GB2191192A

GB2191192A - Trifluoromethyl aromatic compounds

Info

Publication number: GB2191192A
Application number: GB08712344A
Authority: GB
Original assignee: YARSLEY TECHNICAL CENTRE Ltd
Current assignee: YARSLEY TECHNICAL CENTRE Ltd
Priority date: 1986-05-30
Filing date: 1987-05-26
Publication date: 1987-12-09
Anticipated expiration: 2007-05-26
Also published as: GB8613207D0; GB8712344D0; GB2191192B

Abstract

The invention relates to compounds having the formula I, II, III or IV below:- <IMAGE> wherein X represents fluorine or chlorine or CF3 and Y represents -CO2H (which may be esterified), -CHO, -COCH3 or -OH, with the proviso that in general formula (IV) when Y is -CO2H or -CHO, X is not F or Cl. The compounds are useful as intermediates in the preparation of agrochemicals and pharmaceuticals.

Description

SPECIFICATION Trifluoromethyl aromatic compounds This invention relates to trifluoromethyl aromatic compounds and is concerned in one aspect with various novel trifluoromethyl phenyl compounds.

A demand exists for fluoro-substituted aromatic compounds as intermediates for the preparation of a variety of end products, particularly for investigation for activity which may give products of value as pharmaceuticals or agrochemicals.

Useful intermediate compounds should contain a reactive substitutuent group which can be readily further reacted so as to provide a convenient route to other products. One of the most suitable substituents is a carboxylic acid group since this group can be readily further reacted to form amide, amino and acid chloride groups. Other desirable substituent groups are-COCH3, -CHO and -OH.

One of the difficulties of preparing compounds of this kind is predetermining the position in the benzene ring which will be substituted by the reactive substituent group since a mixture of isomers is generally unacceptable as starting materials for the synthesis of an end product.

According to one aspect of the present invention there is provided a trifluoromethyl aromatic compound having the general formula I, 11,111 or IV below:

wherein X represents fluorine or chlorine or CF3 and Y represents-CO2H (which may be esterified), -CHO, -COCH3, or -OH, with the proviso that in general formula (IV) when Y is-CO2H or-CHO, Xis not F or CI.

Other positions in the ring in the above formulae may be substituted by groups which are present in the starting materials and which do not interfere with the method of preparation described hereinafter. An example of a possible substituent group is alkyl, e.g. methyl.

Preferred compounds in accordance with this invention are trifluoromethyl phenyl compounds having one of the above general formulae in which X represents CF3 or F.

Compounds in which Y is a carboxylic acid group have the advantage that they are easily separated by conversion to an ester or salt.

The invention also includes a convenient method which enables the above-described trifluoromethyl phenyl compounds to be obtained in high yield, said method comprising contacting the corresponding fluoro ortrifluoromethylbenzotrifluoridecompound in a non-reactivesolventwith an alkyl lithium compound under anhydrous conditions and reacting the resulting phenyl lithium intermediate in situ with an appropriate reagent to introduce the substituent represented by Y in the above formulae. By the term 'non-reactive solvent' we mean a solvent which does not adversely affect the course of the reaction between the alkyl lithium compound and the trifluoromethyl phenyl compound.

Both halogen and CF3 can be predicted to activate the ring for metalation by the lithium in a position ortho to the halogen or CF3 substituent. Fluorine is found to exert a stronger influence than CF3 in this respect Thus, in the case of the following compounds:

metalation will occur in the 1-position, when X is fluorine or chlorine. In the case where X is -CF3, metalation will occur ortho to either CF3 but since the compound is symmetrical only one singly metalated product is possible.

Similarly, in the case of compounds of the formula:

Metalation will take place in the 1 or 3 positions, ortho to the X substitutuent, when X is F or Cl, but the resultant aryl lithium compounds are identical. Where Xis CF3 metalation is equally likely in the 4 or 6 positions.

In contrast, in the case of compounds of the following general formula the situation is different.

In the case of these compounds metalation of the 1, 3 and 5 positions appears possible with the 1-position being the most favoured on theoretical grounds and the 5-position the least favoured.

In practice, steric influences also seem to play a role to some extent. Thus, when Xis fluorine and the lithium compound is n-butyl lithium, a mixture of products is obtained which generally consists of about 30% of the 3-substituted product and the remainder the 1-substituted compound. Increase in the length or branching of the alkyl chain of the lithium compound appears to have some favourable influence on formation of the 3-substituted product. For example, if compounds of the general formula (VII) (where Xis F or CI) are treated with secondary or tertiary butyl lithium, metalation tends to predominate in the 3-position. Conversely, the use of a shorter chain length alkyl lithium compound (e.g. n-propyl lithium) favours formation of the 1-substituted product.The influence on the favoured metalation position of the length of the alkyl chain or its nature (branched or straight chain) is illustrated in Examples 4, 5 and 12 which follow.

The situation is similar where the X substituent in the 2-position is also CF3. Subject to the steric factor mentioned above the most favoured position for metalation is the 1-position. However, the 3 and 5 positions can be preferentially favoured if steric effects restrict reaction in the 1-position and metalation at more than one position may occur.

However, we have found that where the metalated compounds are converted to the corresponding benzoic acids, the mixture of isomers which are present in some cases (and any disubstituted acids which may be formed) can be easily separated by treating the mixture of acids with an aqueous alkali metal carbonate or bicarbonate and preferentially extracting a carbonate or bicarbonate of the more acidic isomer into the aqueous layer.

The metalation reaction is generally carried out by contacting the trifluoromethyl phenyl compound in tetrahydrofuran (THF) with an alkyl lithium compound at temperatures which are below that at which there is a significant aryne formation. It is important to carry out the metalation reaction under anhydrous conditions and the reactants and solvent should be thoroughly dried priorto use. Normally, the reaction is conducted at temperatures below about -50 C where X in the above formulae is F or CI. Higher temperatures (e.g. ambient) may be desirable when bis-trifluoromethyl compounds are to be produced because of their lower degree of reactivity.

Any alkyl or aryl lithium compound may theoretically be used in the metalation reaction. However, as explained above, n-alkyl lithium compounds having less than 4 carbons are preferred where the objective is to metaiate a compound of general formula (VII) in the 1-position. Also, phenyl lithium is generally less reactive than alkyl lithium compounds. Because of its ready availability n-butyl lithium is often the reagent of choice for metalation of compounds of general formulae (V) & (VI). Branched chain alkyl lithium compounds, especially those containing 4 carbons or more, are preferred where the objective is to metalate compounds of general formula (VII) in the 3-position.

The metalated compounds can be further reacted to introduce the desired substituent in place of lithium without isolation from the solution. In the case of benzoic acids, this can be conveniently achieved by passing gaseous carbon dioxide into the solution containing the reaction product of the alkyl or aryl lithium compound and the trifluoromethyl phenyl starting material. This procedure is operable in large scale production and gives excellent yields.

The invention will be illustrated by the following worked Examples. In the Examples which follow the metalated compound is converted in each case to the corresponding benzoic acid derivative. However, it will be appreciated that other derivatives can be prepared directly from the metalated compound in solution. For example, the corresponding benzaldehydes can be prepared by reaction with N-methyl formanilide.

EXAMPLE 1 2-Fluoro-3-(trifluoromethyl)benzoic acid Reaction of 2-fluorobenzotrifluoride with an ether solution of n-butyllithium.

A dry flask fitted with a magnetic stirrer, nitrogen inlet, thermometer and a septum capped pressure equalising dropping funnel was purged with nitrogen and charged with THF (200 cm3) and 2fluorobenzotrifluoride (16.4g, 0.1 mole). A solution of 1.01 M n-butyllithium in ether (95 cm3, 0.096 mole) was transferred by syringe to the addition funnel and the apparatus was cooled to < -70 . The n-butyllithium solution was added to the rapidly stirred solution of 2-fluorobenzotrifluoride at such a rate that the reaction temperature did not rise above -70". The addition was accompanied by a slow colour change from colourless to pink. After stirring for a further 5 hr. at < -70 the reaction mixture was poured, with stirring, onto an excess of solid carbon dioxide.The excess carbon dioxide was allowed to evaporate and the residual mixture was then evaporated to dryness. The resultant white residue was dissolved in aqueous sodium hydrogen carbonate (^5%) and extracted twice with ether. The aqueous solution was acidified with hydrochloric acid and after filtration the resultant white precipitate was crystallized from petroleum spirit (b.p. 80-1 00 C) to give the title compound (16.2 g, 77.9% yield) m.p. 127"C.

EXAMPLE 2 2- Fluoro-5-(trifluoromethyl)benzoic acid Reaction of 4-fluorobenzotrifluoride with an ether solution of n-butyllithium.

This reaction was carried out as in Example 1 but using 4-fluorobenzotrifluoride (16.4 g, 0.1 mole) and 1.1 so n-butyllithium (86cm3, 0.1 mole). After reaction with solid carbon dioxide and evaporation of solvents, the residue was taken up in water and extracted twice with dichloromethane (100 cm3 and 75 cm3). On acidification of the aqueous layer with hydrochloric acid, an oil formed which crystallised in about one minute.

After standing for about 24 hr the product was collected and recrystallised from petroleum spirit (b.p. 60-80 C) to give the title acid (15.3 9, 73.6% yield) m.p. 101"C.

EXAMPLE 3 2-Fluoro-4-(trifluoromethyl)benzoic acid and 2-fluoro 6-(trifluoromethyl)benzoic acid Reaction of 3-fluorobenzotrifluoride with an ether solution of n-butyllithium.

This reaction was carried out as for Example 2 but using 3-fluorobenzotrifluoride (16.4 g, 0.1 mole) and 1.15M n-butyllithium (86 cm3, 0.1 mole). The reaction mixture was maintained at -65 to -70 C throughout the course of the reaction, during which time the colour changed from colourless through pink, red and finally purple after 5 hr. After carbonation and work-up, an oily part crystalline slurry was precipitated which smelled strongly of pentanoic acid. The crude product was extracted into ether (2x200 cm3) and after separation the ether layer was evaporated to leave an oily semi-crystalline mass which again smelled of pentanoic acid.This mixture was then stirred with water (200 cm3) and solid sodium hydrogen carbonate was added portionwise until the oily portion of the product was dissolved. The crystalline residue was collected by filtration, washed well with water and recrystallised from petroleum spirit (b.p. 80-100"C) to yield 2-fluoro-4-(trifluromethyl) benzoic acid (4.35 g, 20.0% yield,) m.p. 1 69.50C.

Acidification of the aqueous filtrate yielded a colourless oil which crystallised on standing for approximately one month. This product was collected, washed with water and recrystallised from petroleum spirit (b.p.

40-60 C) to yield 2-fluoro-6-(trifluoromethyl) benzoic acid (11.43 g, 55.0% yield) m.p. 84.50C.

EXAMPLE 4 2-Fluoro-4(trifluoromethyl)benzoic acid and 2-fluoro 6-(trifluoromethyl)benzoic acid Reaction of 3-fluorobenzotrifluoride with an ether solution of n-butyllithium.

Example 3 was repeated except that the addition of n-butyllithium was carried out at about -55 . The reaction mixture went through mauve to purple in a few minutes during the addition of the alkyllithium. The mixture was stirred at < 70 for 90 minutes then warmed to between -50 and -60" C for 3 1/2 hr. after which time the phenyllithium solution was almost black in colour. Carbonation and work-up as in Example 3 yielded 2-fluoro-4-(trifluoromethyl)benzoic acid, crystallised from petroleum spirit (b.p. 100-120"C), (4.7 g, 22.6% yield) m.p. 157"C and 2-fiuoro-6-(trifluoromethyl)benzoic acid, (10.26g, 49.3% yield) m.p. 84.50C.

EXAMPLE 5 2-Fluoro-4-(trifluoromethyl)benzoic acid Reaction of 3-fluorobenzotrifluoride with a hydrocarbon solution of s-butyllith iu m.

This reaction was carried out as in Example 1 using THF (100cm3), 3-fluorobenzotrifluoride (8.2 g, 0.05 mole) and 1.1 4M s-butyllithium in cyclohexane (44 cm3, 0.05 mole). The temperature during the addition was maintained at < -65" and the reaction mixture was then stirred for a further 5 hr at < -7.0 . During the addition the reaction mixture became blue, then greenish blue and finally greyish blue after 5 hr. After carbonation the mixture was allowed to stand for about 24 hr then mixed with water (approx. 100 cm3). Evaporation of THF and cyclohexane resulted in an aqueous solution which was filtered to remove a small quantity of insoluble material.Acidification of the filtrate produced a white precipitate which was collected, washed, and crystallized from petroleum spirit (b.p. 100-120") to yield the title compound (7.58 g, 72.9% yield) m.p. 1600.

Examples 6 to 10 were all carried out exactly as in Example 5 apart from any noted differences.

EXAMPLE 6 2-Fluoro-5-(trifluoromethyl)benzoic acid Reaction of 44luorobenzotrifluoride with a hydrocarbon solution of s-butyl lithium.

The reaction mixture was pink at an early stage of the addition and then changed through blue/grey and mauve as the addition ended and finally light brown after 5 hr. The standard 'work-up' yielded an oil which rapidly crystallised and was recrystallised from petroleum spirit (b.p. 8O1 000) to give the title compound (8.859,85.1 % yield) m.p. 100.5"C.

EXAMPLE 7 2-Fluoro-3-(trifluoromethyl)benzoic acid Reaction of 2-fluorobenzotrifluoride with a hydrocarbon solution of s-butyllithium.

The reaction mixture changed colour through pink, mauve, purple, gray and finally brown at the end of the addition. Carbonation and 'work-up' followed by crystallisation from petroleum spirit (b.p. 100-120"C) yielded the title compound (8.45 9,81.3% yield) m.p. 126.5"C.

EXAMPLE 8 2-Fluoro-4-(trifluoromethyl)benzoic acid Reaction of 3-fluorobenzotrifluoride with a hydrocarbon solution of t-butyllithium.

The reaction was carried out as in Example 5 but using 1.7M t-butyllithium in pentane (29.4 cm3, 0.05 mole).

The reaction mixture changed colour through blue to dark brown/black at the end of the addition and finally to dark blue after 5 hr stirring. After carbonation and 'work-up' the title product was crystallised from petroleum spirit (10O1200C), (3.6 g, 34.6%) m.p. 170.5"C.

EXAMPLE 9 2-Fluoro-5-(trifluoromethyl)benzoic)acid Reaction of 4-fluorobenzotrifluoride with a hydrocarbon solution oft-butyllithium.

This reaction was carried out as in Example 8, however, little colour change was noted during the reaction and 30 minutes after the addition of t-butyllithium the mixture was again colourless. After 6 hr the temperature had risen to -62"C and the solution was pale blue. Carbonation and 'work-up' were as usual and crystallisation from petroleum spirit (b.p. 80-100 C) gave the title product (8.74 9,84.0% yield) m.p. 101.S'C.

EXAMPLE 10 2-Fluoro-3-(trifluoromethyl)benzoic acid Reaction of 2-fluorobenzotrifluoride with a hydrocarbon solution of t-butyllithium.

The reaction was carried out as in Example 8 and resulted in a colour change through yellow to orange and dark red/brown after 5 hr. 'Work-up' and crystaliisation from petroleum spirit (b.p. 8O1 000) gave the title product (8.86 g, 85.2%) m.p. 126.50.

EXAMPLE 11 2-Fluoro-4-{trifluoromethyl)benzoic acid and 2-fluoro-6-(trifluoromethyl)benzoic acid Reaction of 3-fluorobenzotrifluoride with a hydrocarbon solution of n-butyllithium.

This reaction was carried out as in Example 5 using 3-fluorobenzotrifluoride (8.2 g, 0.05 mole) in THF (100 cm3). The addition funnel was charged with n-heptane (25 cm3) to which was added a 10.2M solution of n-butyllithium in hexane (4.9 cm3, 0.05 mole). The resultant approximately 1.7M solution was added dropwise to the THF solution of 3-fluorobenzotrifluoride as usual. Carbonation and 'work-up' yielded, after removal of solvents, a cloudy aqueous solution containing some oily material. Extraction with two portions of petroleum spirit (b.p. 40-60") foliowed by evaporation of the combined extracts gave a viscous oil (approx. 20 mg) which was not further investigated. The clear aqueous solution was acidified and extracted twice with ether.

Evaporation of the solvent in an open beaker yielded a mixture of large crystals and oil. This mixture was then filtered and the collected crystals were recrystallised from petroleum spirit (b.p. 8O1 000) to give the 2-fluoro-4-(trifluoromethyl)benzoic acid (22.5 g, 21.6% yield).

The oily filtrate was triturated with petroleum spirit (b.p. 40-60") where upon it slowly solidified. Filtration and crystallization from petroleum spirit (b.p. 40-60") gave the 2-fluoro-6-(trifluoromethyl)benzoic acid (6.69 g, 64.3%) m.p. 80.00.

EXAMPLE 12 2-Fluoro-6-(trifluoromethyl)benzoic acid Reaction of 3-fluorobenzotrifluoride with an ether solution of n-propyllithium.

A solution of n-propyllithium was prepared from lithium shot (8.1 g, 1.16 mole) and 1 -bromopropane (709, 0.57 mole) in diethyl ether (330 cm3).

This reaction was carried out in the same manner as Example 5 but using a 1.33M solution of n-propyllithium in ether (37.6cm3, 0.05 mole). At the end of the reaction the resultant phenyllithium solution was a pale pink colour. Carbonation and the usual 'work-up' procedure yielded an oil which was extracted into ether. Evaporation of the solvent gave an oil which solidified on trituration with petroleum spirit (b.p. 40-60").

Recrystallisation of the resultant product from petroleum spirit (b.p. 40-60") yielded the title product (8.05 g, 77.4%) m.p. 83.0".

EXAMPLE 13 2-Fluoro-4-(trifluoromethyl)benzoic acid Reaction of 3-fluorobenzotrifluoride with a hydrocarbon solution of s-butyllithium.

This reaction was carried out as in Example 5 but on a large scale. Thus a 1 M solution of s-butyllithium in cyclohexane (3353, 0.335 mole) was allowed to react at-65 with 3-trifluorobenzitrifluoride (55 g, 0.3235 mole) in THF (350 cm3). After stirring for 3 1/2 hr at < --700 the aryllithium solution was poured into an ether slurry of crushed 'dry-ice'. After the usual 'work-up' procedure the white product was collected and dried. On attempted crystallisation from petroleum spirit it became apparent that the product contained some insoluble material. Soxhlet extraction with petroleum spirit (100-120 ) resulted in a clear filtrate which on cooling deposited the title compound as fine slightly yellowish crystals (42.9 g, 61.5%).

Claims

1. A trifluoromethyl aromatic compound having the general formula I, II, III or IV below:

wherein X represents fluorine or chlorine or CF3 and Y represents-CO2H (which may be esterified),-CHO,-COCH3 or-OH, with the proviso that in general formula (IV) when Y is-CO2H or-CHO, Xis not F or Cl.

2. Trifluoromethyl phenyl compounds according to claim 1 wherein X is CF3 or F.

3. A method of preparing a trifluoromethyl phenyl compound as claimed in claim 2 which comprises contacting the corresponding fluoro- or trifluoromethylbenzotrifluoride compound with an alkyl lithium compound in an inert solvent under anhydrous conditions and reacting the resulting phenyl lithium intermediate in situ with an appropriate reagent to introduce the substituent represented by Y.

4. A method according to claim 3 in which the reaction mixture was maintained at a temperature below about -50"C during the metalation reaction.

5. A method according to claim 3 or 4 in which the solvent is tetrahydrofuran.

6. A method of separating ortho and para isomers of trifluoromethyl benzoic acids which comprises treating a mixture of isomers with aqueous alkali metal carbonate or bicarbonate and preferentially extracting a salt of the more acidic isomer into the aqueous layer.