GB2155464A - Preparation of benzyl alcohols - Google Patents

Abstract

Optionally-substituted benzoyl halides are reduced to their corresponding benzyl alcohols by an alkali or alkaline-earth metal borohydride in the presence of a phase transfer catalyst or by a specified quaternary ammonium or phosphonium borohydride, in a two phase aqueous/organic medium.

Description

SPECIFICATION Preparation of benzyl alcohols This invention relates to an improved process for the reduction of substituted and unsubstituted benzoyl halides to their corresponding benzyl alcohols.

It is known that borohydrides, including sodium borohydride and long-chain ammonium borohydrides, will reduce the organic functional groups of various compounds such as aldehydes, ketones, esters, nitriles and acid halides (N.G. Gaylord, Reductions with Complex Metal Hydrides, Interscience Publishers Inc.

; J. Am. Chem. Soc. 71, 122 [1949]; Synthesis [1979] 912; J. Org. Chem. 27,3731 [1962]). With compounds like aldehydes and ketones the reduction can be carried out in water or alcohol. However, in the case of acid halides, including benzoyl chloride and 4-nitrobenzoyl chloride, aprotic organic solvents such as anhydrous diethyl ether, dioxane and benzene, have been used to avoid hydrolysis by hydroxylic solvents.

Suprisingly, it has now been found that certain acid halides can be reduced effectively by borohydrides in a two phase aqueous/organic medium. This has the advantages that less expensive solvents can be used and the need to maintain anhydrous conditions is avoided.

According to the present invention there is provided a process for the reduction of a compound of the formula (I):

in which X is halo, especially chloro, and the benzene ring A optionally carries other substituents, to a compound oftheformula (ill):

which process comprises contacting compound (I) with an alkali or alkaline-earth metal borohydride in the presence of a phase transfer catalyst or with a quaternary ammonium or phosphonium borohydride, as hereinafter defined, in a medium comprising an aqueous phase and a water-immiscible organic phase.

Other substituents which may be carried by benzene ring A may be any substituents that do not render compound (I) water soluble to any significant degree. Such substituents include alkyl, preferably C alkyl, especially methyl, alkoxy, preferably C1.4 alkoxy, halo, especially chloro and fluoro, nitro, aryl, preferably optionally sustituted phenyl, aralkyl, preferably optionally sustituted benzyl and aryloxy, preferably optionally substituted phenoxy.

The process of the invention is of particular interest for the reduction of 4-methyl-2,3,5,6tetrafluorobenzoyl chloride.

Any water-immiscible, non-polar solvent may be used to provide the organic phase of the process medium provided it is inert to the reactants. Toluene and carbon tetrachloride are especially mentioned but other solvents which might be used include hydrocarbons such as n-hexane and cyclohexane, and chlorinated hydrocarbons particularly chlorinated alkanes such as chloroform and 1,2-dichloroethane.

Sodium borohydride is a convenient borohydride to use in conjunction with the phase transfer catalyst, although it is envisaged that others such as potassium and lithium borohydrides, may be used.

By the term "phase transfer catalyst" is meant a substance which, being at least partly present in or wetted by a first (usually organic) phase promotes reaction between a reactant in the first phase and a reactant which it transfers from a second (usually aqueous) phase to the first phase. After reaction the phase transfer catalyst is released for transferring further reactant. Phase transfer catalysts are reviewed by E.V. Dehmlow in Angewante Chemie (International Edition) Vol. 13, No.3, 1974, page 170. Other reviews are by Jozef Dockx in Synthesis 1973 at pages 441-456 and by C.M. Starks in the Journal of the American Chemical Society (93) 1, Jan 13 1971, pages 195-199.

Suitably the phase transfer catalyst is a quaternary ammonium or phosphonium salt preferably containing bulky organic groups to make it soluble in the organic phase. The molecular geometry of the quaternary ammonium or phosphonium cation is not thought to be of prime importance, but to confer preferential solubility in the organic phase rather than the aqueous phase it is preferred that the total number of carbon atoms attached to each nitrogen or phosphorus atom is greater than 10. There is little advantage in the number being above 70. It is especially preferred that the number should be in the range of from 16 to 40.

Examples of quarternary ammonium salts are cetyl trimethyl ammonium bromide dicetyldimethyl ammonium chloride octyl tributyl ammonium bromide trioctyl methyl ammonium chloride benzyl dimethyl lauryl ammonium chloride benzyl tri-n-butylammonium chloride dilauryl dimethyl ammonium chloride tetrabutyl ammonium sulphate dieicosyl dimethyl ammonium chloride.

Tetrabutyl ammonium bromide is particularly suitable. Examples of quaternary phosphonium salts are cetyltripropyl phosphonium bromide and triphenylethyl phosphonium bromide.

As an alternative, it is envisaged that a quaternary ammonium or phosphonium borohydride may be used in place of the alkali or alkaline-earth metal borohydride and phase transfer catalyst, the quarternary ammonium or phosphonium cation of the borohydride being as that defined for the quaternary ammonium or phosphonium borohydride can be prepared by metathesis from commercial borohydrides.

In the present invention, compound (I) is thus reduced to compound (II) in a medium comprising water and a water-immiscible organic solvent in the presence of borohydride anions and quaternary ammonium or phosphonium cations in which there are more than 10 and up to 70 carbon atoms per positively charged nitrogen or phosphorus atom.

When an alkali or alkaline-earth metal borohydride and phase transfer catalyst are used, it is convenient to add an aqueous solution of the borohydride to a solution of compound (I) in the organic solvent to which has been added the phase transfer catalyst. Where a quaternary ammonium or phosphonium borohydride is used alone, this might be added to either aqueous or organic phase. The mixed solutions are stirred until reaction is complete, the two phases separated and compound (II) recovered from the organic phase by, for example, removing the organic solvent by evaporation under reduced pressure. Progress of reaction may be followed by periodically analysing samples of the organic phase.

It is an advantage of the present process that reaction takes place at room temperature and is complete at this temperature in, typically, 2 hours. Higher temperatures up to 100"C may be used, if desired, but normally the reaction will be carried out in the range of from 1 00C to 600C.

The proportion of water to water-immiscible organic solvent in the reaction medium is thought not to be critical, it being necessary only to have sufficient of each to dissolve the reactants. Typically, the ratio of the volumes of water to organic solvent is about 1:5.

To ensure complete reduction of the benzoyl halide, at least a stoichiometric amount of borohydride should be used, i.e. 0.5 mol borohydride per mol of benzoyl halide. In the absense of an acid acceptor in the aqueous phase, about 1.2 mols of borohydride per mol of benzoyl chloride is suitable but with an acid acceptor present less may be employed.

The amount of phase transfer catalyst used is typically 20% by weight of the borohydride but less may be used, e.g. 10%, without loss of yield.

The starting compounds of formula (I) may generally be obtained by oxidation or selective oxidation of the appropriate methylbenzene precursor to form the carboxylic acid. The acid halide, which will usually be the acid chloride, is then obtained by reaction of the carboxylic acid with, for example, phosphorous pentachloride orthionyl chloride. Alternatively, the monocarboxylic acid may be obtained by acid hydrolysis of the corresponding nitrile. In particular, 4-methyl-2,3,5,6-tetrafluorobenzoylchloride may be prepared by this latter route, the nitrile being obtained by the process described in UK Application No. 8402802 (filed 02.02.1984).

The compounds (II) obtained by the process are useful chemical intermediates in the synthesis of a variety of products. In particular, 4-methyl-2,3,5,6-tetrafluorobenzyl alcohol may be reacted with thionyl chloride or aqueous HCI to form the corresponding benzyl chloride which is used in the preparation of pesticidal products. In this case, it is an advantage of the process of the invention that the benzoyl chloride precursor and the benzyl chloride derivative can be prepared in the same solvent as that used for the borohydride reduction. This gives a convenient "one-pot" synthesis for the preparation of the benzyl halide from the corresponding carboxylic acid.

The invention is illustrated by the Examples 1,3 and 4. Example 2 is included for comparative purposes only and forms no part of the present invention. Percentages are by weight unless otherwise stated.

EXAMPLE 1 Reduction of4-methyl-2,3, 5, 6-tetrafluorobenzyl chloride 4-Methyl-2,3,5,6-tetrafluorobenzyl chloride (2.5g) was dissolved in toluene (25ml) and tetrabutylammonium bromide (about 0.19) added. Sodium borohydride (0.5g) was dissolved in water (5ml) and the aqueous solution added to the toluene solution dropwise over 30 minutes at 10 to 20"C. The mixed solutions were stirred for four hours at room temperature and the lower aqueous layer then separated. Solvent from the toluene layer was evaporated under reduced pressure leaving an oil which solidified on standing.The solid was identified as 4-Methyl-2,3,5,6-tetrafluorobenzyl alcohol (1.79,75.8% strength : yield 66% on acid chloride, 93.5% strength).

EXAMPLE 2 (comparative) Reduction of 4-methyl-2,3, S 6-tetrafluorobensyl chloride by borohydride in the presence of a quaternary ammonium salt but in the absence of water Sodium borohydride (1 g) was added portionwise over 15 minutes to a stirred solution of 4-methyl-2,3,5,6tetrafluorobenzoyl chloride (2.5g) in toluene (25ml) in the presence of tetrabutylammonium bromide (0.15g) at 10 to 1 5"C. Analysis bygicofa sample of the mixture taken after about 30 minutes indicated no reduction had taken place. The mixture was analysed again 30 minutes after being allowed to warm to room temperature. About 0.5% of the acid chloride was shown to have reacted.The mixture was then heated in steps and the extent of reaction determined by glc analysis after a period of time at a given temperature as shown in the following table.

TABLE Temperature ('C) Time (hers) Extent of Reaction 1%1 40 1 0.6 70 2 2.6 90 7 79 90 3 94 90 (Total 10 at 90"C) 94 3 (Total 15 at 90"C) Part of the reaction mixture (1 Oml) was filtered and toluene removed under reduced pressure to leave a white solid identified as 4-methyl-2,3,5,6-tetrafluorobenzyl alcohol (0.9g, 84.5% strength : reduction yield calculated to be 78%).

The remaining part was treated with water (5ml) - much effervescence - and acidified. The lower aqueous layer was run off and the toluene layer washed with water (5ml). The toluene was removed under reduced pressure leaving the product, 4-methyl-2,3,5,6-tetrafluorobenzyl alcohol (0.79,92% strength : reduction yield calculated to be 66.2%).

EXAMPLE 3 Reduction of benzoyl chloride (wateritoluene) A solution of benzoyl chloride (0.62g; 4.4mol) in toluene (10ml) containing tetrabutylammonium bromide (0.1g) was stirred at room temperature and treated with a solution of sodium borohydride (0.29; 5.2 mmol) in water (2ml). After 20 minutes, examination of the toluene layer by glc (2M LAC-2R-446 (5%) at 120 to 170"C) showed the presence of 23% benzaldehyde, 46% benzyl alcohol and 17% benzoyl chloride. The mixture was stirred for a total of 2 hours to give 2% benzaldehyde and 80% benzyl alcohol. No unreacted benzoyl chloride was detected. Extraction of the aqeous phase did not afford a significant quantity of benzyl alcohol.

The percentages given in this Example are moles % based on the benzoyl chloride used.

EXAMPLE 4 Reduction ofbenzoyl chloride (waterlcarbon tetrachloride) The procedure of Example 3 was repeated except that carbon tetrachloride was used in place of toluene and the analysis of the organic level after 20 minutes was not carried out. After 2 hours, analysis by glc indicated 87% yield of benzyl alcohol in the organic layer and very little benzaldehyde.

Claims (2)

1. A process for the reduction of a compound of the formula (I):

in which X is halo and the benzene ring A optionally carries other substituents, to a compound of the formula 111\

which process comprises contacting compound (I) with an alkali or alkaline-earth metal borohydride in the presence of a phase transfer catalyst or with a quaternary ammonium or phosphonium borohydride in a medium comprising an aqueous phase and a water-immiscible organic phase.

2. A process according to claim 1 in which compound (I) is 4-methyl-2,3,5,6-tetrafluorobenzoyl chloride.