GB2415193A

GB2415193A - Fluorinated arylboronic acids

Info

Publication number: GB2415193A
Application number: GB0413738A
Authority: GB
Inventors: James Sherrington
Original assignee: F2 Chemicals Ltd
Current assignee: F2 Chemicals Ltd
Priority date: 2004-06-19
Filing date: 2004-06-19
Publication date: 2005-12-21
Also published as: GB0413738D0; WO2005123749A1

Abstract

A fluorinated organoboron compound, preferably a fluorinated aromatic or heterocyclic boronic acid or boronic ester. Preferred aromatic groups are naphtalene or benzene and the aromatic ring substituents may comprise a boronic acid or boronic ester group and a fluorinated group. The preferred fluorinated group is a SF5 group and the preferred boronic acid or ester is a derivative of phenylboronic acid which can comprise another substitiuent, preferably halo, most preferably Cl, F, CF3, SF5, or nitro groups. The preferred fluorinated organoboron compounds are (3-pentafluorosulfurylbenzene)boronic acid and (4-pentafluorosulfurylbenzene)boronic acid. The compounds display improved properties for application in liquid crystal technology. In another aspect, a method of preparing a fluorinated organoboron compound comprising (a) providing an organofluorine precursor, preferably an intermediate bromo compound and (b) introducing a boron-containing group into the organofluorine precursor, preferably converting the bromo compound to the corresponding boronic acid or boronic ester.

Description

NOVEL ORGANOFLUORINE COMPOUNDS

Field of the Invention

The present invention is concerned with novel organoboron compounds, most particularly aromatic organoboron compounds. Specifically, the invention relates to boronic acid derivatives comprising sulphur pentafluoride groups, and methods for their preparation.

Background to the Invention

Much interest has recently been shown in the synthesis and use of organoboron compounds, most particularly organoboronic acids, with various aromatic and heterocyclic boronic acids receiving the greatest attention. It has been found that aromatic boronic acids display a range of useful properties and show great potential as intermediates in the synthesis of liquid crystal materials. Thus, the present inventors have sought to provide a range of novel organoboron compounds which display improved properties over the compounds of the prior art and may be used in the production of, inter alla, liquid crystal materials which provide improved performance.

The preparation of organoborane derivatives has been disclosed, for example, in Organometallics, 2, 1311-1316 and 1316-1319 (1983), and Tetrahedron Lett., 29, 2631-2634 (1988). Thus, it is known that phenylboronic acids may be routinely synthesised from the corresponding halobenzene derivatives, preferably bromobenzene derivatives, by formation of the appropriate metallated derivative, either by treatment with an alkyl or aryl lithium compound, such as t-butyl lithium, or by means of a Grignard reaction, using magnesium. The resulting reagent is then reacted with a suitable trialkoxyborane or trihaloborane, such as triisopropoxyborane or boron tribromide, and worked up with aqueous alkali in order to generate the required boronic acid derivative, as follows: Br B(OH)2 i) BuLi or Mg it AX ii) B(oipr)3lNaoH WAX wherein X represents hydrogen or a substituent.

For example, the preparation of a Grignard reagent from 3-bromobenzene sulphur pentafluoride (wherein X = SF5 in the above formula) is disclosed in J.A.C.5., 84, (1962), 3064.

The preparation and use of various polyfluorinated aromatic and heterocyclic derivatives is well documented in the prior art, and the compounds in question have found widespread use, for example as intermediates in the pharmaceutical industry.

Specific examples include intermediates containing trifluoromethyl groups, especially trifluoromethylbenzene derivatives; a favoured end-group in this context is a 3,5-bis(trifluoromethyl)phenyl group which has been developed for use in a range of anti-asthma and anti-arthritis drugs. Such a group may be introduced into a drug molecule by means of a suitable labile group in the 1-position so that, for example, 3,5-bis(trifluoromethyl)bromobenzene is a useful intermediate for the preparation of such drugs.

More recently, it has been found that alternative polyfluorinated derivatives may be obtained by relatively straightforward synthetic procedures to provide a further range of intermediates with potentially widespread industrial applicability. Thus, various organic sulphur pentafluorides, and methods for their preparation, are disclosed in PCT Patent Application WO 97/05106. Subsequently, WO 02/42263 described the preparation and use of trisubstituted compounds, specifically aromatic or heterocyclic compounds, comprising at least one sulphur pentafluoride group and at least one labile group, such as an amino, bromo or nitro group.

Summary of the Invention

Surprisingly, the present inventors have now established that the introduction of sulphur pentafluoride groups into organoboron compounds allows for the preparation of a variety of novel derivatives which display improved properties when compared with known organoboron compounds, and show particular promise for application in liquid crystal technology.

Thus, according to a first aspect of the present invention there is provided a fluorinated organoboron compound. Preferably, said fluorinated organoboron compound comprises a fluorinated boronic acid derivative, most preferably a fluorinated aromatic or heterocyclic boronic acid or boronic ester.

The present invention also envisages methods applicable to the preparation of the compounds of the first aspect of the present invention. Thus, according to a second aspect of the present invention, there is provided a method of preparation of a fluorinated organoboron compound, said method comprising: (a) providing an organofluorine precursor; and (b) introducing a boron-containing group into said fluorinated precursor.

Said organoboron compound includes at least one fluorinated group which, most preferably, comprises a sulphur pentafluoride group.

Detailed Description of the Invention

Especially preferred compounds in the context of the present invention include derivatives of naphthalene and, more particularly, derivatives of benzene. The most preferred compounds are those which comprise two or three aromatic ring substituents, comprising at least one boronic acid or boronic ester group and at least one sulphur pentafluoride group. The most suitable compounds comprise a single boronic acid or boronic ester group. Thus, particularly preferred compounds comprise derivatives of phenyl boronic acid or its esters. Said at least one fluorinated group preferably comprises at least one sulphur pentafluoride group.

The at least one fluorinated substituent in a derivative of phenyl boronic acid or its esters may be located in the o-, m- or p-position relative to the boronic acid group, and the aromatic ring may optionally contain additional substituents, preferably electron-withdrawing groups chosen from, for example, halogenated groups or nitro groups. Typical halogenated groups include chloro, fluoro, trifluoromethyl and sulphur pentafluoride groups. Optimally, the fluorinated organoboron comprises a maximum of one additional substituent.

Particularly preferred compounds in the context of the present invention are of the formula (I) or (II): SF5 X/ 1\s(OH)2 (HO)2B/X where X = SFs, NO2, F. Cl, H (1) (II) Preferred organofluorine precursors in the preparation of said fluorinated organoboron compounds comprise phenyl or naphthyl sulphur pentafluorides and their nitro-substituted analogues, most particularly disubstituted benzene derivatives containing at least one sulphur pentafluoride group. Optionally, at least one additional substituent may also be present and preferred substituents in this context include chloro, fluoro and nitro groups. Amongst the most preferred derivatives are 1,3-bis(pentafluorosulphuryl)benzene, 1,4-bis(pentafluorosulphuryl) benzene, 3pentafluorosulphurylnitrobenzene, 4-pentafluorosulphurylnitrobenzene, 3 trifluoromethylpentafluorosulphurylbenzene and 4-trifluoromethylpentafluorosulphurylbenzene.

Conversion of the said organofluorine precursors to boronic acids or their esters requires the synthesis of an intermediate bromo compound which may be converted to the required boronic acid by means of one of the techniques of the prior art.

Principally, two synthetic routes are available for achieving said conversion, these comprising: (a) reduction of a nitro group to the corresponding amino group, followed by replacement of the amine by a bromo group by diazotisation and treatment with copper(I) bromide according to the Sandmeyer reaction; or (b) direct bromination of the aromatic ring using N-bromosuccinimide.

By the application of these two techniques, it is possible to obtain a wide range of brominated organofluorine precursors, which may subsequently be converted to the relevant boronic acid derivatives. Clearly, however, the first technique is only applicable in the case of derivatives which include a nitro group, so the second

method has wider applicability.

Thus, for example, an organofluorine precursor comprising a nitro group may be treated with a suitable reducing agent, such as iron and hydrochloric acid, to effect reduction to the corresponding amine. Diazotisation of the amine may then be achieved by treatment with sodium nitrite in hydrobromic acid, and the diazo group can subsequently be replaced by a bromo group by reaction with copper(I) bromide in hydrobromic acid. Suitable conditions for the performance of such Sandmeyer reactions may be gleaned from, for example, Vogel's Textbook of Practical Organic Chemistry, 5th Ed, Longman, 1989, p 934. Particularly preferred organofluorine precursors in this context are nitrobenzene derivatives substituted with one or two sulphur pentafluoride groups, for example 3-pentafluorosulphonyluitrobenzene: SF5 SF5 SF5 Fe/MCI in MeOH i) NaNO2/HBr \NO2 \NH2 ii)CuBr/HBr Or Conditions for the reduction and subsequent diazotisation of 3- and 4- pentasulphonylnitrobenzene are reported by R.D. Bowden et al, Tetrahedron, S6, (2000), 3399-3408.

In an alternative embodiment, a bromo group may be introduced into an organofluorine precursor by direct ring bromination with Nbromosuccinimide in trifluoroacetic acid in the presence of a catalytic amount of sulphuric acid. Suitable reaction conditions for such electrophilic bromination reactions are discussed, for example, in Synlett, 1245-1246 (1999). Electrophilic substitution of the aromatic ring in this way may be carried out with organofluorine precursors containing various electron-withdrawing groups in addition to fluorine- containing groups. The precursors comprise at least one fluorine- containing group, preferably at least one sulphur pentafluoride group. Additional electron-withdrawing groups may include chloro, fluoro or nitro groups. Thus, for example, 3- or 4-sulphonylnitrobenzene may conveniently be brominated as follows: SF5 SF5 W NBS JWNO2 Br O2N/ NBS SF5 Conversion of the intermediate bromo derivatives to the corresponding boronic acids or their esters may readily be effected by the known techniques of the prior art. Thus, treatment of the bromo compound with either an alkyl or aryl lithium compound, such as t-butyl lithium, or with lithium metal, or the use of a Grignard reaction employing magnesium, allows for the preparation of the corresponding metallated derivative, which may then be reacted with a suitable trialkoxyborane or trihaloborane, such as triisopropoxyborane or boron tribromide, and subsequently worked up with aqueous alkali, in order to generate the required boronic acid derivative, which may then optionally be esterified by any of the standard techniques well known from the prior art, for example conversion to the corresponding acid chloride and reaction with an alcohol.

The invention will now be illustrated, though without limitation, by reference to the

following examples.

EXAMPLES

Example 1

(a) Synthesis of 3-pentafluorosulphurylbromobenzene A suspension of the hydrobromide salt of 3-pentafluorosulphurylaniline is prepared by dropwise addition of 3-pentafluorosuphurylaniline (109.5 g, 0.5 mol) to 48% w/w hydrobromic acid solution (200 ml) in a 500 ml 3-necked flask fitted with a thermometer and mechanical stirrer. The mixture is stirred rapidly during addition to ensure a fine suspension of acid salt is obtained. The mixture is cooled to between -5 and 0 C in an ice-salt bath. The stirred acid salt is treated dropwise with a chilled solution of sodium nitrite (36.5 g, 0.53 mol) in water (50 ml). The sodium nitrite solution is added at such a rate that the temperature of the reaction does not rise above 0 C. Formation of the 3-pentafluorosulphurylbenzenediazonium bromide salt is evidenced by the dissolution of the hydrobromide salt and formation of a yellow solution. Once addition of the sodium nitrite is complete, the solution of the diazonium salt is kept cold in the ice-salt bath. A solution of copper(I) bromide (76.0 g, 0.53 mol) in 48 % w/w hydrobromic acid (200 ml) is prepared in a 1000 ml 3 necked flask fitted with a thermometer, condenser and dropping funnel. The mixture is heated to 70 C and treated dropwise with the 3-pentafluorosulphuryl- benzenediazonium bromide solution which is added to the dropping funnel in portions to ensure that thermal decomposition does not occur. Once addition is complete, the reaction mixture is cooled to room temperature and extracted with dichloromethane (3 x 100 ml). The organic layers are separated, combined and washed with 10% w/w sodium hydroxide solution (100 ml). The organic layer is washed with water (3 x 100 ml) and dried over magnesium sulphate (50 g). The mixture is filtered and the solvent removed from the filtrate by rotary evaporation.

The resultant orange oil is distilled at reduced pressure to give 3pentafluorosulphuryl bromobenzene as a colourless liquid (99 g, 70 %).

(b) Synthesis of (3-pentafluorosulphurylbenzene)boronic acid A mixture of magnesium turnings (16.8 g, 0.7 mol), anhydrous diethyl ether (50 ml) and 1,2-dibromoethane (0.25 ml) is added to an oven dried 500 ml 3-necked round bottomed flask fitted with a condenser, thermometer and dropping funnel. The apparatus is placed under a constant flow of nitrogen and the mixture heated to 40 C.

A solution of 3-pentafluorosulphurylbromobenzene (169.8 g, 0.6 mol) in anhydrous diethyl ether (200 ml) is added dropwise to the flask containing the magnesium. The temperature of the reaction mixture will increase and should be maintained around 60 C. Once addition is complete the majority of the magnesium will have dissolved to give a dark brown solution. This solution is transferred to a dropping funnel and added dropwise to a solution of triisopropylborate (37.6 g, 0.2 mol) in anhydrous diethyl ether (150 ml) cooled to -78 C in a cardice-acetone bath. The rate of addition is such that the temperature of the reaction mixture does not rise above -70 C. The reaction is stirred for a further 2 h at -70 C and subsequently allowed to warm to 0 C. The cold reaction mixture is added slowly to a chilled 10% w/w solution of sulphuric acid with constant stirring. The mixture is separated and the aqueous layer extracted with diethyl ether (4 x 100 ml). The ether is removed by rotary evaporation and the remaining solution of (3-pentafluorosulphuryl benzene)boronic acid in propanol is treated with water (50 ml) and 10% w/w potassium hydroxide solution until alkaline. The propanol is removed by azeotropic distillation at 45 C and the residue is acidified with a 10% w/w solution of sulphuric acid. The resultant mixture is boiled and the aqueous layer decanted from the resultant brown oil and filtered. The residual oil is extracted with boiling water (4 x 50 ml) and the combined aqueous extracts are cooled to precipitate the boronic acid as a white crystalline solid (xx g, xx %).

Example 2

(a) Synthesis of 4-pentafluorosulphurylbromobenzene A suspension of the hydrobromide salt of 4-pentafluorosulphurylaniline is prepared by dropwise addition of 3-pentafluorosulphurylaniline (109.5 g, 0.5 mol) to 48% w/w hydrobromic acid solution (200 ml) in a 500 ml 3-necked flask fitted with a thermometer and mechanical stirrer. The mixture is stirred rapidly during addition to ensure a fine suspension of acid salt is obtained. The mixture is cooled to between -5 and 0 C in an ice-salt bath. The stirred acid salt is treated dropwise with a chilled solution of sodium nitrite (36.5 g, 0.53 mol) in water (50 ml). The sodium nitrite solution is added at such a rate that the temperature of the reaction does not rise above 0 C. Formation of the 4-pentafluorosulphurylbenzenediazonium bromide salt is evidenced by the dissolution of the hydrobromide salt and formation of a yellow solution. Once addition of the sodium nitrite is complete the solution of the diazonium salt is kept cold in the ice-salt bath. A solution of copper(I) bromide (76.0 g, 0.53 mol) in 48% w/w hydrobromic acid (200 ml) is prepared in a 1000 ml 3 necked flask fitted with a thermometer, condenser and dropping funnel. The mixture is heated to 70 C and treated dropwise with the 4-pentafluorosulphuryl benzenediazonium bromide solution, which is added to the dropping funnel in portions to ensure that thermal decomposition does not occur. Once addition is complete, the reaction mixture is cooled to room temperature and extracted with dichloromethane (3 x 100 ml). The organic layers are separated, combined and washed with 10% w/w sodium hydroxide solution (100 ml). The organic layer is washed with water (3 x 100 ml) and dried over magnesium sulphate (50 g). The mixture is filtered and the solvent removed from the filtrate by rotary evaporation.

The resultant orange oil is distilled at reduced pressure to give 4pentafluorosulphuryl bromobenzene as a colourless liquid (99 g, 70 %).

(b) Synthesis of (4-pentafluorosulphurylbenzene)boronic acid A mixture of magnesium turnings (16.8 g, 0.7 mol), anhydrous diethyl ether (50 ml) and 1,2-dibromoethane (0.25 ml) is added to an oven dried 500 ml 3-necked round bottomed flask fitted with a condenser, thermometer and dropping funnel. The apparatus is placed under a constant flow of nitrogen and the mixture heated to 40 C.

A solution of 4-pentafluorosulphurylbromobenzene (169.8 g, 0.6 mol) in anhydrous diethyl ether (200 ml) is added dropwise to the flask containing the magnesium. The temperature of the reaction mixture will increase and should be maintained around 60 C. Once addition is complete, the majority of the magnesium will have dissolved to give a dark brown solution. This solution is transferred to a dropping funnel and added dropwise to a solution of triisopropylborate (37.6 g, 0.2 mol) in anhydrous diethyl ether (150 ml) cooled to -78 C in a cardice-acetone bath. The rate of addition is such that the temperature of the reaction mixture does not rise above -70 C. The reaction is stirred for a further 2 h at -70 C and subsequently allowed to warm to 0 C. The cold reaction mixture is added slowly to a chilled 10% w/w solution of sulphuric acid with constant stirring. The mixture is separated and the aqueous layer extracted with diethyl ether (4 x 100 ml). The ether is removed by rotary evaporation and the remaining solution of (4-pentafluorosulphuryl benzene)boronic acid in propanol is treated with water (50 ml) and 10% w/w potassium hydroxide solution until alkaline. The propanol is removed by azeotropic distillation at 45 C and the residue is acidified with a 10% w/w solution of sulphuric acid. The resultant mixture is boiled and the aqueous layer decanted from the resultant brown oil and filtered. The residual oil is extracted with boiling water (4 x 50 ml) and the combined aqueous extracts cooled to precipitate the boronic acid as a white crystalline solid (xx g, xx %).

Claims

1. A fluorinated organoboron compound.

2. A compound as claimed in claim 1 which comprises a fluorinated boronic acid derivative.

3. A compound as claimed in claim 1 or 2 which comprises a fluorinated aromatic or heterocyclic boronic acid or boronic ester.

4. A compound as claimed in claim 1, 2 or 3 which comprises a derivative of naphthalene or benzene.

5. A compound as claimed in any one of claims 1 to 4 which comprises two or three aromatic ring substituents comprising at least one boronic acid or boronic ester group and at least one fluorinated group.

6. A compound as claimed in any preceding claim which comprises a single boronic acid or boronic ester group.

7. A compound as claimed in claim 5 or 6 wherein said at least one fluorinated group comprises at least one sulphur pentafluoride group.

8. A compound as claimed in any preceding claim which comprises a derivative of phenyl boronic acid.

9. A compound as claimed in claim 8 which comprises at least one fluorinated group and at least one additional substituent.

10. A compound as claimed in claim 9 wherein said at least one additional substituent comprises at least one electron-withdrawing group.

A compound as claimed in claim 10 wherein said at least one electron withdrawing group comprises at least one halogenated group or nitro group.

12. A compound as claimed in claim 11 wherein said at least one halogenated group comprises at least one chloro, fluoro, trifluoromethyl, or sulphur pentafluoride group.

13. A compound as claimed in any one of claims 9 to 12 which comprises a maximum of one additional substituent.

14. A compound as claimed in any one of claims 8 to 13 which has the formula (I) or (II): SF5 X/\B(OH)2 (HO)2B/\X where X = SF5, NO2, F. Cl, H (I) (II)

15. A method of preparation of a fluorinated organoboron compound as claimed in any one of claims l to 14, said method comprising: (a) providing an organofluorine precursor; and (b) introducing a boron-containing group into said fluorinated precursor.

16. A method as claimed in claim 15 wherein said fluorinated organoboron compound includes at least one sulphur pentafluoride group.

17. A method as claimed in claim 15 or 16 wherein said organofluorine precursor comprises a phenyl or naphthyl sulphur pentafluoride derivative or its nitro

18. A method as claimed in claim 17 wherein said organofluorine precursor comprises a disubstituted benzene derivative containing at least one sulphur pentafluoride group.

19. A method as claimed in claim 17 or 18 wherein said organofluorine precursor comprises at least one additional substituent selected from chloro, fluoro, trifluoromethyl, and nitro groups.

20. A method as claimed in any one of claims 17 to 19 wherein said organofluorine precursor comprises 1,3-bis(pentafluorosulphuryl)benzene, 1,4-bis(pentafluorosulphuryl)benzene, 3-pentafluorosulphuryluitrobenzene, 4 pentafluorosulphuryluitrobenzene, 3-trifluoromethylpentafluorosulphuryl benzene or 4-trifluoromethylpentafluorosulphurylbenzene.

21. A method as claimed in any one of claims 15 to 20 wherein said introduction of a boron-containing group into said fluorinated precursor comprises the steps of: (a) synthesising an intermediate bromo compound; and (b) converting said bromo compound to the corresponding boronic acid or boronic ester.

22. A method as claimed in claim 21 wherein said fluorinated precursor comprises a nitro group and the synthesis of said intermediate bromo compound comprises: (a) reduction of the nitro group to the corresponding amino group; followed by (b) replacement of the amine by a bromo group by diazotisation and treatment with copper(I) bromide according to the Sandmeyer reaction.

23. A method as claimed in claim 21 wherein said fluorinated precursor is subjected to direct bromination of the aromatic ring using N 1 0 bromosuccinimide.

24. A method as claimed in any one of claims 17 to 23 wherein said organofluorine precursor comprises a nitrobenzene derivative substituted with one or two sulphur pentafluoride groups.

25. A method as claimed in claim 24 wherein said organofluorine precursor comprises 3-pentafluorosulphonylnitrobenzene.

26. A method as claimed in claim 25 which comprises the following steps: SF5 SF5 SF5 Fe/MCI in MeOH it 1) NaNO2/HBr \NO2 \NH2 ii) CuBr/HBr Or

27. A method as claimed in claim 23 which comprises the following steps: : NBS:WNo2 Br O2N / NBS C/SF5

28. A method as claimed in any one of claims 21 to 27 wherein the step of conversion of the intermediate bromo derivative to the corresponding boronic acid comprises the steps of: (a) treatment of the bromo compound with a metallating reagent; (b) treatment of the metallating reagent with a trialkoxyborane or trihaloborane; and (c) workup with aqueous alkali.

29. A method as claimed in claim 28 wherein said metallating reagent comprises an alkyl or aryl lithium compound or lithium metal.

30. A method as claimed in claim 29 wherein said alkyl lithium compound comprises t-butyl lithium.

31. A method as claimed in claim 28 wherein said metallating reagent comprises magnesium.

32. A method as claimed in any one of claims 28 to 31 wherein said trialkoxyborane comprises triisopropoxyborane.

33. A method as claimed in any one of claims 28 to 31 wherein said trihaloborane comprises boron tribromide.

34. A method as claimed in any one of claims 21 to 33 wherein said boronic acid is converted to a boronic ester.

35. A fluorinated organoboron compound as hereinbefore described and with reference to the accompanying examples.

36. A method as hereinbefore described and with reference to the accompanying

examples.

37. A fluorinated organoboron compound whenever prepared by the method as claimed in any one of claims 15 to 34.