the aqueous alXali metal or alkaline earth metal compound exerts a decisive influence on the selectivity of the coupling reaction, where it is expedient to use concentrations from about 5 to about 50 % by weight, preferably from about 15 to about 40 % by weight.

The palladium catalyst possible according to the inven-tion is used in the form of metallic palladium on a support material. Possible support materials are for example activated charcoal, potassium carbonate, barium carbonate, silicon, aluminum, titanium oxide or mag-nesium. Palladium on activated charcoal has proven to be the most favorable catalyst form.

The content of metallic palladium lies in the range from about 0.1 to about 20 % by weight, related to the support material; catalysts with about 1 to about 10 % by weight are preferred, preferably 5 % by weight.

It was established that the amount of catalyst used has a decisive influence on the selectivity of the reaction.
Excessive catalyst amounts lead to unwanted side reac-tions, whereas insufficient amounts of the palladium catalyst lead to premature termination of the reaction, or very long reaction times and an increased proportion of uncoupled reduced aromatic starting compounds must be reckoned with. In general the catalyst is used in amounts from about 0.001 to about 50 mmol, preferably from about 0.5 to about 2 mmol of palladium, per mole of aryl halide used.

2~8~2 For repeated application, the catalyst can be used again untreated, or pretreated with alcohols (e.g. methanol, ethanol), polyethers, ethers, or water or steam.

The reducing agent in the present invention can be fGr example alcohols, formaldehyde, formates or hydrazine.
Individual examples for this are methanol, glycerol, ethylene glycol, formalin, paraformaldehyde and sodium formate. Polyhydric alcohols such as ethylene glycol or glycerol are prefera~ly used. The reducing agent as a rule is used in an amount from about 0.1 to about 20 mol, preferably from about 0.1 to about 1 mol per mole of aryl halide used.

In general the reaction medium is a three phase system of organic and aqueous phase as well as the heterogeneous palladium catalyst, for which reason good stirring is of great importance.

With regard to the temperature ranges given previously for the process according to the invention, it can additionally be noted that at temperatures over 120C
working under pressure is required. When working below 50C the reaction becomes very slow; in addition it no longer runs to completion.

In the preferred temperature range the reac~ion times lie between 0.5 and 100 hours, depending on the aryl halide used, the catalyst concentration, the amount of base, the base concentration, the proportion of polyethers and the amount and type of reducing agent used. The reaction initially proceeds very rapidly, so that even after 2 hours conversions of 50 to 70 mol% are achieved. In order to reach conversions over 9S mol%, long reaction times may be required, so that early termination of the reac-tion (80-95 mol% conversion) is convenient.

The reaction of the present invention can be carried out under a protective gas, for example argon or nitrogen. It 2~$~

is preferred to work in the presence of atmospheric oxygen.

~he aryl halide used can be liquid or solid. At the reaction temperature, however, it should be completely liquid or completely in solution.

In principle different aryl halides can be simultaneously used for the reaction according to the invention. Biaryl mixtures are thereby formed, which can however be diffi-cult to separate. The process according to the invention can also be applied to other isocyclic chlorinated or brominated aromatic compounds as well as to heterocyclic chlorinated or brominated aromatic compounds.

The process described here for the preparation of biaryls leads to markedly higher selectivities and yields than is the case with comparable known reactions. Thus, for example, in Synthesis 7, 537-538, 1978 (P. Bamfield and P. M. Quan), the dimerization of 2-bromotoluene is described, which furnishes 2,2~-bitoly' in yields of only 33~. EP 206 543 describes the analogous reaction with 2-chlorotoluene and with 2-bromotoluene with yields of 60 and 55 mol%. The comparable dimerization reaction of 2-bromo-5-fluorotoluene according to the process described here furnishes markedly better yields. The analogous is also true for the dimerization of chloro-benzene and bromobenzene, the yields of which of ~8% and30-65% (Synthesis 7) are markedly surpassed by the process described here and the corresponding fluorinated starting compounds.

The following examples serve to illustrate more closely the process according to the invention, without restricting it thereto.

Example 1 In a 1 liter three necX flask with stirrer, internal thermometer and reflux condenser are placed 457.1 g of ~ ~ t~

35% sodium hydroxide solution, 350.0 g of 4-bromofluoro-benzene (BrFB), 175.0 g of diethylene glycol dimethyl ether, 20.0 g of polyethylene glycol dimethyl ether 500 and 5.8 g of Pd/C (5~, 50% moisture). The reaction S suspension is heated to 100C and during the course of 2 hours 62.1 g of ethylene glycol are added. For a further 16 hours the reaction suspension remains at this temperature. The catalyst is then removed and the organic phase fractionally distilled. For GC analyses of the reaction solution and the yields of isolated 4,4'-difluorobiphenyl see Table 1 which follows.

Melting range: 89.1-91.0C
Solidification point: 88.9C

Example 2 Starting set-up and reaction course analogous to Example 1, with the recycled catalyst from Example 1. For GC
analyses of the reaction solution and the yields of isolated 4,4'-difluorobiphenyl see Table 1 which follows.

Example 3 Starting set-up and reaction course analogous to Example 1, with the recycled catalyst from Example 2. For GC
analyses of the reaction solution and the yields of isolated 4,4~-difluorobiphenyl see Table 1 which follows.

Example 4 In a 1 liter three neck flask with stirrer, internal thermometer and reflux condenser are placed 160.0 g of sodium hydroxide pellets dis~olved in 800.0 g of HzO
together with 260 g of 4-chlorofluorobenzene (ClFB), 90.O g of diethylene glycol dimethyl ether, 20.0 g of polyethylene glycol dimethyl ether 500 and 8.0 g of Pd/C
(5~, 50% moisture) in the reaction vessel. The reaction suspension is heated to 100C and during the course of 4 hours 84.8 g of 87% glycerol are added. For a further 16 hours the reaction suspension remains at this tempera-ture. The catalyst is then removed and the organic phase fractionally distilled. For GC analyses of the reaction solution and the yields of isolated 4,4'-difluorobiphenyl see Table 1 which follows.

Example 5 'rest carried out analogously to Example 1 with the following reaction components: 114 g of 35% sodium hydroxide solution, 94.5 g of 2-bromo-5-fluorotoluene (BrFT), 40.0 g of diethylene glycol dimethyl ether, 5 g of polyethylene glycol dimethyl ether 500, 2.5 g of Pd/C
(5%, 50% moisture) and 21.5 g of 87% glycerol. For GC
analyses of the reaction solution and the yields of isolated 4,4'-difluoro-2,2'-bitolyl see Table 1 which follows.

Solidification point: 22.4C

Example 6 Test carried out analogously to Example 1 with the following reaction components: 114 g of 35% sodium hydroxide solution, 96.5 g of 2,4-difluorobromobenzene (DFBrB), 40.0 g of diethylene glycol dimethyl ether, 5 g of polyethylene glycol dimethyl ether 500, 2.0 g of Pd/C
(5%, 50% moisture) and 21.5 g of 8~% glycerol. The catalyst is removed, the organic phase is freed from solvent and the crude product obtained is recrystallized from chlorobenzene. For GC analyses of the reaction solution and the yields of isolated 2,2',4,4'-tetra-fluorobiphenyl see Table 1 which follows.

Melting range: 141.5-145.5C
Solidification point: 138.1C

Comparison example 1 Starting set-up and test procedure analogously to Example 1 without addition of diethylene glycol dimethyl ether and polyethylene glycol dimethyl ether 500. For GC
analyses of the reaction solution see Table 1 which follows.

2 ~ 2 _ 9 Comparison example 2 Starting set-up and test procedure analogously to Example ?~ without addition of diethylene glycol dimethyl ether and polyethylene glycol dimethyl ether 500. For GC
analyses of the reaction solution see Table 1 which followsO

Comparison example 3 Starting set-up and test procedure analogously to Example

3 without addition of diethylene glycol dimethyl ether and polyethylene glycol dimethyl ether 500. For GC
analyses of the reaction solution see Table 1 which follows.

Comparison example 4 Starting set-up and test procedure analogously to Example S without addition of diethylene glycol dimethyl ether and polyethylene glycol dimethyl ether 500. For GC
analyses of the reaction solution see Table 1 which follows.

2~9~2 Table 1 Ex.lTLme Temp.Yield by GC Yields isol. Ar-X
(h) (C) mol (%) mol (~) sion H-Ar Ar-Ar Ar-Ar* Ar-Ar*
.

1 18100100.0 10.3 89.1 89.1 87.8 BrFB
2 1810088.7 10.8 76.4 86.3 84.8 BrFB
3 2010087.0 13.2 73.6 84.2 82.0 BrFB

4 209587.5 20.7 66.0 75.5 73.2 ClFB

2010090.7 16.6 72.8 80.4 79.5 BrFT

6 18100100 11.8 87.1 87.1 76.3 DFBrB

C1 18100100.0 14.1 82.7 82.7 BrFB
C2 18100100.0 24.4 72.8 72.8 BrFB
C3 1810098.2 27.6 68.9 70.2 BrFB
C4 20100100.0 31.0 65.7 65.7 BrFT

* Yields relative to converted aryl halide In the last column B = benzene and T = toluene.

Claims

Patent claims

1. A process for the preparation of biaryls of the formula (1) R1m - Ar - Ar - R1m (1) in which Ar is a phenylene or naphthylene radical, R1 is a hydrogen, fluorine or chlorine atom or an unbranched or branched alkyl(C1-C6)-, alkyl(C1-C6)-O-, alkyl(C1-C6)-CO- or alkyl(C1-C6)-SO2H radical and m is the number of still unsubstituted =C- positions on the Ar radical, wherein a compound of the formula (2) R1m - Ar -X (2) in which Ar, R1 and m have the meanings cited above and X
is a chlorine or bromine atom, is dehalogenated and dimerized in the presence of a palladium catalyst on a support material, of a reducing agent, a hydrogen halide acceptor, a polyether or polyether mixture and of water at temperatures from about 50 to about 120°C.

2. The process as claimed in claim 1, wherein in the case m = 1, R1 is a fluorine atom.

3. The process as claimed in claim 1, wherein in the case m = 2, R1 is a fluorine atom.

4. The process as claimed in claim 1, wherein in the case m = 2, on the same Ar radical one R1 is a fluorine atom and the other R1 is a methyl group.

S. The process as claimed in at least one of claims 1 to 4, wherein a polyether of the formula R3 - (OCH2 - CH2 - )p OR4 in which R3 and R4 are linear or branched alkyl(C1-C6)-radicals and p is a number from 1 to about 20, is used.

6. The process as claimed in at least one of claims 1 to 5, wherein a mixture of polyethers of the formula given in claim 5 is used.

7. The process as claimed in at least one of claims 1 to 6, wherein a polyether or a polyether mixture is used at about 0.1 to about 500 % by weight, related to the aryl halide used.

8. The process as claimed in at least one of claims 1 to 6, wherein a polyether or a polyether mixture is used at about 1 to about 100 % by weight, related to the aryl halide used.

9. The process as claimed in at least one of claims 1 to 8, wherein an inorganic alkali metal or alkaline earth metal compound or sodium methylate is used as hydrogen halide acceptor.

10. The process as claimed in at least one of claims 1 to 9, wherein the hydrogen halide acceptor is used at about 0.5 to about 10 mol, per mole of aryl halide used.

11. The process as claimed in at least one of claims 1 to 10, wherein an about 5 to about 50 percent by weight aqueous solution of the hydrogen halide acceptor is used.

12. The process as claimed in at least one of claims 1 to 10, wherein an about 15 to about 40 percent by weight of aqueous solution of the hydrogen halide acceptor is used.

13. The process as claimed in at least one of claims 1 to 12, wherein a palladium catalyst on activated charcoal or calcium carbonate is used.

14. The process as claimed in at least one of claims 1 to 13, wherein a palladium catalyst is used at about 0.1 to about 10 % by weight, related to the support material.

15. The process as claimed in at least one of claims 1 to 13, wherein palladium is used at about 0.001 to about 50 mmol, per mole of the aryl halide used.

16. The process as claimed in at least one of claims 1 to 15, wherein a palladium catalyst on support material, previously used repeatedly in the dehalogenation and dimerization, is used.

17. The process as claimed in at least one of claims 1 to 16, wherein monohydric or polyhydric alcohols, formalde-hyde, formates or hydrazine are used as reducing agent.

18. The process as claimed in at least one of claims 1 to 16, wherein methanol, glycerol, ethylene glycol, form-alin, paraformaldehyde or sodium formate are used as reducing agent.

19. The process as claimed in at least one of claims 1 to 18, wherein the reducing agent is used at about 10 to about 200 mol%, per mole of aryl halide used.