EP0198743B1 - Process for the electrosynthesis of ketones - Google Patents

Abstract

The invention relates to a process for the synthesis of ketones by electrochemical reduction of organic halides in the presence of organic acid anhydrides in an electrolysis cell in an organic solvent medium containing a supporting electrolyte. The anode is a metal chosen from the group consisting of magnesium, aluminium, zinc and their alloys. This process has the advantage of being simple and readily capable of being converted to an industrial scale, particularly because of the possibility of employing a cell which has only one compartment. It can be applied to the electrosynthesis of numerous ketones.

Description

The invention relates to a process for the electrosynthesis of ketones by electrochemical reduction of organic halides in the presence of derivatives of organic acids, process implemented in an electrolysis cell in organic solvent medium containing an indifferent electrolyte.

Ketones are compounds commonly used in practically all fields of the chemical industry, in particular as solvents or synthesis intermediates.

SHONO, in Chemistry Letters, 1977, pages 1021 1024, describes the electrosynthesis of benzylic ketones by electrochemical reduction of benzylic chlorides in the presence of carboxylic acid chlorides in acetonitrile or N, N-dimethylformamide (DMF) medium. The cell necessarily comprises two compartments separated by a ceramic diaphragm and the anode is made of carbon.

The concentration of indifferent electrolyte is high (close to 1 M) and this inherently to the process.

In acetonitrile, the yields of isolated benzylic ketones vary, depending on the product, between 29 and 73%. The use of DMF instead of acetonitrile leads in all cases to a considerable drop in this yield.

Faradic yields are always very low, taking into account that a quantity of current corresponding to 4 Faraday is passed through per mole of benzyl chloride.

The object of the present invention is in particular to simplify such a process and to improve the reaction yields.

The Applicant has now discovered that such an objective is unexpectedly achieved when, in a combined manner, an organic acid anhydride is used as an organic acid derivative and an anode consumable in a metal chosen from the group consisting of magnesium, zinc, aluminum and their alloys.

The process according to the invention for the electrosynthesis of ketones by electrochemical reduction of organic halides in the presence of organic acid derivatives in an electrolysis cell provided with electrodes in an organic solvent medium containing an indifferent electrolyte is characterized in that an anode consumable in a metal chosen from the group consisting of magnesium, aluminum, zinc and their alloys is used and in that the organic acid derivatives are anhydrides of organic acids.

• ^* on obtient ainsi, pour un solvant donné, des rendements massiques et faradiques plus élevés alors que le procédé est applicable à l'électrosynthèse de nombreuses cétones et qu'il est très nettement plus simple de mise en oeuvre, dans la mesure où il peut être réalisé dans une cellule d'électrolyse à un seul compartiment, sans diaphragme ni fritté, ce qui est un avantage important, notamment au stade industriel.

Compared to the above process constituting the closest state of the art:

• ^* higher mass and faradaic yields are thus obtained for a given solvent, while the process is applicable to the electrosynthesis of numerous ketones and it is very much simpler to use, insofar as it can be made in a single compartment electrolysis cell, without diaphragm or sintered, which is an important advantage, especially at the industrial stage.

• ^* La concentration en électrolyte indifférent peut être nettement inférieure.
• * On ne constate pas de dégradation du solvant à l'anode comme lorsqu'on utilise une anode inerte.

Likewise, the possibility of carrying out electrolysis at constant intensity rather than at controlled potential also simplifies this implementation.

• ^* The concentration of indifferent electrolyte may be significantly lower.
• * No degradation of the solvent is observed at the anode as when an inert anode is used.

These advantages are particularly interesting.

• - une chaîne aliphatique ou cycloaliphatique, substituée ou non substituée, saturée ou non saturée.

According to a particular embodiment of the invention, the organic halides correspond to the general formula R _l X in which X represents a halogen chosen from the group consisting of chlorine, bromine and iodine and R ₁ represents:

• - an aliphatic or cycloaliphatic chain, substituted or unsubstituted, saturated or unsaturated.

Preferably, R ₁ represents an aliphatic chain substituted with at least one aromatic group, for example in benzyl chloride, benzyl bromide, 1-phenyl 1-chloro ethane and 1-phenyl 1-chloro propane.

In general, R ₁ can carry non-electro-reducible functions or more difficult to reduce than the R ₁ -X bond, under the experimental conditions of electrosynthesis. Such non-electroreducible functions are, for example, the cyano, ether, sulfide or ester functions.

dans laquelle R₂ représente:

• - une chaîne aliphatique ou cycloaliphatique, substituée ou non substituée, saturée ou non saturée,
• - un groupement aryle, substitué ou non substitue,
• - un hétérocycle aromatique, substitué ou non substitué, comme par exemple le cycle furanne, thiophène ou pyridine,
  • et R₃ représente:
• - une chaîne aliphatique ou cycloaliphatique, substituée ou non substituée, saturée ou non saturée,
• - un groupement aryle substitué ou non substitué,
• - un hétérocycle aromatique, substitué ou non substitué, comme par exemple le cycle furanne, thiophène ou pyridine,
• - un groupement OR₄ dans lequel R₄ représente:
  • ^* une chaîne aliphatique ou cycloaliphatique, substituée ou non' substituée, saturée ou non saturée,
  • ^* un groupement aryle, substitué ou non substitue,
  • ' un hétérocycle aromatique, substitué ou non substitué, comme par exemple le cycle furanne, thiophène ou pyridine,
  
  ou bien encore R₂ et R₃ forment au moins un cycle, substitué ou non substitué, comme c'est le cas par exemple pour l'anhydride phtalique ou l'anhydride succinique.

According to another particular embodiment of the invention, the anhydrides of organic acids correspond to the general formula

in which R ₂ represents:

• - an aliphatic or cycloaliphatic chain, substituted or unsubstituted, saturated or unsaturated,
• - an aryl group, substituted or unsubstituted,
• - an aromatic heterocycle, substituted or unsubstituted, such as for example the furan, thiophene or pyridine ring,
  • and R ₃ represents:
• - an aliphatic or cycloaliphatic chain, substituted or unsubstituted, saturated or unsaturated,
• - a substituted or unsubstituted aryl group,
• - an aromatic heterocycle, substituted or unsubstituted, such as for example the furan, thiophene or pyridine ring,
• - an OR ₄ group in which R ₄ represents:
  • ^* an aliphatic or cycloaliphatic chain, substituted or unsubstituted, saturated or unsaturated,
  • ^* an aryl group, substituted or unsubstituted,
  • a substituted or unsubstituted aromatic heterocycle, such as for example the furan, thiophene or pyridine ring,
  
  or alternatively R ₂ and R ₃ form at least one ring, substituted or unsubstituted, as is the case for example for phthalic anhydride or succinic anhydride.

When R ₃ represents an OR ₄ group, the corresponding anhydrides are then mixed anhydrides of carboxylic acids and carbonic acid. In all other cases, they are anhydrides of carboxylic acids.

lorsque les halogénures organiques répondent à la formule générale R₁X.We obtain ketones corresponding to the general formula:

when the organic halides correspond to the general formula R ₁ X.

In general, R ₂ and R ₃ can carry non-electro-reducible functions, or more difficult to reduce than the R ₁ -X bond, under the experimental conditions of electrosynthesis, and none of the functions carried by R ₁ or R ₂ does must be more electrophilic than the anhydride function itself.

Preferably, R ₂ and R ₃ represent a linear or branched alkyl chain.

Also preferably, R ₂ and R ₃ are identical.

In a particularly preferred manner, R ₂ and R ₃ are identical and represent an alkyl chain, linear or branched, as is the case for example for acetic anhydride.

Electrosynthesis can be carried out in the presence of a catalyst, an organometallic complex of a transition metal, such as nickel or palladium. This complex can be bi or polymetallic. Preferably, the NiBr ₂ (Bipyridine) complex is used.

When the halide is difficult to reduce or when the anhydride is easily reducible, it turns out that the use of such a complex very clearly improves the yield.

According to the process which is the subject of the present invention, an anode made of a metal chosen from the group consisting of magnesium, aluminum, zinc and their alloys is used. The term "their alloys" means any alloy containing at least one of the three aforementioned metals, namely magnesium, aluminum and zinc.

This anode can have any shape and in particular all the classic forms of metal electrodes well known to those skilled in the art (twisted wire, flat bar, cylindrical bar, renewable bed,, balls, fabric, grid, etc.).

Preferably, a cylindrical bar of diameter adapted to the dimensions of the cell is used. For example, for a cell whose total volume is between approximately 50 cm ³ and approximately 500 cm ³ , the diameter of the bar is of the order of 1 cm.

Before use, it is preferable to clean the surface of the anode, chemically (by diluted HCI for example) or mechanically (file, Emeri cloth for example) so as to remove in particular the metal oxide often present on the surface of the metal.

The cathode is any metal such as stainless steel, nickel, platinum, gold, silver, or carbon. It is preferably formed by a grid or a cylindrical plate arranged concentrically around the anode.

The electrodes are supplied with direct current via a stabilized power supply.

The organic solvents used in the context of the present invention are all the low-protic solvents usually used in organic electrochemistry. Examples include DMF, acetonitrile, tetramethylurea (TMU), tetrahydrofuran (THF) and tetrahydrofuran-hexamethylphosphorotriamide mixtures. Preferably, DMF is used.

The indifferent electrolytes used can be those usually used in organic electrochemistry. Mention may be made, for example, of the salts whose anion is a halide, a carboxylate, an alcoholate, a perchlorate or a fluoroborate and the cation a quaternary ammonium, lithium, sodium, potassium, magnesium, zinc or aluminum.

Among these salts, mention may in particular be made of tetraalkyl ammonium tetrafluoroborates (tetrabutylammonium tetrafluoroborate, for example) tetrabutylammonium perchlorate, tetraalkyl ammonium halides (tetrabutylammonium chloride or tetrabutylammonium iodide and, for example, lithium tetrabutylammonium iodide).

Preferably, the concentration of indifferent electrolyte in the organic solvent is between 0.01 M and 0.5 M.

Also preferably, the concentration of organic halides in the organic solvent is between 0.2 M and 2 M.

The ratio of concentrations in the organic solvent between the organic acid anhydride and the organic halide can be arbitrary. It is preferable to use an excess of anhydride and in particular a concentration ratio of between 1 and 20.

• 1) dans une cellule d'électrolyse classique, bien connue de l'homme de métier, ne comportant qu'un seul compartiment,
• 2) à une température généralement comprise entre -20°C et +80°C, de préférence comprise entre -10'C et +40° C, avantageusement voisine de 0° C.
• 3) sous une densité de courant sur la cathode variant de préférence entre 0,1 et 10 A/dm². On opère en général et de façon préférée à intensité constante, mais on peut également opérer à tension constante, à potentiel contrôlé ou avec intensité et potentiel variables,
• 4) sous agitation de la solution, par exemple par l'intermédiaire d'un barreau aimanté, après avoir dégazé la solution par barbotage d'un gaz inerte, azote ou argon par exemple.

The electrolysis is carried out:

• 1) in a conventional electrolysis cell, well known to those skilled in the art, comprising only one compartment,
• 2) at a temperature generally between -20 ° C and + 80 ° C, preferably between -10 ° C and + 40 ° C, advantageously close to 0 ° C.
• 3) at a current density on the cathode preferably varying between 0.1 and 10 A / dm ² . We generally operate and preferably at constant intensity, but we can also operate at constant voltage, with controlled potential or with variable intensity and potential,
• 4) with stirring of the solution, for example by means of a magnetic bar, after having degassed the solution by bubbling with an inert gas, nitrogen or argon for example.

After passage of an amount of current corresponding to approximately 2 Faraday (2 X 96500C) per mole of organic halides or optionally until complete transformation of these, the electrolysis is stopped. The main constituents of the mixture, namely the unreacted organic halide, are then assayed in a manner known to a person skilled in the art, on an aliquot of the solution, by gas chromatography (GC). desired products as well as certain by-products of the reaction. The desired products are then extracted, isolated and purified in a conventional manner.

It is possible, for example, to evaporate the reaction solvent and the light compounds under vacuum, then to hydrolyze the remaining residue, for example using dilute hydrochloric acid.

The ketones are then extracted, for example with ether. After evaporation of the extraction solvent, a crude product is isolated, which is identified by its IR and NMR spectra and whose purity or composition is determined by GC. The product (s) is optionally purified, for example by distillation.

The pure ketone thus isolated (purity verified by CPG) is identified by its IR and NMR spectra.

The invention is illustrated by the nonlimiting examples which follow. To carry out these examples, a conventional electrolysis cell was used, with a total volume of approximately 250 cm ³ , comprising only one compartment and equipped with pipes allowing the arrival and the exit of the inert gas, the possible samples of solution. during electrolysis, as well as the electrical passages.

The anode is formed by a cylindrical bar 1 cm in diameter. It is introduced into the cell by a central tube and is thus located approximately in an axial position relative to the cell.

The cathode consists of a cylindrical metallic felt arranged concentrically around the anode. The working surface of the cathode is of the order of 1 dm ² . The cell is immersed in a thermostatic bath set to the chosen temperature.

The particular operating conditions (nature of the electrodes, of the indifferent electrolyte, of the solvent used, the reaction temperature, etc.) are specified elsewhere for each example.

Examples 1 to 7 - Synthesis of benzylmethylketone (phenylacetone) from benzyl chloride and acetic anhydride.

For these examples, the anode is made of magnesium or aluminum, the cathode made of nickel, the solvent DMF (110 g) and the electrolyte indifferent tetrabutylammonium fluoroborate (2 g or 6 mmol).

After electrolysis (2.2 Faraday per mole of benzyl chloride), the remaining benzyl chloride, toluene, which is a by-product of reduction of benzyl chloride, and benzylmethylketone, are dosed by GC on an aliquot. on the one hand in free form and on the other hand in the form of its enol acetate.

After evaporation of the DMF and hydrolysis of the residue by hot diluted HCl, the benzylmethylketone is isolated by extraction with ether. Pure benzylmethylketone was identified by its IR and NMR spectra and its purity was checked by GC.

The electrolysis operating conditions specific to each example as well as the results obtained are collated in Table 1.

Example 8 Synthesis of 4 tert-butylphenylacetone of formula

à partir de 4 tertiobutylphénylchlorométhane et d'anhydride acétique.

from 4 tert-butylphenylchloromethane and acetic anhydride.

The conditions specific to this example are the same as those of Example 4 but replacing the benzyl chloride by the 4 tert-butylphenylchloromethane of formula

After electrolysis (2.2 Faraday per mole of the organic halide), the solvent is evaporated and the residue obtained is hydrolyzed by hot diluted HCl. The 4 tert-butylphenylacetone is then isolated by extraction with ether and then distillation under vacuum. The pure tertiary butylphenylacetone 4 thus isolated (yield 73% was identified by its IR and NMR spectra and its purity was checked by CPG.

Example 9 Synthesis of 3,4 Dimethoxyphenylacetone of Formula

à partir de 3,4 diméthoxyphénylchlorométhane et d'anhydride acétique.

from 3,4 dimethoxyphenylchloromethane and acetic anhydride.

The conditions specific to this example are the same as those of Example 4 but by replacing the benzyl chloride by the 3,4 dimethoxyphenylchloromethane of formula

After electrolysis (2.2 Faraday-per mole of the organic halide), the solvent is evaporated and the residue obtained is hydrolyzed by hot diluted HCl. The 3,4 dimethoxyphenylacetone is then isolated by extraction with ether and then vacuum distillation.

The pure dimethoxyphenylacetone 3,4 thus isolated (yield 25%) was identified by its IR and NMR spectra and its purity was checked by CPG.

Examples 10 to 20

According to the same procedure as in Example 1, various ketones are prepared from the halides and anhydrides indicated in Table II. The results and operating conditions of these tests are also grouped in this table.

For examples 15 and 19, a mixture of ketones is obtained.

For Examples 16 and 20, a mixture of ketone and ester is obtained, the ketone being preferably obtained (eg 16: 95% ketone, 5% ester; eg 20: 75% ketone and 25% d 'ester).

Example 21 Synthesis of 4-oxo 6-methyl 6-heptenoic acid of formula

à partir de 35 mmol de 3-chloro 2-méthyl 1-propène (chlorure de méthallyle) et 35 mmol d'anhydrique succinique.

from 35 mmol of 3-chloro 2-methyl 1-propene (methallyl chloride) and 35 mmol of succinic anhydrous.

The solvent is DMF (30 cm ³ ), the anode is made of zinc and the cathode made of stainless steel. The reaction temperature is 20 ° C. The supporting electrolyte is tetrabutyl ammonium iodide (2 10- ² M).

- The solution also contains 1.5 mmol of an organometallic complex catalyst of a transition metal, namely the NiBr ₂ -2.2'bipyridyl complex also called NiBr ₂ (Bipyridine) or NiBr _Z Bipy. To prepare this catalyst was added 2 10- ² mol of NiBr ₂ and 2 10- ² mol of 2,2'-bipyridine in 120 cm ³ of absolute ethanol. Stir 24 h at 20 ° C. NiBr ₂ Bipy precipitates (light green precipitate). This precipitate is isolated by filtration, then washed with acetone (20 to 25 cm ³ ) and then dried under vacuum at 20 ° C. 1.8 10- ² mol of NiBr ₂ Bipy are recovered (yield 90 %).

- The electrolysis is carried out under a current density on the cathode of 2A / dm ² . After passing an amount of current corresponding to 3 Faraday per mole of halide, the electrolysis is stopped. The DMF is then evaporated under vacuum and the residue is hydrolyzed using dilute hydrochloric acid. The desired product is then extracted with ether and then the ethereal phase is washed with an aqueous sodium hydroxide solution. The aqueous phase is then acidified (hydrochloric acid) and then extracted again with ether.

After evaporation of the ether, 4-oxo 6-methyl 6-heptenoic acid, identified by its IR and NMR spectra, is isolated, with a yield of 30% relative to the starting halide.

The ketones obtained by this process are particularly useful as starting materials for the manufacture of medicament or perfumery products or useful in the phytosanitary field. Thus, by way of example, phenylacetone is used to manufacture amphetamines, trifluoromethylphenylacetone, phenoxyphenylbutanone and dimethoxyphenylacetone are used respectively to manufacture fenfluramine, fenoprofen and methyldopa. In perfumery and in the phytosanitary field, tertiobutylphenylacetone is used to make the lilial.

Claims (15)

1. Process for electrosynthesis of ketones by electrochemical reduction of organic halides in the presence of organic acid derivatives in an electrolysis cell equipped with electrodes in an organic solvent medium containing a supporting electrolyte, characterized in that a sacrificial anode made of a metal chosen from the group consisting of magnesium, aluminium, zinc and alloys thereof is employed and in that the organic acid derivatives are anhydrides of organic acids.

2. Process according to Claim 1, characterized in that the organic halides correspond to the general formula R_lX in which X denotes a halogen and R₁ denotes a saturated or unsaturated, substituted or unsubstituted, aliphatic or cycloaliphatic chain.

3. Process according to Claim 2, characterized in that R₁ denotes an aliphatic chain substituted by at least one aromatic group.

4. Process according to any one of the preceding Claims, characterized in that the anhydrides of organic acids correspond to the general formula

in which R₂ denotes:

- a saturated or unsaturated, substituted or unsubstituted, aliphatic or cycloaliphatic chain,

- a substituted or unsubstituted aryl group,

- a substituted or unsubstituted aromatic heterocyclic ring, and R₃ denotes:

- a saturated or unsaturated, substituted or unsubstituted, aliphatic or cycloaliphatic chain,

- a substituted or unsubstituted aryl group,

- a substituted or unsubstituted aromatic heterocyclic ring

- a group -OR₄ in which R₄ denotes:

a saturated or unsaturated, substituted or unsubstituted, aliphatic or cycloaliphatic chain,

a substituted or unsubstituted aryl group,

a substituted or unsubstituted aromatic heterocyclic ring

or else R₂ and R₃ form at least one substituted or unsubstituted ring.

5. Process according to Claim 4, characterized in that R₂ and R₃ are identical.

6. Process according to either of Claims 4 and 5, characterized in that R₂ and R₃ denote an alkyl chain.

7. Process according to any one of the preceding Claims, characterized in that the organic solvent is N,N-dimethylformamide (DMF).

8. Process according to any one of the preceding Claims characterized in that the concentration of organic halides is between 0.2 M and 2 M.

9. Process according to any one of the preceding Claims, characterized in that the ratio of the concentrations of the anhydride of an organic acid and the organic halide in the organic solvent is between 1 and 20.

10. Process according to any one of the preceding Claims, characterized in that the temperature of electrolysis is between -20°C and +80°C, preferably between -10°C and 40°C.

11. Process according to any one of the preceding Claims, characterized in that the cathode current density is between 0.1 A/dm² and 10 A/dm².

12. Process according to any one of the preceding Claims, characterized in that the electrolysis is conducted at constant intensity.

13. Process according to any one of the preceding Claims, characterized in that the concentration of supporting electrolyte is between 0.01 M and 0.5 M.

14. Process according to any one of the preceding Claims, characterized in that the electrolys is is conducted in the presence of an organometallic complex of a transition metal.

15. Process according to Claim 14, characterized in that the complex is NiBr₂(bipyridine).