WO1998024740A1 - Fluorination of carbonyl-substituted aromatic compounds - Google Patents

Fluorination of carbonyl-substituted aromatic compounds Download PDF

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Publication number
WO1998024740A1
WO1998024740A1 PCT/GB1997/003332 GB9703332W WO9824740A1 WO 1998024740 A1 WO1998024740 A1 WO 1998024740A1 GB 9703332 W GB9703332 W GB 9703332W WO 9824740 A1 WO9824740 A1 WO 9824740A1
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fluorine
aromatic compound
compound
acid
alkyl
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PCT/GB1997/003332
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French (fr)
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John Stewart Moilliet
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F2 Chemicals Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B39/00—Halogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C07C49/825—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups all hydroxy groups bound to the ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups

Definitions

  • This invention relates to the fluorination of aromatic compounds and more particularly to the fluorination of aromatic compounds substituted by a moiety having a carbonyl group adjacent the aromatic ring. It also relates to novel fluorinated aromatic compounds.
  • Vanillin (3-methoxy-4-hydroxybenzaldehyde) has the structure
  • the compound has at the 1 -position an electron- withdrawing group, which withdraws electrons from the benzene ring in particular the mesomeric (resonance) effect (although there is a minor inductive effect also).
  • the compound has at the 3 -position an electron- donating group having a lone pair of electrons.
  • aromatic compounds have been fluorinated by nucleophilic substitution using KF or HF.
  • Nucleophilic substitution gives fluorination at different positions with respect to other substituents to electrophilic substitution. It would therefore be desirable to fluorinate aromatic compounds directly by fluorine by electrophilic substitution.
  • a number of difficulties arise in this respect.
  • fluorine is a powerful oxidising agent and in many cases the primary reaction of fluorine with an organic compound will be oxidation.
  • fluorine would be expected very rapidly to convert an aldehyde group to a carboxyl group, especially in the case of vanillin which is oxidised by moist air (Tiemann. Berichte 8 1 123).
  • direct fluorination of aromatic compounds is in general completely non-selective, resulting in fluorine substitution at all available positions. This happens for example with nitro- substituted aromatic compounds (J S Moilliet. International Fluorine Conference. September 1997, St Louis, Russia).
  • the nitro group is very similar to the carbonyl groups in terms of its effects upon the electron charge distribution of an aromatic compound and normally the two substituents give analogous substitution patterns.
  • the present invention provides the fluorination by fluorine of carbonyl-substituted aromatic compounds and a method for the selective fluorination by fluorine of aromatic compounds having 1.3 -substitution by carbonyl and a moiety having a lone pair of electrons adjacent the aromatic ring. As described further below, it also provides novel fluoro-aromatic compounds.
  • the invention provides a method of fluorinating an aromatic compound substituted by a moiety comprising a carbonyl group, comprising contacting the compound with fluorine.
  • the carbonyl group is directly bonded to the aromatic ring structure.
  • the carbonyl group is preferably not a carboxyl group.
  • This reaction proceeds without significant oxidation of the carbonyl group to a carboxyl group (in the event that the carbonyl group is not already part of a carboxyl group) but normally produces an unpredictable mixture of isomers.
  • highly selective fluorination may be obtained at the 2-position of an aromatic compound substituted at its 1 -position by a carbonyl group and at its 3-position by a moiety having a lone pair of electrons adjacent the aromatic ring, by contacting the aromatic compound with fluorine (F 2 ) in the presence of a strong acid.
  • the lone pair of electrons are usually on an oxygen atom, for example on the oxygen atom of a hvdroxy group (-OH) or of an alkoxy group (O-alkyl).
  • Another atom which bears an electron lone pair is nitrogen.
  • the alkyl group may be substituted by one or more substituents substantially inert to fluorine (i.e. not significantly reacting with it in the method of the invention); as such substituents may be mentioned fluorine itself, hvdroxy and alkoxy. although any substituent should not be an electron withdrawing group in a position effective to pull in the lone pair of electrons.
  • the carbonyl group preferably is in the form of the residue of an aldehyde group (-CHO). Alternatively, it may be in the form of a residue of a ketone (-COR 1 . where R is typically alkyl optionally substituted by one or more substituents substantially inert to fluorine) or of a residue of a carboxyl group (- COOH).
  • the aromatic ring of the aromatic compound is usually a benzene ring, although it may in principle be any aromatic ring, for example a fused ring. Apart from the substituents at the 1 and 3 positions and the substitutable site at the 2-position.
  • the aromatic compound in principle may at each position be unsubstituted or substituted, in the latter case typically by substituents substantially inert to fluorine such as, for example, alkyl, suitably substituted alkyl, hvdroxy or alkoxy (the alkyl residue of which again may be suitably substituted).
  • the aromatic compound is substituted at the 4-position, notably by hvdroxy (as in the case of vanillin) or alkoxy.
  • the starting compounds include those of the formula:
  • R is for example hydrogen, hydroxyl or an organic moiety substantially inert to fluorine, especially alkyl optionally substituted by one or more substituents inert to fluorine;
  • R 1 is for example hydrogen or an organic moiety substantially inert to fluorine, especially alkyl optionally substituted by one or more substituents inert to fluorine, provided that any such substituents inert to fluorine are not effective to pull in the lone pairs of electrons on the oxygen;
  • R 2 is for example R or OR;
  • R 3 and R are for example independently R or OR or together form an aromatic ring which is optionally of 6 members in total and/or substituted by one or more R 1 groups.
  • Those compounds which contain alkyl groups are not limited as to the size of the alkyl group or groups, since they do not take part in the reaction, but as exemplary groups may be mentioned methyl and ethyl as well as other groups containing up to 12 carbon atoms, e.g. up to 4 or 6 carbon atoms.
  • the selective fluorination reaction is carried out in the presence of a strong acid, for example a strong mineral acid such as. e.g.. sulfuric. nitric or phosphoric acid, or another acid with a comparable pKa. Sulfuric acid is preferred.
  • a strong acid for example a strong mineral acid such as. e.g.. sulfuric. nitric or phosphoric acid, or another acid with a comparable pKa.
  • Sulfuric acid is preferred.
  • the acid is in practice concentrated and thus free or almost free of water, with which fluorine is reactive: thus sulfuric acid will normally be concentrated (about 98%) or oleum.
  • the fluorine is usually diluted with nitrogen or another inert gas.
  • the process is typically performed by combining the aromatic compound and the acid, which procedure may involve dissolving the aromatic compound, and passing through the resultant mixture a gaseous mixture of fluorine and an inert diluent gas.
  • the mixture will normally be agitated, e.g. stirred, while the gas is passed through it.
  • the mixture is suitably maintained at temperature of from 0 °C to 50 °C while it is contacted with the fluorine. In one class of processes, the temperature is from 30 °C to 40 °C.
  • the resultant fluorinated compound may be isolated and. if desired, purified, for example by conventional techniques, e.g. by extraction into a suitable solvent optionally preceded by distillation or filtration.
  • One procedure for making 2-fluorovanillin comprises: dissolving vanillin in sulfuric acid: stirring the resultant solution at 5 °C while passing through it a gaseous mixture of fluorine (25%) in nitrogen; after sufficient fluorine has been passed through for it to have been added in a mole ratio (F 2 :vanillin) of 1.1 : 1. terminating the reaction by drowning it out into an ice/water mixture: and isolating the product by filtration followed by extraction of the filtrate by dichloromethane.
  • the products of the selective process include compounds of the formula:
  • R. R 1 . R 2 , R 1 and R 4 are as described above.
  • the compounds in which R is H and R' is methyl lack novelty but the remainder are novel and included in the invention.
  • the invention provides compounds of the preceding formula in which R is OH or alkyl and R 1 is alkyl. preferred alkyl groups being as described previously, methyl being most preferred.
  • R 2 is OH. OCH, or other alkoxy. or H.
  • R' and R 4 are both hydrogen in preferred compounds: less preferred R 3 and R 4 groups are set out above and include, in particular, alkyl. alkoxy and hydroxy.
  • the fluorinated products of the processes of the invention may be used as intermediates in the preparation of further products, for example pharmaceuticals or agrichemicals, by a process involving one or more steps.
  • the invention therefore includes a method as described above and which further comprises subjecting the resultant fluorinated compound to one or more additional processes.
  • the products of the processes are also useful for research.
  • the substrate was dissolved in concentrated (98%) sulfuric acid (150ml) and the solution was stirred until it reached a temperature of from 30 to 40 °C.
  • the fluorine was then turned off and the nitrogen flow maintained for a further 15 mins.
  • the contents of the reactor were then poured out onto ice (circa 500g) and extracted three times with methylene chloride. In some cases it was also necessary to filter each time to remove black tarry solid. This solid was found not to contain any of the desired product.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

A method of fluorinating an aromatic compound substituted by a moiety comprising a carbonyl group comprises contacting the compound with fluorine. A selective method of fluorinating in the 2-position an aromatic compound substituted at its 1-position by a carbonyl group and at its 3-position by a moiety having a lone pair of electrons adjacent the aromatic ring comprises contacting the aromatic compound with fluorine (F2) in the presence of a strong acid such as concentrated sulfuric acid. Typical products of the selective process are of formula (I) where R is hydrogen, hydroxyl or alkyl optionally substituted by one or more substituents inert to fluorine; R1 is hydrogen or alkyl optionally substituted by one or more substituents inert to fluorine and not effective to pull in the lone pairs of electrons on the adjacent oxygen; R2 is H, R or OR; and R?3 and R4¿ are each independently H, R or OR or together form an aromatic ring. Those compounds in which R is not hydrogen are included in the invention.

Description

FLUORINATION OF CARBONYL-SUBSTITUTED AROMATIC COMPOUNDS
This invention relates to the fluorination of aromatic compounds and more particularly to the fluorination of aromatic compounds substituted by a moiety having a carbonyl group adjacent the aromatic ring. It also relates to novel fluorinated aromatic compounds.
Vanillin (3-methoxy-4-hydroxybenzaldehyde) has the structure
Figure imgf000003_0001
and therefore has at the 1 -position an electron- withdrawing group, which withdraws electrons from the benzene ring in particular the mesomeric (resonance) effect (although there is a minor inductive effect also). The compound has at the 3 -position an electron- donating group having a lone pair of electrons.
It is known that halogenation and other electrophilic substitution of vanillin takes place at the 5-position. In this respect, some exemplary literature references are given below:
Chlorination reaction using chlorine in chloroform
Raiford. Lichty JACS 52 4576 (1930) Hann J4GS 47 2000 (1925) Hann, Spencer JACS 49 535 (1927)
Bromination with bromine
Bradv. Dunn JCS 1 15 1859 (1915) Tiemann. Haarmann Berichte 7 615
lodination with iodine
Raiford. Wells JACS 57 2500 (1935)
Sulfonation with fuming sulfur ic acid
Finger. Schott Journal Praktische Chemie 1 15 287
Nitration in nitric acid
Vogl. Mo atshefte 20 385 (1899)
Historically, aromatic compounds have been fluorinated by nucleophilic substitution using KF or HF. Nucleophilic substitution of course gives fluorination at different positions with respect to other substituents to electrophilic substitution. It would therefore be desirable to fluorinate aromatic compounds directly by fluorine by electrophilic substitution. However, a number of difficulties arise in this respect.
Thus, fluorine is a powerful oxidising agent and in many cases the primary reaction of fluorine with an organic compound will be oxidation. For example, fluorine would be expected very rapidly to convert an aldehyde group to a carboxyl group, especially in the case of vanillin which is oxidised by moist air (Tiemann. Berichte 8 1 123). Further, direct fluorination of aromatic compounds is in general completely non-selective, resulting in fluorine substitution at all available positions. This happens for example with nitro- substituted aromatic compounds (J S Moilliet. International Fluorine Conference. September 1997, St Petersburg, Russia). The nitro group is very similar to the carbonyl groups in terms of its effects upon the electron charge distribution of an aromatic compound and normally the two substituents give analogous substitution patterns. J The present invention provides the fluorination by fluorine of carbonyl-substituted aromatic compounds and a method for the selective fluorination by fluorine of aromatic compounds having 1.3 -substitution by carbonyl and a moiety having a lone pair of electrons adjacent the aromatic ring. As described further below, it also provides novel fluoro-aromatic compounds.
In one aspect, therefore, the invention provides a method of fluorinating an aromatic compound substituted by a moiety comprising a carbonyl group, comprising contacting the compound with fluorine. In a preferred class of methods, the carbonyl group is directly bonded to the aromatic ring structure. The carbonyl group is preferably not a carboxyl group.
This reaction proceeds without significant oxidation of the carbonyl group to a carboxyl group (in the event that the carbonyl group is not already part of a carboxyl group) but normally produces an unpredictable mixture of isomers. However, highly selective fluorination may be obtained at the 2-position of an aromatic compound substituted at its 1 -position by a carbonyl group and at its 3-position by a moiety having a lone pair of electrons adjacent the aromatic ring, by contacting the aromatic compound with fluorine (F2) in the presence of a strong acid. In this reaction, the lone pair of electrons are usually on an oxygen atom, for example on the oxygen atom of a hvdroxy group (-OH) or of an alkoxy group (O-alkyl). Another atom which bears an electron lone pair is nitrogen. The alkyl group may be substituted by one or more substituents substantially inert to fluorine (i.e. not significantly reacting with it in the method of the invention); as such substituents may be mentioned fluorine itself, hvdroxy and alkoxy. although any substituent should not be an electron withdrawing group in a position effective to pull in the lone pair of electrons.
In both the selective and non-selective reactions, the carbonyl group preferably is in the form of the residue of an aldehyde group (-CHO). Alternatively, it may be in the form of a residue of a ketone (-COR1. where R is typically alkyl optionally substituted by one or more substituents substantially inert to fluorine) or of a residue of a carboxyl group (- COOH). The aromatic ring of the aromatic compound is usually a benzene ring, although it may in principle be any aromatic ring, for example a fused ring. Apart from the substituents at the 1 and 3 positions and the substitutable site at the 2-position. the aromatic compound in principle may at each position be unsubstituted or substituted, in the latter case typically by substituents substantially inert to fluorine such as, for example, alkyl, suitably substituted alkyl, hvdroxy or alkoxy (the alkyl residue of which again may be suitably substituted).
In some methods, the aromatic compound is substituted at the 4-position, notably by hvdroxy (as in the case of vanillin) or alkoxy.
Thus, the starting compounds include those of the formula:
Figure imgf000006_0001
where
R is for example hydrogen, hydroxyl or an organic moiety substantially inert to fluorine, especially alkyl optionally substituted by one or more substituents inert to fluorine;
R1 is for example hydrogen or an organic moiety substantially inert to fluorine, especially alkyl optionally substituted by one or more substituents inert to fluorine, provided that any such substituents inert to fluorine are not effective to pull in the lone pairs of electrons on the oxygen;
R2 is for example R or OR; R3 and R are for example independently R or OR or together form an aromatic ring which is optionally of 6 members in total and/or substituted by one or more R1 groups.
Those compounds which contain alkyl groups are not limited as to the size of the alkyl group or groups, since they do not take part in the reaction, but as exemplary groups may be mentioned methyl and ethyl as well as other groups containing up to 12 carbon atoms, e.g. up to 4 or 6 carbon atoms.
The selective fluorination reaction is carried out in the presence of a strong acid, for example a strong mineral acid such as. e.g.. sulfuric. nitric or phosphoric acid, or another acid with a comparable pKa. Sulfuric acid is preferred. The acid is in practice concentrated and thus free or almost free of water, with which fluorine is reactive: thus sulfuric acid will normally be concentrated (about 98%) or oleum.
The fluorine is usually diluted with nitrogen or another inert gas.
The process is typically performed by combining the aromatic compound and the acid, which procedure may involve dissolving the aromatic compound, and passing through the resultant mixture a gaseous mixture of fluorine and an inert diluent gas. In practice, the mixture will normally be agitated, e.g. stirred, while the gas is passed through it. The mixture is suitably maintained at temperature of from 0 °C to 50 °C while it is contacted with the fluorine. In one class of processes, the temperature is from 30 °C to 40 °C.
The resultant fluorinated compound may be isolated and. if desired, purified, for example by conventional techniques, e.g. by extraction into a suitable solvent optionally preceded by distillation or filtration.
One procedure for making 2-fluorovanillin comprises: dissolving vanillin in sulfuric acid: stirring the resultant solution at 5 °C while passing through it a gaseous mixture of fluorine (25%) in nitrogen; after sufficient fluorine has been passed through for it to have been added in a mole ratio (F2:vanillin) of 1.1 : 1. terminating the reaction by drowning it out into an ice/water mixture: and isolating the product by filtration followed by extraction of the filtrate by dichloromethane.
UK patent application 9625156.6 from which priority is claimed indicated that the product of the above procedure, which product is included in the invention, was 5- fluorovanillin but it has now been ascertained that it is the 2-isomer:
Figure imgf000008_0001
The products of the selective process include compounds of the formula:
Figure imgf000008_0002
where R. R1. R2, R1 and R4 are as described above. Of these, the compounds in which R is H and R' is methyl lack novelty but the remainder are novel and included in the invention. In particular, the invention provides compounds of the preceding formula in which R is OH or alkyl and R1 is alkyl. preferred alkyl groups being as described previously, methyl being most preferred. In one preferred class of compounds. R2 is OH. OCH, or other alkoxy. or H. R' and R4 are both hydrogen in preferred compounds: less preferred R3 and R4 groups are set out above and include, in particular, alkyl. alkoxy and hydroxy.
The fluorinated products of the processes of the invention may be used as intermediates in the preparation of further products, for example pharmaceuticals or agrichemicals, by a process involving one or more steps. The invention therefore includes a method as described above and which further comprises subjecting the resultant fluorinated compound to one or more additional processes. The products of the processes are also useful for research.
EXAMPLES
General Procedure
The substrate was dissolved in concentrated (98%) sulfuric acid (150ml) and the solution was stirred until it reached a temperature of from 30 to 40 °C. A gaseous mixture of nitrogen (50ml/min) and fluorine (7ml/min) was passed through until a 1.2 molar excess of fluorine had been added. The fluorine was then turned off and the nitrogen flow maintained for a further 15 mins. The contents of the reactor were then poured out onto ice (circa 500g) and extracted three times with methylene chloride. In some cases it was also necessary to filter each time to remove black tarry solid. This solid was found not to contain any of the desired product.
The solution of product and any residual starting material was rotary evaporated to remove the methylene chloride then the residue was distilled by a short path distillation unit under vacuum (e.g. a Kuegel-Rohr apparatus).
1. Fluorination of 4-hydroxy 3-methoxybenzaldehyde (vanillin)
15.2g (0.1 mole) of vanillin were converted as above to give 1 1.2g of crude product. This was distilled to give a mixture (lO.g) of starting material and 2-fluorovanillin. The latter was isolated by extraction with dichloromethane at pH 8 to 7 and characterised by 1H NMR (doublet of doublets at 7.55 ppm. H at C6. and a doublet at 6.8ppm, H at C5). The structure was further confirmed by X-ray crystallography. The final yield was 49% at a conversion of 61%.
2. Fluorination of 4-hydroxy-3-methoxybenzoic acid (vanillic acid)
10. Og (0.06mole) of vanillic acid were reacted following the procedure outlined above. The weight of crude product was 8.8g, which was dissolved in methanol (20ml) and sulfuric acid (2ml) and refluxed for 4 hours. The reaction mixture was poured out into 50 ml of water and extracted into methylene chloride. After drying, the organic solution was rotary evaporated to give 2.6g of mixed esters. These were separated by flash vacuum chromatography using a mixture of methanol (8%) and toluene (92%) as eluent. The product (0.8g) was shown by 1H NMR to be the 2-fluoro isomer. (H at C6. doublet of doublets, 9.1; H at C5. doublet. 8.3). The compound is novel and included in the invention.
3. Fluorination of 3 ,4-dimethoxybenzaldehyde (veratraldehyde)
10. Og (O.Oόmole) of veratraldehyde were reacted as above to give 9.3g of crude product. This was distilled to give 6.9g of a mixture of 2-fluoroveratraldehyde and starting material. Gas chromatographic analysis showed that the mixture consisted of 3.6g of product and 3.2g of starting material. This represents a yield of 46% at a conversion of 68%. The 1H NMR has signals at 6.7 (doublet of doublets) and 5.9 (doublet) indicating the fluorine was in the 2 position.
Fluorination of 3-methoxybenzaldehyde (m-anisaldehyde)
9.3g (0.07mole) of m-anisaldehyde were reacted as outlined above and gave 5.9g of crude product which on distillation yielded 5.6g of a mixture consisting of starting material (l .lg) and 2-fluoro-3-methoxybenzaldehyde (4.0g). 19F NMR of the fluorinated product showed a singlet at -141.0ppm. Also present were less than 2% of the other two monofluoro isomers. 5. Fluorination of 3 ,4-dimethoxyacetophenone
10. Og (0.056mole) of 3,4-dimethoxyacetophenone were reacted with fluorine by the method outlined above. After drowning out onto ice and extraction into dichloromethane the residue was distilled to give 9.3g of crude product. This was shown by GC-MS Η and l9F NMR to be a mixture of starting material (3.9g) and 2-fluoro-3,4- dimefhoxyacetophenone (2.5g). 'H NMR showed a complex peak at 6.7ppm and a doublet at ό. lppm and the 19F a singlet at -124.4ppm. The product compound is novel and included in the invention.
6. Fluorination of 3-methoxyacetophenone
10. Og of 3-methoxyacetophenone were fluorinated and worked-up as outlined above to give 9.4g of a crude mixture. 9.g were distilled to give a mixture of starting material (4.2g) and a monofluorinated methoxyacetophenone (3.4g). I9F NMR indicated that this was probably the 2-isomer with a singlet at -129.0ppm. This product is novel and included in the invention.
7. Fluorination of Vanillin
20. Og of vanillin were dissolved in 150ml of sulphuric acid and stirred at 5°C while a gaseous mixture of fluorine (25%) in nitrogen was passed through it at 50ml/min. After a total of 3.5 litres (0.146 moles, mole ratio 1.1 : 1. F : starting material) had been added the reaction was terminated by drowning out into an ice/water mixture (500ml).
To this slurry, 20g of Celite* filter-aid was added and the mixture was stirred for 10 mins. After filtration, the filtrate was extracted twice with dichloromethane and the organic layer, after drying over magnesium sulfate, was evaporated to give 9.5g of solid. The residue from the filtration was washed thoroughly with dichloromethane and the resulting solution was evaporated to give a further 3.0g of material. The combined solids were analysed by GC and shown to contain 4.0g of a mono-fluorinated vanillin (32% yield). Analysis by 13C, 1H and 19F NMR showed that the isomer made was 2- fluorovanillin.
In order to illustrate the importance of the use of sulfuric acid as the solvent (ie a strong acid which is able to protonate a carbonyl group) some reactions were also carried out in formic acid. This is a good solvent for fluorinations using elemental fluorine. However in these cases the selectivity is totally lost. Reactions were also carried out in which the carbonyl group of the aromatic compound was replaced by a nitro group, and in which the 3-position substituent was removed: selectivity towards the 2-position was lost in both cases.
8. Fluorination of 3-methoxybenzaldehyde in Formic Acid
7.0g of 3-methoxybenzaldehyde were fluorinated in a solution of formic acid with 10% fluorine at 3 °C. The products were isolated by drowning out into water than extracting into dichloromethane. The GC-MS indicated that three isomers of fluoro 3- methoxybenzaldehyde had been formed in a ratio 17:22:60. (The third was the 2- fluoroisomer).
9. Fluorination of 4-hydroxy-3-methoxybenzaldehyde (vanillin) in Formic Acid
20. Og of vanillin were formulated as in Example 8 above. The product showed by GC- MS that all three monofluorinated isomers had been formed in a ratio 8:3:1 1.
10. Fluorination of 3, 4-dimethoxy nitrobenzene
18.2g of 3.4-dimethoxy nitrobenzene were fluorinated in sulfuric acid as in the general procedure above. The resulting crude product (15.7g) was distilled to give a mixture of starting material (10.2g) and a mixture of two isomers of fluorodimethoxy nitrobenzene (4.6g). These were in a ratio of approximately 2: 1.
1 1. Fluorination of 4-methoxybenzaldehyde (p-anisaldehyde) 13.6g of 4-methoxybenzaldehyde were fluorinated following the general procedure outlined above. The crude product (14.2g) was distilled to give a mixture of starting material (83g) and 3-fluoro-4-methoxybenzaldehyde (3.5g). (There was none of the 2- fluoro- isomer formed.).

Claims

1. A method of fluorinating an aromatic compound substituted by a moiety comprising a carbonyl group, comprising contacting the compound with fluorine.
2. A method of claim 1 which is a method of fluorinating in the 2-position an aromatic compound substituted at its 1 -position by a carbonyl group and at its 3-position by a moiety having a lone pair of electrons adjacent the aromatic ring, the method comprising contacting the aromatic compound with fluorine (F2) in the presence of a strong acid.
3. A method of claim 2 in which the lone pair of electrons are on an oxygen atom.
4. A method of claim 3 in which the oxygen atom is part of a hydroxy group or of an alkoxy group.
5. A method of any of claims 1 to 4 in which the carbonyl group is part of a residue of an aldehyde group (-CHO).
6. A method of any of claims 1 to 4 in which the carbonyl group is part of a residue of a ketone or of a carboxyl group.
7. A method of claim 6 in which the ketone residue is of the formula -COalkyl.
8. A method of any of claims 1 to 7 in which the aromatic compound has a single 6- membered aromatic ring.
9. A method of any of claims 1 to 7 in which the aromatic compound has a fused aromatic ring.
10. A method of any of claims 1 to 9 in which the aromatic compound is substituted at the 4-position.
1 1. A method of claim 1 or claim 2 in which the aromatic compound is vanillin.
12. A method of any of claims 1 to 1 1 in which the acid is H2SO4.
13. A method of any of claims 1 to 12 in which the acid is water- free or almost water- free.
14. A method of any of claims 1 to 13 in which the fluorine is in admixture with an inert diluent gas.
15. A method of claim 14 in which the inert diluent gas is nitrogen.
16. A method of fluorinating vanillin, comprising contacting a solution of the vanillin in a mineral acid with fluorine.
17. A method of claim 15 in which the acid is H2SO .
18. A method of claim 15 or claim 16 in which the fluorine is in an inert gas.
19. A method of any of claims 1 to 18 which further comprises subjecting the resultant fluorinated compound to one or more additional processes.
20. A compound of the formula
Figure imgf000015_0001
where
R is hydroxyl or alkyl optionally substituted by one or more substituents inert to fluorine; R1 is hydrogen or alkyl optionally substituted by one or more substituents inert to fluorine and not effective to pull in the lone pairs of electrons on the adjacent oxygen; R2 is H. R or OR; and R3 and R4 are each independently H. R or OR or together form an aromatic ring.
21. A compound of claim 20 in which: R is hydroxyl or alkyl; R' is hydrogen or alkyl: R2 is hydrogen, hydroxyl. alkoxy or alkyl: and R3 and R4 are hydrogen or alkyl.
22. A compound of claim 21 in which:
R is hydroxyl or alkyl;
R1 is alkyl:
R2 is hydrogen, hydroxyl or alkoxy: and
R3 and R4 are hydrogen.
AMENDED CLAIMS
[received by the International Bureau on 27 Apri l 1998 (27.04.98) ; original claims 1 -22 replaced by amended claims 1 -18 (2 pages) ]
1. A method of fluorinating in the 2 -position an aromatic compound substituted at its 1 -position by a carbonyl group and at its 3 -position by a moiety having a lone pair of
5 electrons adjacent the aromatic ring, the method comprising contacting the aromatic compound with fluorine (Fj) in the presence of a strong acid.
2. A method of claim 1 in which the lone pair of electrons are on an oxygen atom.
0 3. A method of claim 2 in which the oxygen atom is part of a hydroxy group or of an alkoxy group.
4. A method of any of claims 1 to 3 in which the carbonyl group is part of a residue of an aldehyde group (-CHO). 5
5. A method of any of claims 1 to 3 in which the carbonyl group is part of a residue of a ketone or of a carboxyl group.
6. A method of claim 5 in which the ketone residue is of the formula -COalkyl. 0
7. A method of any of claims 1 to 6 in which the aromatic compound has a single 6- membered aromatic ring.
S. A method of any of claims 1 to 6 in which the aromatic compound has a fused 5 aromatic ring.
9. A method of any of claims 1 to 8 in which the aromatic compound is substituted at the 4-position.
0 10. A method of claim 1 or claim 2 in which the aromatic compound is vanillin.
11. A method of any of claims 1 to 10 in which the acid is HjSOA.
12. A method of any of claims 1 to 11 in which the acid is water-free or almost water- free.
13. A method of any of claims 1 to 12 in which the fluorine is in admixture with an inert diluent gas.
14. A method of claim 13 in which the inert diluent gas is nitrogen.
15. A method of fluorinating vanillin, comprising contacting a solution of the vanillin in a mineral acid with fluorine.
16. A method of claim 14 in which the acid is H2SO4.
17. A method of claim 14 or claim 15 in which the fluorine is in an inert gas.
18. A method of any of claims 1 to 17 which further comprises subjecting the resultant fluorinated compound to one or more additional processes.
PCT/GB1997/003332 1996-12-04 1997-12-03 Fluorination of carbonyl-substituted aromatic compounds WO1998024740A1 (en)

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GB9625156.6 1996-12-04

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0512715A2 (en) * 1991-05-10 1992-11-11 Zeneca Limited Verfahren zur Herstellung einer in 3-Stellung fluorierten aromatischen Verbindung
WO1995016649A1 (en) * 1993-12-16 1995-06-22 Bnfl Fluorochemicals Ltd. Fluorination process

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0512715A2 (en) * 1991-05-10 1992-11-11 Zeneca Limited Verfahren zur Herstellung einer in 3-Stellung fluorierten aromatischen Verbindung
WO1995016649A1 (en) * 1993-12-16 1995-06-22 Bnfl Fluorochemicals Ltd. Fluorination process

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
JIN F Q ET AL: "[4+2] and [2+2] cycloadditions of 1,1-difluoro-2-triphenylsiloxybut a-1,3-diene with electron-deficient alkynes", J. FLUORINE CHEM. (JFLCAR,00221139);95; VOL.71 (1); PP.1-4, SHANGHAI INSTITUTE OF ORGANIC CHEMISTRY, CHINESE ACADEMY OF SCIENCES, 354 FENGLIN LU;SHANGHAI; 200032; PEOP. REP. CHINA (CN), XP002055324 *
KATSOULOS G ET AL: "The metalation of fluoroanisoles: optional regioselectivity due to metal mediated control", SYNLETT (SYNLES,09365214);91; (10); PP.731-2, UNIV. LAUSANNE;INST. CHIM. ORG.; LAUSANNE; CH-1005; SWITZ. (CH), XP002055323 *
NIE J Y ET AL: "Synthesis of fluoro- and polyfluoro-veratraldehydes by electrophilic fluorination", J. FLUORINE CHEM. (JFLCAR,00221139);95; VOL.74 (2); PP.297-301, NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES, NATIONAL INSTITUTES OF HEALTH;BETHESDA; 20892-0810; MD; USA (US), XP002055322 *
STEGMANN H B ET AL: "Synthesis and EPR investigations of fluorocatecholamines", J. CHEM. SOC., PERKIN TRANS. 2 (JCPKBH,03009580);94; (3); PP.547-55, UNIV. TUEBINGEN;INST. ORG. CHEM.; TUEBINGEN; D-720 76; GERMANY (DE), XP002055321 *

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