Electrophilic fluorination

Abstract: N -fluorotriazinium salts, especially those of the following Formula I, are electrophilic fluorinating agents useful in fluorinating, preferably in a nitromethane solvent, carbanionic species and/or activated aromatic compounds: wherein three A moieties are independently CR, where each R is, independently, hydrogen, halogen, (primary, secondary or tertiary) amino, hydroxyl, amino, cyano, perfluorothio hydroxysulphonyl, halosulphonyl, hydrocarbyloxysulphonyl,, or a carbon-containing substituent selected from optionally substituted hydrocarbyl, hydrocarbyloxy, hydrocarbyloxycarbonyl, and hydrocarbylthio groups; two A moieties are independently Z, where each Z is independently nitrogen or a quaternary nitrogen atom and Y is a counterion or group of counterions which are inert to chemical attack by fluorine, and oligomers or polymers thereof in which adjacent triazinium moieties are linked by a common R substituent. Preferably the cation of the salt is 2,4,6-trichloro-1,3,5-triazinium.

Description: This invention relates to electrophilic fluorination and in particular to the use of N -fluorotriazinium salts as electrophilic fluorinating agents. The invention provides a method of electophilically fluorinating a substrate, especially an organic substrate using N -fluorotriazinium salt fluorinating agents and has particularly, but not exclusive, application to the fluorination of electron-rich species, for example activated aromatic compounds (i.e. carrying electron-donating substituents) or overt or covert carbanions. At least the preferred tri(halo or trifluoromethyl)- substituted N -fluorotriazinium salts are sufficiently strong fluorinating agents to readily fluorinate unsubstituted aromatic substrates and aromatic substrates having one or more electron-withdrawing substituents. Fluorination is an important process in many areas of industry, in particular where the synthesis of speciality chemicals is concerned. Known fluorination methods are conveniently categorized according to the perceived manner in which the fluorinating agents provide fluorine for combination with an active site in an organic molecule, namely as fluorine atom (F • ), fluoride ion (F - ) or, conceptually, fluoronium ion (F + ). Fluorinations involving fluorine atom are notoriously exothermic and non-selective, hence "light" strategic fluorination of organic compounds (that is, the introduction of one or two fluorine substituents or a trifluoromethyl group at key molecular sites) rests on the availability of versatile ranges of nucleophilic and electrophilic sources of fluorine. Of late, the use of N -fluoro compounds has become one of the most widely used methods for the selective formation of carbon-fluorine bonds via "electrophilic" mechanisms. A recent comprehensive review of this synthetic methodology contains no reference to N-F reagents derived from triazines (see G.G. Furin in Methods of Organic Chemistry (Houben-Weyl): Volume E10a; Organofluorine Compounds (ed. B. Baasner, H. Hagemann, and J.C. Tatlow), Georg Thieme Verlag, Stuttgart, 1999, pp. 432-499. 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (so-called F-TEDA-BF 4 ) is a known, commercially available (under the trade name "Selectfluor") fluorinating agent and is useful as a general purpose fluorinating agent. However this material has only a moderate fluorinating power and is able to fluorinate benzene only under forcing conditions, for example under reflux for 24 hours. The chemistry of F-TEDA-BF 4 has been reviewed by R. E. Banks in J. Fluorine Chemistry 87 (1998) 1-17. N -Fluoropyridinium salts and ring-substituted analogues thereof, e.g. N -fluoropyridinium triflate, are known for use as a fluorinating agent but have relatively low fluorinating power (see EP-A-0204535). US-A-4828764 discloses that certain N -fluoro- N -perfluoroalkyl or perfluoroaryl sulphonamides including, inter alia , those of the formula R f SO 2 NFR are electrophilic fluorinating agents. In this formula R f represents a perfluorinated C 1 -C 30 alkyl, C 3 -C 30 cycloalkyl, C 6 -C 14 aryl substituted C 1 -C 10 alkyl or a C 6 -C 14 aryl group and R represents a C 1 -C 30 alkyl, C 3 -C 30 cycloalkyl, C 6 -C 14 aryl substituted C 1 -C 10 alkyl, or C 6 -C 14 aryl group optionally substituted with one or more inert substituents including, inter alia, fluorine and, when R f is trifluoromethyl, R alternatively can represent perfluoromethylsulphonamido. The preferred fluorinating agents are stated to be N -fluorobis-(trifluoromethanesulphonyl)imide (R f = CF 3 and R = CF 3 SO 2 ), known as DesMarteau's Reagent, and N -fluoro- N -methyltrifluoromethanesulphonamide (R f = CF 3 and R = CH 3 ). DesMarteau's Reagent is a powerful electrophilic fluorinating agent which is capable of converting benzene to fluorobenzene at room temperature but is hazardous, time-consuming and expensive to prepare requiring eight or nine reaction steps from readily available material. Only a very limited number of other known fluorinating agents are strong enough to fluorinate benzene without forcing conditions but they often provide relatively low yields or require special precautions. Those reported to fluorinate benzene include, in addition to DesMarteau's Reagent, CF 3 OF, XeF 2 , NF 4 + BF 4 - , N 2 F + AsF 6 - , N -fluoropentachloropyridinium triflate, perfluoro-[ N -fluoro- N -(4-pyridyl)methanesulphonamide] and N -fluoro-2,6-bis(methoxycarbonyl)pyridinium triflate. Very few of these compounds, only NF 4 + BF 4 - and XeF 2 , are known to fluorinate aromatic substrates having electron-withdrawing substituents such as nitrobenzene.. N -Fluorotriazinium salts of the following Formula A are known: wherein: (i) X = H & Y - = AsF 6 - (Ref. 1 - see below) (ii) X = F & Y - = AsF 6 - (Ref. 2 - see below) (iii) X = F & Y - = BF 4 - (Ref. 3 - see below) and (iv) X = Cl & Y - = AsF 6 - (Refs. 2 & 4 - see below). The N -fluorotriazinium salts of Formula A are reported to be oxidising agents of use in, for example, organometallic chemistry. The cationic component of compounds of Formula A in which X is H, F and Cl have been described as "oxidative fluorinators" and a qualitative scale for their oxidising strength and that of NF 4 + has been computed ab initio (Ref. 3 - see below). Ref. 1 = Broschag et al . Inorg. Chim. Acta, 205 (1993) 167-173; Ref. 2 = Schleyer et al. Inorg. Chem. 32 (1993) 1523-1524; Ref. 3 = Schulz and Klapötke J. Organometal. Chem. 480 (1994) 195-197; and Ref. 4 = Broschag et al . Z. Anorg. Allg. Chem., 620 (1994) 1132-1136. There is a statement in Schleyer et al. that 1-fluoro-2,4,6-trichloro- s -triazinium hexafluoroarsenate (Formula A; X = Cl; and Y - = AsF 6 - ) "is a promising fluorination agent" but no further details were provided or subsequently reported. It is believed that uses of the compounds of Formula A other than as oxidising agents was not contemplated or investigated. In particular, there is no disclosure in the prior art of any of these compounds being evaluated as oxidative fluorinators (as distinct from non-fluorinating oxidising agents) despite the computed values reported in Refs. 3 and 4. We have now found that certain N -fluorinated triazinium salts are excellent electrophilic fluorinating agents yet do not possess some of the drawbacks of known electrophilic fluorinating agents. European Patent Application No. 01308933.9 (filed 19th October 2001 claiming the priority date of 24th October 2000) discloses and claims electrophilic fluorinating agents which are triazinium compounds of the following Formula B: wherein: three A moieties are independently CR, where each R is independently, hydrogen, halogen, hydroxyl, amino, cyano, perfluorothio, hydroxysulphonyl, halosulphonyl, hydrocarbyloxysulphonyl, or a carbon-containing substituent selected from optionally substituted hydrocarbyl, hydrocarbyloxy, hydrocarbyloxycarbonyl, and hydrocarbylthio groups, and at least one R is neither hydrogen nor halogen; two A moieties are independently Z, where each Z is independently nitrogen or a quaternary nitrogen atom; and Y - is a counterion or group of counterions which are inert to chemical attack by fluorine, and oligomers or polymers thereof in which adjacent triazinium moieties are linked by a common R substituent. In its broadest aspect, the present invention provides a method of electrophilic fluorination which comprises contacting an organic substrate with a N -fluorotriazinium salt electrophilic fluorinating agent wherein the N-fluorotriazinium salt is either a 1,2,4-triazinium compound of the following Formula IA or, especially, a 1,3,5-triazinium compound of the following Formula IB: wherein: R 1 , R 2 and R 3 are, independently, hydrogen (for Formula IA only), halogen (for Formula IA only), amino, hydroxyl, cyano, perfluorothio, hydroxysulphonyl, halosulphonyl, hydrocarbyloxysulphonyl, or a carbon-containing substituent selected from optionally substituted hydrocarbyl, hydrocarbyloxy, hydrocarbytoxycarbonyl, and hydrocarbylthio groups; Z 1 and Z 2 are nitrogen; and Y - is a counterion or group of counterions which are inert to chemical attack by fluorine, and oligomers or polymers thereof in which adjacent triazinium moieties are linked by a common R substituent. N -Fluorotriazinium salts have a high fluorinating power which allows substrates which are difficult to fluorinate using known fluorinating agents to be fluorinated especially electron-rich species for example carbanionic and/or activated aromatic substrates. Also they may be employed to fluorinate substrates which may presently be fluorinated electrophilically using known fluorinating agents but under milder reaction conditions due to the effective fluorinating power of the N -fluorotriazinium cation. The N -fluorotriazinium salts used in the present invention belong to a group of compounds of the following Formula I: wherein: three A moieties are independently CR, where each R is independently, hydrogen, halogen, hydroxyl, amino, cyano, perfluorothio, hydroxysulphonyl, halosulphonyl, hydrocarbyloxysulphonyl, or a carbon-containing substituent selected from optionally substituted hydrocarbyl, hydrocarbyloxy, hydrocarbyloxycarbonyl, and hydrocarbylthio groups; two A moieties are independently Z, where each Z is independently nitrogen or a quaternary nitrogen atom; and Y - is a counterion or group of counterions which are inert to chemical attack by fluorine, and oligomers or polymers thereof in which adjacent triazinium moieties are linked by a common R substituent. The presently most preferred compounds are those in which each of R 1 , R 2 and R 3 for Formulae IA is halogen or trifluoromethyl and those in which each of R 1 , R 2 and R 3 for Formula IB is trifluoromethyl. As mentioned above, the N -fluoro-trihalotriazinium and N -fluoro-tris(trifluoromethyl)triazinium salts are remarkably strong fluorinating agents capable of room temperature fluorination of unsubstituted aromatic substrates such as benzene and aromatic substrates having one or more electron-withdrawing substituents such as chlorobenzene or nitrobenzene. The said carbon-containing substituent(s) may be unsubstituted and contain only hydrogen and carbon atoms, and in the case of hydrocarbyloxy and hydrocarbylthio, also an oxygen or sulphur atom respectively, or they may be substituted and contain one or more heteroatoms for example oxygen, nitrogen, halogen and sulphur, and/or heterogroups, for example carbonyl, ester and amide links. Thus, optionally the carbon-containing substituent(s) may contain a heteroatom in the carbon chain and/or may be substituted with a substituent containing a heteroatom such as, for example, OH, alkoxy and halogen, for example chlorine, bromine and especially fluorine. One or more (including all) hydrogen atoms in the said carbon-containing substituent(s) may be substituted as desired. The hydrocarbyl and hydrocarbyloxy groups may be alkyl, alkenyl, aryl, aryloxy and alkoxy groups which optionally are substituted. Preferably the alkyl and alkoxy group have from 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms and especially 1 to 4 carbon atoms, for example methyl, ethyl, methoxy and ethoxy. Preferably the alkenyl group and aryl group have from 2 to 12, especially 2 to 8, carbon atoms and from 6 to 12, especially 6 to 9, carbon atoms respectively. In one embodiment, at least one of R 1 , R 2 and R 3 for Formulae IA and IB, is selected from hydrohaloalkyl groups, especially hydrofluoroalkyl groups, and perhaloalkyl groups, especially perfluoroalkyl groups. Examples of suitable perfluoroalkyl groups include trifluoromethyl, pentafluoroethyl and perfluorooctyl groups and examples of suitable hydrofluoroalkyl groups include 2,2,2-trifluoroethyl, 2,2,3,3-tetrafluoropropyl and H(CF 2 CF 2 ) p CH 2 groups (where p is at least 2). Perhaloalkyl groups may be preferred in some cases due to the absence of a carbon-hydrogen bond which may be susceptible to electrophilic fluorination. In another embodiment, preferred for ease of synthesis, at least one of R 1 , R 2 and R 3 for Formulae IA and IB, is selected from hydrohaloalkoxy groups, especially hydrofluoroalkoxy groups, and perhaloalkyl groups, especially perfluoroalkyl groups. Examples of suitable perfluoroalkoxy groups include trifluoromethoxy, pentafluoroethoxy and perfluorooctoxy groups and examples of suitable hydrofluoroalkoxy groups include 2,2,2-trifluoroethoxy and 2,2,3,3-tetrafluoropropoxy. Particularly preferred are H(CF 2 CF 2 ) p CH 2 O groups (where p is at least 2) which are readily available using known telomer alcohols of the corresponding formula H(CF 2 CF 2 ) p CH 2 OH. In another embodiment, at least one R 1 , R 2 and/or R 3 for Formulae IA and IB, is a thio analogue of the aforementioned hydrohaloalkoxy and perhaloalkoxy groups, for example trifluoromethylthio (CF 3 S), or a perfluorothio group such as pentafluorothio (SF 5 ). The terms aryl and aryloxy include moieties which contain aliphatic as well as aromatic groups. Preferred aryl and aryloxy groups include phenyl, phenoxy, and groups of formula C 6 H 5 (CH 2 ) r [OC 2 H 4 ] q O t where q is 0 to 6, r is 0 to 8 and t is 0 or 1, which may be optionally substituted, preferably with fluorine. It is preferred that at least one of R 1 , R 2 and R 3 for Formulae IA and IB, is hydrocarbyl, hydrocarbyloxy, hydrohalocarbyl, hydrohalocarbyloxy, perhalocarbyl, or perhalocarbyloxy, , and Z, or Z 1 and Z 2 for Formulae IA and IB, and Y - are as defined above. It is especially preferred that R 1 , R 2 and R 3 for Formulae IA and IB, are identical in a given compound. Examples of especially preferred compounds are those in which all of R 1 , R 2 and R 3 are methyl, methoxy, trifluoromethoxy groups, or, most preferably for Formula IA, halogen or trifluoromethyl and, for Formula IB, trifluoromethyl. A practical advantage of R 1 , R 2 and R 3 being the same group is the manufacture of the compound may be simplified and isomers or a mixture of compounds is less likely to be produced. R 1 , R 2 and R 3 for Formulae IA and IB, may be selected so as to provide technical advantages to the compound of Formula I in addition to the fluorination characteristics such as improving the solubility of the compound in non-polar solvents and solvents of low polarity. Thus greater flexibility in chemical synthesis involving electrophilic fluorination is also provided by the compounds of Formula I. The compounds of Formulae IA and IB can be oligomers or polymers in which adjacent triazinium moieties are linked by a common R substituent, for example, a hydrocarbyl, perfluorohydrocarbyl or hydrocarbyldioxy group. Presently preferred linking groups are dioxyphenyl, di(oxycarbyl)phenyl, alkylenedioxy or bis(oxyaryl)alkylene groups, such as, for example, 1,5-dioxypent-2,4-diyl (i.e. -O-CH 2 -CH-CH 2 -CH-CH 2 -O-), 1,3-bis( p -oxyphenyl)prop-1,3-diyl (i.e. - p -OC 6 H 4 -CH-CH 2 -CH-C 6 H 4 O- p -), or 1,3-bis( m / p -oxymethylphenyl)prop-1,3-diyl (i.e. - m / p -OCH 2 C 6 H 4 -CH-CH 2 -CH-C 5 H 4 CH 2 O- m / p -). The compounds of Formulae IA and IB contain one fluorinated quaternary nitrogen atom in the triazinium ring. Both Z 1 and Z 2 for Formulae IA and IB, are nitrogen and the most preferred compounds are those of the following Formula II: wherein R 1 , R 2 , R 3 and Y - are as defined above. Examples of preferred compounds according to the invention are those having a triazinium cation as shown below in Formulae III to VII, especially those of Formulae IV, V and VI. 1-fluoro-2,4,6-trimethyl-1,3,5-triazinium 1-fluoro-2,4,6-trimethoxy-1,3,5-triazinium 1-fluoro-2,4,6-tris(trifluoromethyl)-1,3,5-triazinium The counterion Y - is resistant to chemical attack by fluorine and desirably, is thermally stable and possesses low environmental toxicity. The counterion(s) can be any anion(s) which can be counterion(s) to the triazinium cation. The counterion(s) may have a single charge or a multiple charge or be a group of counterions so as to balance the charge of the triazinium moiety. Also the counterion may be a counterion to more than one mole of the triazinium cation, for example where the cation has a single charge and the counterion has a multiple charge. Suitably the counterion is weakly nucleophilic. Suitable anions include fluoride; fluorosulphate (SO 3 F - ); alkanesulphonate, especially methanesulphonate (CH 3 SO 3 - ); alkyl sulphate, especially methyl sulphate (CH 3 SO 4 - ); perfluoroalkanesulphonate, preferably triflate (CF 3 SO 3 - ) and nonaflate (C 4 F 9 SO 3 - ); arenesulphonate, especially tosylate (i.e. p -toluenesulphonate; p -CH 3 C 6 H 4 SO 3 - ); alkanecarboxylate; perfluoroalkanecarboxylate; tetrafluoroborate (BF 4 - ); tetraphenylborate (Ph 4 B - ); hexafluorophosphate (PF 6 - ); hexafluoroantimonate (SbF 6 - ); hexafluoroarsenate (AsF 6 - ); chlorate (ClO 3 - ); sulphate (SO 4 2- = 2Y - ); hydrogen sulphate (HSO 4 - ) and F(HF) x - where x is at least 1. Presently preferred counterions include fluoride, tetrafluoroborate, triflate, tosylate, hexafluoroarsenate and hexafluorophosphate. Preferably, the compounds of Formulae IA and IB are prepared using a solvent-based process which comprises contacting a triazine compound with a fluorine source under acidic conditions in a solvent which is inert under the process conditions. Suitably the fluorine source is an electrophilic fluorine source such as, for example, fluorine gas or a mixture of fluorine gas and a neutral compound derivable from a fluorine-containing counterion Y - by removing at least one fluoride ion from Y - , for example boron trifluoride. Preferably, the fluorine source is fluorine gas. While the fluorine gas may be used without dilution, in general, it is preferable to use fluorine gas diluted with an inert gas so that the volume of the inert gas is between 99.9% and 50% for controlling the vigorous reaction. Suitable inert gases include nitrogen, helium and argon. The triazine compound to be fluorinated is suitably a compound of the Formula VIII and may be obtained by subjecting a compound or a mixture of compounds of formula RCN to a known process for producing a triazine compound of formula (RCN) 3 wherein R is independently R 1 , R 2 or R 3 as described herein: The fluorination process is carried out in the presence of an acid which may be a Brønsted acid (organic or mineral) or a Lewis acid. The level of acid is suitably adjusted so as to reduce and desirably avoid double protonation of the triazine compound and to provide a yield (as determined by 19 F NMR) of F-N + of at least 20% and desirably of at least 50%. Desirably the molar ratio of acid to triazine substrate is 0.5 to 2.5, preferably 1 to 2.2. Preferable examples of Brønsted acid have pKa in the range from 12.4 to 4.6 and include halogenated alcohols, for example chlorodifluoroethanol, dichlorofluoroethanol, chlorooctafluoro-t-butanol, trifluoroethanol tetrafluoropropanol, pentafluoropropanol, hexafluoroisopropanol, octafluoropentanol, and nonafluoro-t-butanol. Fluorinated alcohols, particularly those which are free of chlorine, are especially preferred. Other acids which are especially preferred include acids of the counterion Y - described above, for example anhydrous hydrofluoric acid, hexafluoroantimonic acid, tetrafluoroboric acid and triflic acid, sulphuric acid, methanesulphonic acid, acetic acid and trifluoroacetic acid. Brønsted acids may be used in the form of a complex with, for example, ethers, water, alcohols, nitriles, or carboxylic acids and may be used in the form of an aqueous solution. Preferably, the solvent is non-aqueous and it is presently particularly preferred that the solvent is acetonitrile, a halogenated, especially fluorinated, alcohol or, especially, nitromethane. In this connection, it is believed that there has not been any previous proposal to use nitromethane as a solvent, or for any other purpose, with any N-F or + N-F reagent. If desired the same material may be used as both the acid and the solvent. The reaction to produce compound of Formulae IA and IB is carried out at a temperature at which the solvent is in the liquid phase and suitably at a sufficiently low temperature that reaction due to a free radical mechanism is reduced and suitably avoided. The particular temperature selected depends on the solvent and also the reactants. By way of example only, the reaction suitably may be carried out at a temperature of -40 to 10 °C. A temperature of -40 to -20 °C is preferred for acetonitrile and a temperature of -10 to 5 °C is preferred for hexafluoroisopropyl alcohol. The reaction may be carried out at elevated pressure although this is not essential. Fluorination of the triazine compound may be carried out using a stirred-tank batch reactor. Where the fluorine source is gaseous, the fluorine source is suitably admitted either as neat gas at sub-atmospheric pressure or as a continuous flow of fluorine blended with nitrogen or other inert diluent at about atmospheric pressure. Advantageously, the process for producing compound of Formulae IA and IB may be operated as a continuous process. The compounds of Formulae IA and IB may be used as electrophilic fluorinating agents in a similar manner to Selectfluor™ and in manner know in the art (see, for example, R.E. Banks et al . J. Chem. Soc. Perkin Trans. I, 1996, 2069). The fluorinating agent may be contacted with the substrate neat and optionally at elevated temperature. If desired the fluorination process may be carried out in a solvent, for example acetonitrile or, especially, nitromethane. As mentioned above, it is believed that there has not been any previous proposal to use nitromethane as a solvent, or for any other purpose, with any N-F or + N-F reagent. When a compound of Formulae IA and IB has been used in a fluorination reaction and so depleted in fluorine, it may be recovered and regenerated by introducing the fluorine source for reuse in further fluorination reactions. The compounds of Formulae IA and IB may be used to fluorinate organic compounds, for example nucleosides, nucleoside bases and steroids, or cationic organometallic compounds for example cyclopentadienides. They are especially useful in fluorinating carbanionic and/or aromatic substrates and in particular aromatic substrates having electron-withdrawing substituents, for example halo or nitro substituents. In a preferred embodiment of the fluorination aspect invention, a fluorinated steroid is prepared by contacting a steroid or a suitable derivative such as a steroidal enol acetate or silyl enol ether with a fluorinating agent of Formulae IA and IB optionally in the presence of a solvent and optionally at elevated temperature. Preferably, the steroid is fluorinated at the 6 and/or 16 position. Compounds of Formulae IA and IB may be isolated or used without separation from the reaction mixture. If desired, the reaction mixture may be fed to a separate fluorination reactor or the compound of Formulae IA and IB may be purified or otherwise treated prior to use. The invention is illustrated by the following non-limiting Examples. Example 1 Preparation of 1-fluoro-2,4,6-tris(trifluoromethyl)1,3,5-triazinium triflate 2,4,6-Tris(trifluoromethylyl)-1,3,5-triazine (0.2 g, 0.7 mmol), triflic acid (0.11 g, 0.73 mmol) and hexafluoroisopropanol (80 cm 3 ) were placed in a flow fluorination reactor, cooled (-5°C), stirred vigorously and treated with a 1:9 (vol./vol.) fluorine-nitrogen blend (flow rate of 130 cm 3 per minute) until the exit gas gave a strong positive test (Kl) for fluorine. A small sample (10 cm 3 ) of the resultant colourless reaction solution was tested for oxidation properties with aqueous Kl and gave a strong positive test. The remaining reaction solution was evaporated under reduced pressure, yielding a colourless oily material, which fumed when exposed to air. The 19 F NMR spectrum of this material (in CD 3 CN) contained the expected OTf and CF 3 at δ F + 0.5 -6.0 (s; TFA ref.) ppm as well as a weak absorption at + 28.3 (br. s) assignable to the + NF function of 1-fluoro-2,4,6-tris (trifluoromethyl)-1,3,5-triazinium triflate. The reaction was repeated a number of times, but no pure + NF salt was isolated, believed to be due to the hygroscopic nature of + NF salt and its reactivity towards water. Example 2 (i) Preparation of 2,4,6-trimethoxy-1,3,5-triazine Cyanuric chloride (5.0 g, 27 mmol) was added dropwise to a cold (-5 °C ) stirred solution of sodium methoxide (5.0 g, 93 mmol) in dry methanol (50 cm 3 ); the mixture was then allowed to warm to room temperature and then refluxed for 3.0 hours. The reaction mixture was filtered to isolate inorganic salts and the filtrate freed from solvent (Rotavapor™) yielding an off-white solid which was dissolved in diethyl ether (50 cm 3 ). The ethereal solution was washed with water (3 x 30 cm 3 ), charcoaled, dried over MgSO 4 and finally evaporated (Rotavapor™) to give pure 2,4,6-trimethoxy-1,3,5-triazine (4.3 g, 25 mmol, 93%) as a crystalline white solid. Product Analysis (2,4,6-trimethoxy-1,3,5-triazine): M.P. 136 °C. Found: C, 42.2; H, 5.1; N, 24.4%. Calculated for C 6 H 9 N 3 O 3 : C, 42.1; H, 5.3; N, 24.6%], δ 1 H (CDCl 3 ) 4.1 (s, 3 x OCH 3 ) ppm, δ 13 C (CDCl 3 ) 175.5 (C=N), 58.4 (s, 3 x OCH 3 ) ppm. (ii) Production of 1-fluoro-2,4,6-trimethoxy-1,3,5-triazinium triflate A homogeneous mixture of 2,4,6-trimethoxy-1,3,5-triazine (0.1g; 0.585 mmol), triflic acid (0.1 g; 0.66 mmol) and acetonitrile (80cm 3 ) was placed in a flow fluorination reactor, cooled to -35 °C, stirred vigorously and treated with a 1:9 (volume/volume) blend of fluorine and nitrogen gas at a flow-rate of 130 cm 3 /minute until the exit gas gave a strong positive test for fluorine (using potassium iodide). The solution was concentrated under reduced pressure to 10cm 3 and dry dichloromethane (30cm 3 ) was added. A white solid material was obtained by suction filtration, and was washed with dry diethyl ether (30cm 3 ) and dried in vacuo and characterised by elemental analysis and NMR spectroscopy as 1-fluoro-2,4,6-trimethoxy-1,3,5-triazinium triflate. The product (1-fluoro-2,4,6-trimethoxy-1,3,5-triazinium triflate) was obtained in a yield (0.18g; 0.53 mmol) of 91 % based on the triazine starting material. Product Analysis (1-fluoro-2,4,6-trimethoxy-1,3,5-triazinium triflate): M.P. 186 °C; Found: C, 23.4; H, 2.5; N, 11.8%. Calculated for C 7 H 9 F 4 N 3 O 6 S. H 2 O; C, 23.5; H, 3.1; N, 11.8%; δ H (CD 3 CN, TMS (trimethylsilane)) 4.59 (s, 2 x OCH 3 ), 4.42 (s, OCH 3 ) ppm.; δ c (CD 3 CN) 167.6 (s, C=N), 156.1 (q, CF 3 SO 3 - , J CF 276 Hz), 61.2 (s, 2 x OCH 3 ), 59.6 (s, OCH 3 ) ppm; δ F (CD 3 CN, TFA) 18.65 (br s, N + F), 1.72 (s, CF 3 SO 3 - ) ppm. Example 3 Production of 1-fluoro-2,4,6-trimethoxy-1,3,5-triazinium triflate The procedure of Example 2 was repeated except that hexafluoroisopropanol was used as the solvent and the reaction was carried out at -5 °C. The product (1-fluoro-2,4,6-trimethoxy-1,3,5-triazinium triflate) was characterised using elemental analysis and NMR spectroscopy and obtained in a yield of 98%. Example 4 Production of 1-fluoro-2,4,6-trimethoxy-1,3,5-triazinium hexafluoroantimonate The procedure of Example 3 was repeated except that the reactants employed were 2,4,6-trimethoxy-1,3,5-triazine (0.5g; 2.92 mmol) and hexafluoroantimonic acid (0.69g; 2.92 mmol) and diethyl ether (50cm 3 ) instead of dichloromethane was used in the "work-up". The product (1-fluoro-2,4,6-trimethoxy-1,3,5-triazinium hexafluoroantimonate) was characterised by NMR spectroscopy and elemental analysis and obtained in a yield (1.22g; 2.86 mmol) of 98%. Product Analysis (1-fluoro-2,4,6-trimethoxy-1,3,5-triazinium hexafluoroantimonate): M.P. 211 °C (dec). Found: C, 17.1; H, 1.9; N, 9.5; Sb, 28.9%. Calculated for C 6 H 9 F 7 N 3 O 3 Sb: C, 17.0; H, 2.1: N, 9.9; Sb, 28.6%; δ H (CD 3 CH, TMS) 4.59 (s, 2 x OCH 3 ), 4.44 (s, OCH 3 ) ppm; δ c (CD 3 CN) 167.7 (s, C=N), 61.1 (s, 2 x OCH 3 ), 59.4 (s, OCH 3 ) ppm; δ F (CD 3 CN, TFA) 18.88 (br s, N + F), -20.75 to -79.96 (complex, SbF 6 - ) ppm. The structure was confirmed by single crystal X-ray analysis (bond length: F-N, 1.354 A). Example 5 (i) Preparation of 2,4,6-trimethyl-1,3,5-triazine A stainless steel pressure vessel (100 cm 3 ) was charged with dry acetonitrile (10.0 g, 244 mmol) and yttrium triflate (1.07 g, 2 mmol). The vessel was cooled (-196 °C), evacuated and charged with anhydrous ammonia (4.2 cm 3 , 247 mmol), sealed and then heated for 24 hours at 200 °C. The autoclave was cooled to room temperature before the volatile material (unchanged ammonia) was allowed to bleed off. Diethyl ether (300 cm 3 ) was added to the reaction mixture and the insoluble material removed by filtration, dissolved in ethyl acetate (30 cm 3 ), washed with water (3 x 20 cm 3 ), dried with MgSO 4 then evaporated (Rotavapor™) to give 4-amino-2,6-dimethylpyrimidine (22.0 g, 179 mmol, 73%) as a crystalline white solid. Product Analysis (4-amino-2,6-dimethylpyrimidine): M.P. 184 °C. Found: C, 58.2; H, 7.5; N, 34.3%. Calculated for C 6 H 9 N 3 :C, 58.5; H, 7.4; N, 34.2%; δ H (CD 3 CH, TMS) 6.0 (s, HC=C), 5.2 (br.s, NH 2 ), 2.2 (s, CH 3 ) and 2.1 (br.s, CH 3 ) ppm. Rotary evaporation of the ethereal solution provided 5.0 g (41 mmol, 17%) of an off-white solid; this was purified by vacuum sublimation to give pure 2,4,6-trimethyl-1,3,5-triazine as a crystalline white solid. Product Analysis (2,4,6-trimethyl-1,3,5-triazine): M.P. 56 °C. Found: C, 58.3; H, 7.6; N, 33.8%. Calculated for C 6 H 9 N 3 : C, 58.5; H, 7.3; N, 34.2%; δ H (CD 3 CN 3 , TMS) 2.52 (s, 3 x CH 3 ) ppm; δ C ( CDCl 3 ) 176.3 (s, C=N), 25.8 (s, CH 3 ) ppm. (ii) Production of 1-fluoro-2,4,6-trimethyl-1,3,5-triazinium triflate The procedure of Example 2 was repeated except that the reactants employed were 2,4,6-trimethyl-1,3,5-triazine (0.1g) and triflic acid (0.12g). The product (1-fluoro-2,4,6-trimethyl-1,3,5-triazinium triflate) was characterised using elemental analysis and NMR spectroscopy as hexahydrated 1-fluoro-2,4,6-trimethyl-1,3,5-triazinium triflate and obtained in a yield of 68%. Product Analysis (1-fluoro-2,4,6-trimethyl-1,3,5-triazinium triflate): M.P. 205 °C (dec); Found: C, 21.8; H, 3.0; N, 9.7%. Calculated for C 7 H 9 F 4 N 3 O 3 S.6H 2 O: C, 21.1; H, 5.3; N, 10.5%; δ H (CD 3 CN, TMS) 2.4 (d., 2 x CH 3 ), 2.1 (s, CH 3 ) ppm.; δ C (CD 3 CN) 178.4 (s, C=N), 168.6 (q, CF 3 J CF 287.3 Hz), 26.6 (s, 2 x CH 3 ), 23.5 (s, CH 3 ) ppm; δ F (CD 3 CN 3 , TFA) 1.43 (s, CF 3 ) 19.2 (br s, N + F) ppm. Examples 6 to 15 Production of a variety of 1-fluoro-2,4,6-trimethoxy-1,3,5-triazinium salts A variety of salts were produced using different acids and with different ratios of acid to substrate as set out in Table 1. The procedure of Example 2 was followed in producing these salts. Example Acid Acid:substrate (moles) + N- F % yield 9 Triflic 1.1:1 89 10 Triflic 1.5:1 76 11 Triflic 2:1 5 12 Sulphuric (98%) 1.2:1 91 13 Sulphuric (98%) 2:1 82 14 Tetrafluoroboric (48%) 1.1:1 77 15 Tetrafluoroboric (48%) 2:1 23 16 Trifluoroacetic 1.8:1 92 17 Acetic 2.1:1 85 18 Anhydrous hydrogen fluoride 1:1 94 As shown by Table 1, the yield of 1-fluoro-2,4,6-trimethoxy-1,3,5-triazinium salts was sensitive to the amount of Brønsted acid used in the synthesis. When a 1.5 or less molar equivalent of triflic acid was used, the simple triflate salt of the triazine was obtained in high yields. However, the use of more than 1.5 molar equivalents of triflic acid caused the yield of the + N-F salt to depreciate greatly and mainly the + N-H salt was produced. Similar results were obtained with other acids. Example 16 Fluorination of phenyl lithium using 1-fluoro-2,4,6-trimethoxy-1,3,5 -t riazinium triflate 1 Mole of phenyl-lithium (in dry diethyl ether) was added dropwise to a stirred suspension of 1 mole of 1-fluoro-2,4,6-trimethoxy-1,3,5-triazinium triflate in dry diethyl ether at a temperature of about -70 °C. The mixture was stirred for 2 hours and then allowed to warm slowly to room temperature overnight with continuous stirring. The reaction mixture was filtered and distilled. The residue was analysed by 19F NMR spectroscopy (in CDCl 3 ; TFA ref.) and showed the characteristic absorption for fluorobenzene at δ F -36.2ppm. Attempts to fluorinate benzene or methoxybenzene using 1-fluoro-2,4,6-trimethoxy-1,3,5-triazinium triflate or 1-fluoro-2,4,6-trimethyl-1,3,5-triazinium triflate under similar conditions to those successfully used in Example 16 to fluorinate phenyl lithium were unsuccessful.

Claims: A method of electrophilic fluorination which comprises contacting an organic substrate with a N -fluorotriazinium salt electrophilic fluorinating agent wherein the N -fluorotriazinium salt is either a N -fluoro-1,2,4-triazinium compound of the following Formula IA: wherein: R 1 , R 2 and R 3 are, independently, hydrogen, halogen, hydroxyl, amino, cyano, perfluorothio, hydroxysulphonyl, halosulphonyl, hydrocarbyloxysulphonyl, or a carbon-containing substituent selected from optionally substituted hydrocarbyl, hydrocarbyloxy, hydrocarbyloxycarbonyl, and hydrocarbylthio groups; Z 1 and Z 2 are nitrogen; and Y - is a counterion or group of counterions which are inert to chemical attack by fluorine, or is an oligomer or polymer thereof in which adjacent triazinium moieties are linked by a common R substituent, or a N -fluoro-1,3,5-triazinium compound of the following Formula IB: wherein: R 1 , R 2 and R 3 are, independently amino, hydroxyl, cyano, perfluorothio, hydroxysulphonyl, halosulphonyl, hydrocarbyloxysulphonyl, or a carbon-containing substituent selected from optionally substituted hydrocarbyl, hydrocarbyloxy, hydrocarbyloxycarbonyl, and hydrocarbylthio groups; Z 1 and Z 2 are nitrogen; and Y - is a counterion or group of counterions which are inert to chemical attack by fluorine, or is an oligomer or polymer thereof in which adjacent triazinium moieties are linked by a common R substituent. A method according to Claim 1, wherein, in Formula IA, R 1 , R 2 and R 3 , are selected from halogen and trifluoromethyl. A method according to Claim 2, wherein, in Formula IA, R 1 , R 2 and R 3 , are selected from chlorine, fluorine and trifluoromethyl. A method according to Claim 1 wherein, in Formula IB, R 1 , R 2 and R 3 , are trifluoromethyl. A method according to Claim 2 or Claim 3, wherein an unsubstituted aromatic substrate or an aromatic substrate having one or more electron-withdrawing substituents is contacted with a N -fluoro-trihalotriazinium salt. A method according to Claim 5, wherein the aromatic substrate is chlorobenzene or nitrobenzene. A method according to any one of the preceding claims, wherein the substrate is an electron-rich species. A method according to Claim 7, wherein the electron-rich species is a carbanionic substrate. A method according to Claim 7, wherein the electron-rich species is an activated aromatic substrate. A method according to Claim 7, wherein the electron-rich species is steroid or derivative thereof. A method according to any one of Claims 1 to 10, wherein R 1 , R 2 and R 3 , are identical. A method according to Claim 11, wherein, in Formula IA, each of R 1 , R 2 and R 3 is chlorine. A method according to any of Claims 1 to 12, wherein the N- fluorotriazinium salt is a N -fluoro-1,3,5-triazinium compound of the following Formula II: wherein R 1 , R 2 , R 3 and Y - are as defined in the relevant claim. A method according to Claim 13 wherein the N -fluorotriazinium salt is a N -fluoro-1,3,5-triazinium compound having Formula II in which each of R 1 , R 2 and R 3 is a methoxy group. A method according to Claim 13 wherein the N -fluorotriazinium salt is a N -fluoro-1,3,5-triazinium compound having Formula II in which each of R 1 , R 2 and R 3 is a methyl group. A method according to any one of Claims 1 to 15, wherein Y - is selected from fluoride, fluorosulphate, alkanesulphonate, alkyl sulphate, perfluoroalkanesulphonate, arenesulphonate, alkanecarboxylate; perfluoroalkanecarboxylate, tetrafluoroborate, tetraphenylborate, hexafluorophosphate; hexafluoroantimonate; hexafluoroarsenate; chlorate; sulphate (= 2Y - ), hydrogen sulphate and F(HF) x - where x is at least 1. A method according to Claim 16, wherein Y - is selected from fluoride, tetrafluoroborate, triflate, tosylate, hexafluoroarsenate and hexafluorophosphate. A method according to Claim 17, wherein Y - is triflate.

Inventors: BANKS RONALD ERIC, BESHEESH MOHAMED KHALIFA, BANKS, RONALD ERIC, BESHEESH, MOHAMED KHALIFA
Applicants: AIR PROD & CHEM, AIR PRODUCTS AND CHEMICALS, INC.
Application year: 2001
Main classification: C07B39
IPC codes: C07B39, C07C205, C07D251, C07C41, C07C17