EP0100877A1 - Preparation process of arylacetic and arylpropionic acids - Google Patents

Abstract

The process includes an electrochemical reduction, under carbon dioxide atmosphere, of benzyl type ArCH2X or ArCH(CH3)X halogenides. According to the invention, the process consists of operating in the presence of a catalyst containing at least one organometallic complex derived from a transition metal combined with a bidentate or tetradentate coordinate.

Description

The invention relates to the preparation of arylacetic and arylpropionic acids from halides of the benzyl type, of formula Ar CH ₂ X and Ar CH (CH ₃ ) x or Ar denotes a substituted or unsubstituted aromatic group and X a halogen.

The manufacture of arylacetic and arylpropionic acids is of great importance, since they constitute an essential class of anti-inflammatory drugs, anesthetics and are also precursors in the preparation of penicillins.

It is known to manufacture them from benzyl halides by cyanidation, carbonation or carbonylation. However, these reactions are most often delicate, of low selectivity and of poor yield.

We also know that it is possible to electro synthesize aromatic carboxylic acids Ar C0 ₂ H from aromatic halides and C0 ₂ under atmospheric pressure using catalysts formed by organic nickel complexes.

Such a process was for example described in the article published in the New Journal of Chemistry, vol. 5, n ° 12 - 1981 pages 621 et seq., Relating to the work carried out by Messrs TROUPEL, PERICHON and FAUVARQUE and Madame ROLLIN.

More specifically, in this process, triphenylphosphine P (C ₆ H ₅ ) ₃ was used to form the organic nickel complexes.

However, it has been found that the process described above was not directly applicable to the case of benzylic halides because in this case only the formation of a bibenzyl compound was observed. Thus, in the case where the process is applied to benzyl chloride C ₆ H ₅ CH ₂ C1, only dibenzyl C ₆ H ₅ -CH ₂ -CH ₂ -C ₆ H ₅ is obtained.

The present invention makes it possible to remedy this drawback and to easily obtain arylacetic and arylpropionic acids by electrosynthesis.

It relates to a process for the preparation of arylacetic and arylpropionic acids, comprising an electrochemical reduction, under a carbon dioxide atmosphere, of benzyl halides of formula Ar CH ₂ X or Ar CH (CH ₃ ) X, characterized by fact that said reduction is carried out in the presence of a catalyst comprising at least one organo-metallic complex derived from a transition metal associated with a bidentate or tetradentate ligand.

By bidentate ligand is meant a ligand which has two coordination sites on the metal used. By tetradentate ligand is meant a ligand which has four coordination sites on the metal used.

The transition metal is chosen so that it forms, with the preceding ligands, an electroreducible organometallic complex capable in its reduced form of reacting with the benzyl halide. The metal is advantageously chosen from the group comprising nickel and cobalt.

According to the invention, the organometallic complex is chosen from the group formed on the one hand by nickel bis cyclooctadiene and on the other hand by metal ligated halides, of formula Ni Y ₂ L, Y being a halogen, L bipyridyl or a diphosphine-type ligand of formula _PR2 - ( _CH2 ) _n - PR ₂ , in which P denotes the phosphorus which is a coordination site, R being a radical chosen from the group formed by the phenyl radical and the aliphatic radicals, n being an integer less than or equal to 4.

When R is the phenyl radical, n can be equal to 2, 3 or 4. When R denotes the methyl radical, advantageously n = 2.

According to one embodiment of the invention, diphenyl phosphinoethane (DPPE) of formula: P (C ₆ H ₅ ) ₂ - ( ^CH ₂ ) ₂ - P (C ₆ H ₅ ) ₂ is used as the ligand L.

It is also possible to use diphenyl phosphino propane (DPPP) of formula P (C ₆ H ₅ ) ₂ - (CH2) 3 - P (C6HS) 3 or dimethyl phosphino ethane (DMPE) of formula P (CH ₃ ) ₂ - ( CH ₂ ) ₂ -P (CH ₃ ) ₂ ·

According to another embodiment of the invention, the catalyst consists of a complex M 'salen where M' represents nickel or cobalt and "salen" represents the tetradentate bis salicylidene ethylene diamine ligand, the catalyst having the formula.

Advantageously, cobalt will be used which forms with the "salen" ligand a complex more easily electroreducible than the corresponding complex of nickel.

The organometallic catalysts according to the invention can be used alone or as a mixture.

It is also possible to add to them a cocatalyst constituted by a metal ligated halide of formula M Yp L ' ₂ , L' being an ooordinate of formula PR ' ₃ , -R' being chosen from the group formed by the alkyl and aryl radicals, M being a transition metal, advantageously nickel.

Thus, the second ligand L 'can be used as triphenyl phosphine (TPP) of formula P (C ₆ H ₅ ) ₃ , tributyl phosphine P (C ₄ H ₉ ) ₃ , tricyclohexyl phosphine P (C ₆ H ₁₁ ) ₃ .

Advantageously, the catalyst used comprises approximately four molar equivalents corresponding to the first complex MY ₂ L for a molar equivalent corresponding to the second complex M ₁ Y ₂ L ' ₂ .

According to another characteristic of the invention, the catalyst comprises at least one organometallic complex of the aforementioned type to which a monodentate or bidentate ligand of the aforementioned type is added, for example cyclooctadiene (COD) or bipyridyl.

Other characteristics of the invention will emerge from the description which follows, relating to various examples of implementation of the invention.

The single figure very schematically represents an electrolysis cell usable for the implementation of the invention.

The cell is designated by the reference 1. It comprises two separate compartments, a cathode compartment 2 and an anode compartment 3. The cathode 4 can be constituted by a felt, a fabric or a braid of carbon fibers or by a sheet of mercury , of surface about 20 cm ² . The cathode conductor constituted by a copper wire is designated by the reference 5.

The anode 6 can be of the alterable metal, lithium, copper, etc. type or of the unalterable type, carbon or metal, associated with an oxidizable electrolyte (oxalate for example). The anode conductor, consisting of a copper wire, is designated by the reference 7.

In view of the electrochemical reduction, the conductors 5 and 7 are connected to an appropriate generator.

The reference 8 designates a sintered glass separating the 2 compartments.

The reference 9 designates a magnetic bar used for agitating the medium.

The solvent of the electrolyte is formed by a mixture comprising by volume 2/3 of an aprotic solvent, such as tetrahydrofuran (THF), 1/3 of dipolar aprotic solvent such as hexamethylphosphorotriamide (HMPT) or N- methyl pyrrolidone, or tetramethylurea.

The electrolyte can be chosen identical or different in the anode 3 and cathode 2 compartments; it is used at a concentration of about 0.1 to 0.3 moles per liter. Thus in the anode compartment 3 the electrolyte 10 can be of the oxidizable type, advantageously a sodium or lithium oxalate, or non-oxidizable, associated with a soluble anode, for example lithium perchlorate (Li Cl 0 ₄ ), tetrafluoborate of tetrabutyl ammonium "C ₄ Hg) ₄ NB ^F ₄ ).

In the cathode compartment 2, a non-reducible electrolyte 11 (Li C10 ₄ , tetrabutylammonium tetrafluoborate) is used in which the benzyl halide and the catalyst according to the invention are introduced.

A reference electrode 15, consisting of a silver wire immersed in an aprotic solvent solution containing silver perchlorate at a concentration of 0.1 mol / liter, makes it possible to identify the potential of the cathode.

The arrows 12 and 13 symbolize the introduction, if necessary, of an inert gas into the anode 3 and cathode 2 compartments. Furthermore, carbon dioxide can be introduced into the cathode electrolytic solution by the tube 1U at the atmospheric pressure or slightly higher.

In order to avoid side reactions, the residual water contained in the electrolytic medium is carefully removed.

This elimination can be done for example by adding a magnesium, such as C ₂ H ₅ MgX ', X' being a halogen, for example Br, in solution in ether or tetrahydrofuran.

For the preparation of phenylacetic acid C ₆ H _S CH ₂ CO ₂ H, 5 milli-moles of benz chloride ^and C ₆ H ₅ CH ₂ Cl are introduced into the cathode compartment 2. The catalyst in accordance with the invention in an amount such that to one mole of benzyl chloride corresponds 0.1 gram atom of transition metal.

Carbon dioxide is then bubbled through the cathode compartment of the cell, at atmospheric pressure or slightly higher.

The reaction medium is maintained at ambient temperature or cooled by an external circulation of cold water.

The electrochemical reduction is then carried out at controlled potential.

Thus, the potential of the agitated mercury sheet, compared to the Ag / AgClO _{4 system} , is maintained at approximately - 2.6 V.

The electrochemical reduction is carried out until the amount of current passed corresponds to a predetermined value, or until the current is zero.

The current density at the start of the reduction is approximately 35 mA / cm ² _.

The solution is then hydrolyzed in an acid medium and extracted with ether.

The ethereal phase is stirred with aqueous sodium hydroxide and then separated.

Analysis by vapor phase chromatography of the ethereal phase makes it possible to calculate the amount of C ₆ H ₅ CH ₂ Cl remaining, as well as the amount of C ₆ H ₅ - CH ₂ -CH2 - C ₆ H ₅ formed.

The basic aqueous phase is acidified, saturated with NaCl, then extracted with ether. The ethereal phase is dried over MgSO ₄ , then evaporated.

The phenylacetic acid formed is thus recovered, which is characterized by its IR and ¹ H NMR spectra and its melting point.

• Dans un premier temps, on forme électrochimiquement un complexe intermédiaire par insertion du métal de transition, par exemple le nickel, au sein de la liaison C-Cl du chlorure de benzyle.

The principle of the method, exposed for the manufacture of phenylacetic acid from benzyl chloride, in the presence of a NiY ₂ L ligand halide is as follows:

• First, an intermediate complex is electrochemically formed by insertion of the transition metal, for example nickel, within the C-Cl bond of benzyl chloride.

We first have the reaction:

This step is not necessary if a zerovalent nickel complex such as Ni (COD) _{2 is used} , but such complexes, which are very oxidizable in air, are less convenient to handle.

The Ni ° L complex is generally very reactive and not very stable. Its stability is increased by the presence of another bidentate ligand in the medium chosen so as to weakly complex Ni ° L, for example COD or bipyridyle, which are relatively weak ligands of zerovalent nickel and do little to hinder its subsequent reaction with the chloride. benzyl.

Then we have:

The overall balance being

This complex can be reduced electrochemically according to:

This intermediate can evolve by giving dibenzyl _C6H5 - _CH2 - _CH2 - _C6H5 , but in the presence of C0 ₂ we obtain phenylacetic acid with regeneration of the zero nickel complex are worth:

The catalytic cycle can then continue. Overall we have the reaction:

The reactions are analogous from other organometallic complexes in accordance with the invention.

Several examples of preparation were carried out from C ₆ H ₅ CH ₂ Cl by modifying the nature of the catalytic species, as well as the temperature of the medium.

For these examples, we measured the percentage T1 of C ₆ H _S CH ₂ Cl consumed compared to the initial quantity, the percentage RC (chemical yield) of C ₆ H ₅ CH ₂ COOH formed compared to the quantity of C ₆ H ₅ CH ₂ Cl consumed, the percentage T3 of C ₆ H ₅ -CH ₂ -CH ₂ -C ₆ H ₅ formed relative to the quantity of initial C ₆ H ₅ CH ₂ Cl, the faradic yield RF, representing the quantity of acid formed relative to the amount of electricity consumed assuming the stoichiometric equation.

For all these examples, the reaction medium contained 0.1 gram atom of nickel per 1 mole of C ₆ H ₅ CH ₂ Cl, the pressure of C0 ₂ was 1 atmosphere, the potential was maintained at -2.6 V, unless otherwise stated; the solvent of the electrolyte consisted of THF / HMPT (ratio 2/3, 1/3) for examples 1 to 12, (ratio 1/2, 1/2) for examples 13 and 14; for examples 1 to 9 the electrolyte was 0.1 M Li C104; for Examples 10 to 12, the cathode electrolyte was 0.3 M tetrabutylamonium tetrafluoborate, the anode electrolyte being 0.1 M lithium oxalate, with a carbon anode; for examples 13 and 14 the electrolyte was Li Cl0 ₄ 0.2 M.

1st EXAMPLE: Catalytic species

NiCl ₂ , DPPE and NiCl ₂ , (TPP) 2 in a 4/1 molar ratio

Temperature 20 ° C

Electrolysis stop at zero current.

2nd EXAMPLE: Catalytic species

NiCl ₂ DPPE and NiCl ₂ (TPP) ₂ in a 4/1 molar ratio

Temperature 0 ° C

Electrolysis stopped after 8 hours.

We see that at 0 ° the electrolysis is much slower than at 20 ° C.

EXAMPLE 3 Catalytic species

NiCl ₂ DPPE and NiCl ₂ (TPP) ₂ in a 19/1 molar ratio

Temperature 20 ° C

Electrolysis stopped after 8 hours.

4th EXAMPLE: Catalytic species

NiCl ₂ DPPE and NiCl ₂ (TPP) ₂ in a 19/1 molar ratio

Temperature 0 ° C

Electrolysis stopped after 3 p.m.

5th EXAMPLE: Catalytic species

NiCl ₂ , DMPE and NiCl ₂ (TPP) ₂ in a 4/1 molar ratio

Temperature 20 ° C

Electrolysis stops when the current becomes too low.

6th EXAMPLE: Catalytic species

NiCl ₂ , DMPE and NiCl ₂ (TPP) ₂ in a 19/1 molar ratio

Same conditions as example 5

EXAMPLE 7 Catalytic species

NiCl ₂ , DPPP and NiCl ₂ (TPP) ₂ in a 4/1 molar ratio

Same conditions as Example 5.

EXAMPLE 8

Same conditions as Example 5. 9th EXAMPLE: Catalytic species

NiCl ₂ , DPPE

Same conditions as Example 5.

EXAMPLE 10 Catalytic species

NiCl ₂ , DPPP + COD in molar proportion 1/1

Temperature 20 ° C

Electrolysis completed in 5 hours.

EXAMPLE 11 Catalytic species

Nickel bis cyclooctadiene

Temperature 20 ° C

Electrolysis stopped after 20 hours.

12th EXAMPLE Catalytic species

NiCl ₂ , bipyridyle

Temperature 20 ° C

Electrolysis for 25 hours

EXAMPLE 13 Catalytic species

Cobalt salen

C0 ₂ at atmospheric pressure

Electrolysis at - 2.3 V on mercury cathode with the reduction potential of Co salen; total conversion in 20 hours.

14th example

Same conditions as for Example 13 but under two atmospheres of C0 ₂ . The results of the measurements are explained in the following table:

We have seen that it was desirable to carry out the electrochemical reduction in a single step.

Indeed, if we proceed in two stages, the first stage corresponding to the formation of the intermediate complex C ₆ H ₅ CH ₂ Ni Cl L, operation carried out under neutral gas, the second to the reduction of this complex in the presence of CO ₂ , the biaryl derivative is preferably formed.

Thus if we take again the conditions of the 1st example by carrying out a first electrochemical reduction under argon at a potential of -2,1 V, followed by a second reduction in the presence of C0 ₂ at a potential of -2,6 V, the value obtained for T3 goes from 18 to 48.

Examples corresponding to the preparation of arylpropionic acids have also been produced.

We thus proceeded to the synthesis of phenyl propionic acid C ₆ H ₅ CH (CH ₃ ) COOH from C ₆ H ₅ CH (CH ₃ ) Cl.

Due to the structure of this compound, there is an additional parasitic reaction, leading by elimination of H Cl to the formation of styrene. To avoid this reaction, it is advantageous on the one hand to conduct the operation at a temperature below ambient temperature, for example at 0 ° C., on the other hand to add when the catalyst is Ni Y ₂ L an additional bidentate , COD or bipyridyle for example, which weakly coordinates with zerovalent nickel.

The use of Co salen as a catalyst does not require additional coordination.

Several preparation examples were carried out from ^C ₆ ^H ₅ - CH (CH ₃ ) Cl.

For all these examples, the percentage T'1 of C ₆ H ₅ CH (CH ₃ ) Cl consumed was measured with respect to the initial quantity, the chemical yield RC 'and the faradaic yield RF'. The secondary product is styrene. We have the overall reaction:

For examples 15 to 20, the reaction medium contained 0.1 gram atom of nickel per 1 mole of C ₆ H ₅ CH (CH ₃ ) Cl, the pressure of C0 ₂ was 1 atmosphere, the temperature 0 °, the potential was maintained at approximately -2.4, -2.6 V relative to the Ag ⁺ / Ag reference electrode. For example 21, the catalytic species consisted of Co salen.

For examples 15 to 20 and the cathode electrolyte is tetrabutylammonium tetrafluoborate 0.3 M, for example 21, Li Cl0 ₄ 0.2 M. The solvent of the electrolyte was THF - HMPT (ratio 2/3, 1/3).

15th EXAMPLE Catalytic species

Ni Cl ₂ , DPPP

copper anode

electrolysis to zero current

T1 ': 40, RC': 57, RF ': 73.

16th EXAMPLE Catalytic species

Ni Cl ₂ , DPPE + COD DPPE and COD in a molar ratio of 1/1, copper anode

electrolysis in 20 hours

T1 ': 72, RC': 82, RF ': 74.

17th EXAMPLE Catalytic species

Ni C1 ₂ , DPPP + COD DPPP and COD in a molar ratio of 1/1,

copper anode,

electrolysis stopped at 55% of the theoretical amount of electricity

RC ': 71 RF': 94

18th EXAMPLE Catalytic species

Ni C1 ₂ , DPPP + bipyridyle, DPPP and bipyridyle in a molar ratio of 1/1,

copper anode

T1 ': 82, RC': 51, RF ': 44

19th EXAMPLE

Catalytic species

Ni C1 ₂ , DPPP + COD, DPPP and COD in a molar ratio of 1/1,

platinum anode,

0.1 M sodium oxalate anode electrolyte

T1 ': 100 RC': 75 RF ': 75

20th example Catalytic species

Ni Cl ₂ , DPPP + COD DPPP and COD in a molar ratio of 1/1. cathode braided carbon fibers and no longer mercury

platinum anode, anodic electrolyte: lithium oxalate complete electrolysis in 12 hours

T1 ': 96 RC': 89 RF ': 93

21st EXAMPLE Catalytic species

Co salen

C0 ₂ under 1 atmosphere

electrolysis at - 2 volts at 20 ° C Tl ': 100 RC': 60

espèce catalytique : Ni Cl₂, DPPP + COD DPPP et COD dans un rapport molaire de 1/1 à 0°CThe process described above can thus be directly applied to the synthesis of a commercial anti-inflammatory, naproxen, depending on the reaction.

catalytic species: Ni Cl ₂ , DPPP + COD DPPP and COD in a molar ratio of 1/1 at 0 ° C

T1 ': 100 RC': 66 RF ': 66

Of course, the invention is in no way limited to the embodiments which have been given only by way of example.

Claims (19)

1 / Process for the preparation of arylacetic and arylpropionic acids, comprising an electrochemical reduction, under an atmosphere of carbon dioxide, of benzyl halides, of formula Ar CH ₂ X or Ar CH (CH) ₃ X, characterized in that said reduction is carried out in the presence of a catalyst comprising at least one organometallic complex derived from a transition metal associated with a bidentate or tetradentate ligand. 2 / A method according to claim 1, characterized in that the transition metal is chosen from the group comprising nickel and cobalt. 3 / A method according to claim 2, characterized in that the organometallic complex is chosen from the group formed on the one hand by nickel bis cyclooctadiene and on the other hand by liganded metal halides, of formula Ni YL, Y being a halogen, L bipyridyl or a diphosphine-type ligand of formula PR ₂ - (CH ₂ ) _n - PR ₂ in which P denotes phosphorus, R being a radical chosen from the group formed by the phenyl radical and the aliphatic radicals, n being an integer less than or equal to 4. 4 / A method according to claim 3, characterized in that R is the phenyl radical and n = 2, 3 or 4. 5 / A method according to claim 3, characterized in that R is the methyl radical and n = 2. 6 / A method according to claim 2, characterized in that the catalyst is a complex M 'salen or M' represents nickel or cobalt and salen the tetradentate bis salicylidene ethylene diamine ligand. 7 / A method according to one of claims 1 to 6, characterized in that the catalyst further comprises a cocatalyst consisting of a metal ligated halide of formula M ₁ Y ₂ L ' ₂ , L' being a ligand of formula PR ' ₃ , R 'being chosen from the group formed by the alkyl and aryl radicals, M ₁ being a transition metal. 8 / A method according to claim 7, characterized in that the catalyst comprises approximately four molar equivalents of MY ₂ L for a molar equivalent of MiY2 ^L ' ₂ . 9 / A method according to one of claims 1 to 6, characterized in that the catalyst comprises in addition to the organometallic complex a monodentate or bidentate ligand. 10 / A method according to claim 9, characterized in that said ligand is chosen from the group formed by cyclooctadiene and bipyridyl. 11 / Method according to one of claims 9 and 10, characterized in that the organometallic complex and said ligand are in a molar ratio of 1/1. 12 / A method according to one of claims 2 to 11, characterized in that the reaction mixture comprises for a molecule of benzyl halide 0.1 gram atom of nickel or cobalt. 13 / A method according to one of claims 1 to 12, characterized in that the reaction medium is maintained at room temperature or lower during the preparation process. 14 / A method according to one of claims 1 to 13, characterized in that the products used are anhydrous. 15 / A method according to one of claims 1 to 14, characterized in that the carbon dioxide is used at atmospheric or similar pressure. 16 / A method according to one of claims 1 to 15, characterized in that the electrochemical reduction is carried out in an electrolysis cell comprising a cathode compartment and an anode compartment, the cathode consisting of a felt, a fabric or a carbon braid, or a sheet of mercury, the anode being constituted by an alterable metal, such as lithium or copper or by an unalterable material, the electrolyte comprising a solvent comprising a mixture of an aprotic solvent, such as tetrahydrofuran and a dipolar aprotic solvent, such as hexamethylphosphorotriamide, N-methylpyrrolidone or tetramethylurea. 17 / A method according to claim 16, characterized in that the anode being constituted by an unalterable metal, the electrolyte present in the anode compartment, consists of an oxalate, such as a sodium or lithium oxalate. 18 / A method according to claim 14, characterized in that the anode being constituted by an alterable metal the electrolyte present in the anode compartment includes lithium perchlorate or tetrabutylammonium tetrafluoborate. 19 / A method according to claim 16, characterized in that the electrolyte present in the cathode compartment comprises lithium perchlorate or tetrabutylammonium tetrafluoborate.

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