PREPARATION OF SELECTIVELY FLUORINATED ORGANIC COMPOUNDS

Abstract: The present invention provides a method of selectively fluorinating a carbon-hydrogen bond at an unactivated saturated sp<3> hybridised carbon atom of an organic compound, the method including reacting the organic compound with elemental fluorine gas, characterised in that the reaction is carried out in the presence of a basic compound. The method enables the selective transformation of carbon-hydrogen bonds to carbon-fluorine bonds in molecules where the hydrogen atom is attached to a fully saturated unactivated sp<3> hybridised carbon atom such as a tertiary carbon atom found in many saturated hydrocarbon compounds and steroid derivatives. Advantageously, the method may be carried out at or just below room temperature.

Description: Preparation of Selectively Fluorinated Organic Compounds The present invention relates to the selective fluorination of organic compounds. Most reported reactions with electrophilic fluorinating reagents involve transformation of activated carbon-hydrogen bonds to carbon-fluorine bonds, that is where the hydrogen atom is attached to a carbon which is part of or bears a functional group or which is directly bonded to another carbon atom which is part of or bears a functional group. For example the hydrogen atom is attached to a carbon atom that is sp 2 hybridised (alkenes, aromatics, carbonyl derivatives, etc) or to a carbon atom that bears a negative charge (carbanions, etc) or which must form, for example, an enol before fluorination can occur as with β-dicarbonyl compounds. Selective transformation of carbon-hydrogen bonds to carbon-fluorine bonds, in which the hydrogen atom is attached to a fully saturated unactivated sp 3 hybridised carbon atom, in a simple, one-step process would be particularly advantageous. This is especially so as it would enable fluorination of many important hydrocarbon and steroid derivatives for example where fluorination at a tertiary carbon atom may be desired. However, fluorination of saturated systems is very difficult. Barton and co-workers (Nouv. J. Chem. 1980 4 239) have demonstrated that selective monofluorination at tertiary centres in adamantoid and steroid structures is possible and, more recently, Rozen (J Org. chem. 1987 52 2769) has accomplished a number of such substitution reactions with both functionalised, and unfunctionalised, aliphatic and cyclic hydrocarbons (including steroids). The reactions used elemental fluorine and a solvent system comprising trichlorofluoromethane and chloroform at low temperature (- 78°C). Rozen emphasised that the addition of chloroform is essential because it possesses relatively acidic hydrogen atoms and thus it functions as an acceptor for the counterion of the electrophile, i.e. the fluoride ion, by a hydrogen bonding process as shown below. Overall, the method of Rozen suffers from the disadvantages that trichlorofluoromethane is an ozone depleting substance which is now precluded from use under the Montreal protocol and low temperatures of-78°C are required. If the reaction is carried out at higher temperatures than -78°C, the fluorination becomes non-selective and consequently an unviable synthetic process. According to the present invention there is provided a method of selectively fluorinating a carbon-hydrogen bond at an unactivated saturated sp hybridised carbon atom of an organic compound, the method including reacting the organic compound with elemental fluorine gas, characterised in that the reaction is carried out in the presence of a basic compound. Advantageously, the method may be carried out at or just below room temperature. Advantageously, the reaction may be carried out using readily available and cheap substances. The invention results from the surprising finding that the use of a substance basic in nature is effective in enabling the selective fluorination of unactivated saturated sp3 hybridised carbon atoms to carried out in a controlled manner at room temperature or just below. Compounds possessing a lone pair of electrons have been found to be particularly effective as the basic compound. Preferably, therefore, the basic compound is a compound having a functional group containing a lone pair of electrons. Such functional groups will, of course, be readily apparent to the person skilled in the art. The invention involves a completely different approach to the prior art which stresses the need for a substance having acidic hydrogens, not a basic character. The presence of acidic hydrogens in the basic compound is in most cases deleterious to the method as it may lead to reaction of the basic compound itself with the fluorine. The basic compound should be largely inert with respect to the fluorine gas. Thus, the basic compound preferably comprises a functional group having a lone pair of electrons and lacks any substantially acidic hydrogen atoms. Preferably, the basic compound contains a functional group selected from the group consisting of nitrile, ether, tertiary amine, nitro where the compound is Ci and amide where the compound is Cj. Examples of suitable basic compounds include acetonitrile, propionitrile, tetrahydrofuran, diethyl ether, nitromethane and dimethylformamide. It will be appreciated that nitro and amide compounds generally have relatively acidic hydrogens in the 2-position relative to those functional groups and so are only effective where the compound is Ci such that there are no hydrogens in the 2-position as in nitromethane and dimethyl formamide. Amines may be oxidised to the nitrile unless a tertiary amine is used. Most preferably, the basic compound comprises a nitrile functional group. Especially advantageous basic compounds are acetonitrile and propionitrile. The basic compound may be present in amounts ranging from a minor amount in the reaction medium to where the basic compound substantially forms the reaction medium. The basic compound may act as the solvent for the organic compound to be fluorinated. Preferably, the reaction is carried out in a temperature range -60°C to +150°C. More preferably, the reaction is carried out in a temperature range from about 0°C to about +30°C. The reaction may be performed by passing fluorine into a solution of the organic compound in a suitable vessel. Alternatively, a flowing stream of the solution may be contacted with a gaseous flow of fluorine in counter-current or co-current fashion. Preferably the fluorine gas is diluted before use by mixing with an inert gas such as helium or nitrogen. The concentration of fluorine in the inert gas may be from 1% to 50% by volume, preferably from 2% to 25% by volume an especially from 5% to 15% by volume. The ratio of fluorine gas to organic compound to be fluorinated may be varied within wide limits although it is preferred that the molar ratio is in the range 0.5 to 10 : 1 and more preferred that it is 1 to 3 : 1. When the fluorination reaction of the process is complete, the selectively fluorinated organic compounds may be isolated by purging with an inert gas to remove any residual fluorine gas or hydrogen fluoride formed during the reaction, followed by dilution with water and extraction of the selectively fluorinated organic compound into a suitable solvent followed by, for example, purification by distillation or column chromatography. The term unactivated saturated sp carbon atom used herein means a saturated sp hybridised carbon atom not directly bonded to any functional group. That is to say, any carbon atom which is part of a functional group (e.g. carbonyl C=O) or is bearing a functional group (e.g. C-OH) must be at least two atoms distant from the carbon which is bonded to the hydrogen atom that is replaced by fluorine. In the prior art, functional groups such as for example carbonyl were directly bonded, i.e. less than two carbons distant, to the carbon atom which is bonded to the hydrogen atom that is replaced by fluorine. Thus, in the prior art, the functional group would activate the carbon-hydrogen bond on the saturated carbon atom. The unactivated saturated sp 3 hybridised carbon atom may be bonded to three other carbon atoms and a hydrogen atom, i.e. a tertiary-carbon atom. The saturated sp 3 hybridised carbon atom may be bonded to two other carbon atoms and two hydrogen atoms, i.e. a secondary carbon atom. The saturated carbon atom may form part of a cyclic structure, e.g. a saturated tertiary carbon atom may form part of a cyclic structure such as decalin or adamantane. Where the saturated carbon atom is a secondary carbon atom it too may form part of a cyclic structure. The present invention may be used to convert a wide range of organic compounds such as those represented by 1, 9, 10, 11, 12, 13, 14 below to the corresponding fluorinated analogues 2, 3, 4, 5, 6, 7, 8. r (CR 1 R 2 ) ϊr - 10 11 14 r(CR,R 2 )H— R-O- - In structures 2, 3, 4, 5, 6, 7, 8 and 1, 9, 10,11,12,13,14 the groups R h R 2 , R 3 , R 4 , R 5 , R* and R 7 may be independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, etc. Where any of the groups Ri, R , R 3 , Ri, R 5 , δ and R 7 is an alkyl, cycloalkyl or aryl substituent, the said group may include one or more optional substituents or hetero-atoms. The structures represented by formulae 3, 4, 5, 7, 8, 9, 10, 11, 13, 14 are cyclic and n may be an integer in the inclusive range from 1 to 8. The n values are independent of each other. Embodiments of the present invention will now be described, by way of example only, with reference to the following examples. Example 1 - Fluorination of adamantane Elemental fluorine (205 mmol) as a 10% (v/v) mixture with nitrogen was passed through a stirred, cooled (0°C) mixture of adamantane (4.00 g, 29 mmol) and dry acetonitrile (140 cm 3 ). After addition of the fluorine, the reaction mixture was poured into water, neutralised (NaHCO 3 ) and extracted three times using dichlormethane. The combined dried (MgSO ) organic extracts were evaporated to give a brown solid. Column chromatography on silica gel using 6: 1 cyclohexane-DCM was used to isolate 1- fluoroadamantane (2.06 g, 65%, 70% conv.) as a white solid from this brown solid; mp 256-258°C (Lit.257-259°C) (Found: C, 77.8; H, 9.9. C 10 H 15 F requires: C,77.9;H,9.8%); δ F (376 MHz) 128.8 (s); δ H (400 MHz) 1.62 (2 H, m, 4-H), 1.88 (2 H, m, 2-H), 2.23 (1 H, s, 3-H); δ c (101 MHz) 31.7 (d, 3 J CF 9.9, C-3), 36.1 (d, 4 J CF 1.9, C-4), 43.0 (d, 2 J CF 17.2, C- 2), 92.8 (d, 'J CF 183.1, C-l); m/z (EI + ) 154 (M + , 75%). Example 2 - Fluorination of c/s-decalin in acetonitrile Elemental fluorine (363 mmol) as a 10% mixture with nitrogen was passed through a stirred, cooled (0°C) mixture of c/s-decalin (10.00 g, 73 mmol) and dry acetonitrile (140 cm 3 ). After addition of the fluorine, the reaction mixture was poured into water, neutralised (NaHCO ) and extracted three times using dichlormethane. The combined dried (MgSO 4 ) organic extracts were evaporated to give a yellow crude product mixture (10.34 g) which contained 9-cw-fluorodecalin. Preparative GC gave 9-et_y-fluorodecalin (3.74 g, 52%, 64% conv.) as a colourless oil; bp 202°C (Found: M + , 156.1314.C 10 Hι 7 F requires M + , 156.1313); δ F (470mHz) 146.51(m); δ H (500 MHz) 1.20-1.85 (m); δ c (101 MHz) 23.2 (br s, C-2, C-3 and C-8), 26.5 (s, C-7), 28.2 (s, C-l), 30.4 (s, C-9), 35.5 (d, 2 J CF 28.6, C-6), 40.8 (br d, C-4 and C-10), 96.9 (d,'j CF 169.8, C-5); m/z (El) 156 (M + , 15%), 136 (100, M-HF). Example 3 - Fluorination of c/s-decalin in nitromethane Elemental fluorine (208 mmol) as a 10% (v/v) mixture with nitrogen was passed through a stirred, cooled (0°C) mixture of cw-decalin (5.74 g, 42 mmol) and dry nitromethane (140 cm 3 ). After addition of the fluorine, the reaction mixture was poured into water, neutralised (NaHCO 3 ) and extracted using dichlormethane. The combined, dried (MgSO 4 ) organic extracts was evaporated to give an orange crude product mixture (7.41 g) which contained c/ ' _y-9-fluorodecalin (2.91 g, 33%, 97% conv.), tar residue (43 weight %), a small amount of difluorodecalin; m/z (El) 174 (M + , 65%), 154 (4, M + -HF); a small amount of trifluorodecalin; m/z (El) 192 (M + , 36%), 172 (13, M + - HF), a trace amount of tetrafluorodecalin; m/z (El) 210 (M + , 11%), 190 (12, M + -HF) and, other unidentified products Example 4 - Fluorination of -decalin in propionitrile As above using cz ' s-decalin (5.74 g, 42 mmol) and elemental fluorine (208 mmol) in propionitrile (140 cm ) gave, an orange crude product mixture (9.03 g) which contained cis -5-fluorodecalin (2.36 g, 50%, 72% conv.); data as above, a trace amount of difluorodecalin; data as above; a trace amount of trifluorodecalin; data as above and, a trace amount of other unidentified products. Example 5 - Fluorination of trfl«_y-decalin Elemental fluorine (302 mmol) as a 10% mixture with nitrogen was passed through a stirred, cooled (0°C) mixture of tra -decalin (10.43 g, 76 mmol) and dry acetonitrile (140 cm 3 ). After addition of the fluorine, the reaction mixture was poured into water, neutralised (NaHCO 3 ) and extracted using dichlormethane. The combined, dried (MgSO 4 ) organic extracts was evaporated to give a yellow crude product mixture (12.15 g) which contained trα -9-fluorodecalin. Preparative GC gave 9-trans- fluorodecalin (4.11 g, 51%, 68% conv.) as a colourless oil; bp 197°C (Found: M + , 156.1313.Cι 0 Hι 7 F requires: M + , 156.1314); δ F (470 MHz) 146.51 (m); δ H (500 MHz) 1.20 - 1.85 (m); δ c (101 MH Z ) 23.2 (br s, C-2, C-3 and C-8), 26.5 (s, C-7), 28.2 (s, C-l), 30.4 (s, C-9), 35.5 (d, 2 J CF 28.6, C-6), 40.8 (br d, C-4 and C-10), 96.9 (d, 'J CP 169.8, C-5; m/z (El) 156 (M + , 15%), 136(100, M-HF). Example 6 - Fluorination of cvclohexane Elemental fluorine (208 mmol) as a 10% mixture with nitrogen was passed through a stirred, cooled (0°C) solution of cyclohexane (21.84 g, 260 mmol) and dry acetonitrile (140 cm 3 ). After addition of the fluorine, the reaction mixture was poured into water, neutralised (NaHCO 3 ) and extracted using dichlormethane. The combined, dried (MgSO 4 ) organic extracts were evaporated using a vigereux column to give a yellow crude product mixture (17.13 g) which contained fluorocyclohexane (4%, 98% conv.). Purification by preparative GC gave fluorocyclohexaneas a colourless oil; bp 101- 103°C; δ F (376 MHz) 171.47 (br s); δ H (400 MHz) 1.30 - 1.75 (10 H, m, 2-H, 3-H and 4-H), 4.57 (1 H, d sept., 2 J HF 48.8, J H H 3.6, 1-H); δC (100 MH Z ) 22.8 (d, 3 J CF 7.7, C- 3), 25.2 (d, 4 J CF 1.5, C-4), 32.3 (d, 2 J CF 18.7, C-2), 91.5 (d, 'J CF 169.8, C-l); m/z (EI + ) 102 (M + , 8%), 82(40, M + -HF). Example 7 - Fluorination of Norbornane By the same process as described above, norbornane (4.93 g, 51 mmol), elemental fluorine (195 mmol) and anhydrous acetonitrile (140 cm 3 ) gave a reaction mixture which was poured into iced water (150 cm 3 ), neutralised (NaHCO3) and filtered to remove the solid brown crude product (7.02 g) which contained norbornane (52 area %), exo- and e«dø-2-fluoronorbornane (1.43 g, 41%, 60% conv.) (32 area %) in the ratio of 5.3 : 1.0 respectively and, unidentified products (16 area %). Purification of the crude product by preparative scale GC gave a sample of exo- and endo-2- fluoronorbornane as an isomeric mixture and as a white solid; mp 54-60°C (sealed tube) (Found: volatility prevented high resolution MS determination); δF (376MHz) 160.48 (m, exo), 189.85 (ddd, 2 JRF 57.9, 3 JRF 29.3, JHF \ 6 , endo); δH (400MHz) 0.91-2.49 (69.3 H, m, CH2 and CH), 4.58 (5.3 H, dm, 2 J HF 56.4, CHF- exo), 5.02 (1.0 H, dm, 2 J HF 57.9, CUF-endo); e o-2-fluoronorbornane δc(100MHz) 22.3 (d, 3j CF 10.3, C-6), 27.9 (s, C-5), 34.7 (d, 3 J C F 1.2, C-7), 34.8 (s, C-4), 39.9 (d, 2j C F 19.3, C-3), 42.0 (d, 2 J CF 19.4, C-l), 96.2 (d, cF 181.6, C-2); endo-2- fluoronorbornane δc(100MHz) 19.9 (d, 3 JcF 10.3, C-6), 29.1 (s, C-5), 36.5 (d, 3 JCF 2.3, C-4), 36.9 (d, 3j CF 4.9 C-7), 37.2 (d, 2 J CF 22.1, C-3), 41.2 (d, 2 J CF 17.5, C-l), 94.7 (d, 1 JCF 184.0, C-2); m/z (EI+) 1 14 (M+ 1 1%), 99 (20). Example 8 - Fluorination of 2-Methylheptane By the same process as described above, 2-methylheptane (8.21 g, 72 mmol), elemental fluorine (72 mmol) anhydrous acetonitrile (140 cm 3 ) gave a pale yellow crude product mixture (9.27 g) which contained 2-methylheptane (15 area %), at least four isomers of fluoromethylheptane (65 area %) including l-fluoro-2-methylheptane (1.12 g, 15%, 81% conv.) and l-fluoro-6-methylheptane (0.67 g, 9%, 81% conv.) and, unidentified products (20 area %). Purification by preparative scale GC gave an isomeric mixture of l-fiuoro-2-methylhepatne (A) and 1 -fluoro-6-methylheptane (B) as a colourless liquid; (Found: C, 71.2; H, 12.5. C8H17F requires: C, 72.7; H, 13.0%); δF (376MHz) 218.38 (m, B), 222.65 (dt, 2 J HF 47.8, 3 JRF 18.8, A); 8H (400MHz) 0.80-1.00 (16.0 H, m, CH2 and/or CH3), 1.04-1.85 (27.0 H, m, CH2 and/or CH3), 4.26 (1.7 H, dm, JHF 48.0, CH2F-A), 4.44 (1.0 H, dm, 2 j HF 47.6, CH2F-B); δc(100MHz) 14.1 (s, CH3), 15.8 (s, CH3), 15.9 (s, CH3), 22.6 (s, CH2), 25.4 (d, JCF 5.4, CH2), 26.5 (s, CH2), 27.0 (s, CH2), 27.9 (s, CH-B), 30.4 (d, 2 JCF 19.5, C- 2-B), 32.0 (s, CH2), 32. 3 (d, 3 JcF 5.8, CH2), 34.0 (d, 2 J CF 18.1, CH-A), 38.8 (s, CH2), 84.3 (d, !JCF 164.7, CH2F-A), 88.3 (d, IJcF 168.9, CH2F); m/z (EI+) 132 (M+ 1%), 117(1), 97 (10), 83 (95). Example 9 - Fluorination of π-Decane By the same process as described above, /.-decane (1 1.08 g, 78 mmol), elemental fluorine (78 mmol) and anhydrous acetonitrile (140 cm 3 ) gave a brown crude product mixture (12.07 g) which contained decane (37 area %), 2-, 3-, 4- and 5-fluorodecane (4.80 g, 63%, 61% conv.) (37 area %) in the ratio of 1.0 : 1.1 : 1.2 : 2.6 not necessarily respectively, a trace amount of 1 -fluorodecane; δF(188 MHz) -217.56 (m) and, unidentified products (26 area %). Purification of the crude product by preparative scale GC gave an analytically pure sample of 2-, 3-, 4- and 5-fluorodecane as an isomeric mixture and as a colourless liquid (Found: C, 74.7; H, 13.4. C10H21F requires: C, 74.95; H, 13.2%);δF (376 MHz) -172.46 (m, JRF 19.2), -180.38 (m, JHF 17.3), -180.71 (m, JHF 17.2), -181.62 (m, JRF 18.8); δπ (400 MHz) 0.85-0.98 (4.5 H, m, CH2 and/or CH3), 1.24-1.70 (14.8 H, m, CH2 and/or CH3), 4.30-4.74 (1.0 H, m, CHF); δc(100 MHz) 9.4 (s, CH3), 9.4 (s, CH3), 13.9 (s, CH3), 14.0 (s, CH3), 14.1 (s, CH3), 18.4 (d, 3 JCF 4.6, CH 2 ), 21.0 (d, 2j CF 22.9, CH 3 ), 22.6 (s, CH 2 ), 22.7 (s, CH2), 24.8 (d, 3 JCF 4.6, CH 2 ). 25.2 (d, 3 J C F 5.0, CH 2 ), 25.6 (d, J F 5.0, CH 2 ), 27.3 (d, 3 JCF 4.6, CH2), 28.1 (d, J CF 21.3, CH2), 29.2 (d, 3j CF 2.6, CH2), 29.2 (s, CH2), 29.5 (d, 4j CF 1.2, CH ), 29.7 (s, CH 2 ), 31.7 (d, 3j CF 4.2, CH 2 ), 31.8 (d, 3j CF 4.1, CH ), 31.9 (s, CH 2 ), 34.7 (d, 2j CF 20.5, CH 2 ), 34.9 (d, 2j CF 20.9, CH 2 ), 35.1 (d, 2j CF 21.0, CH2), 35.2 (d, 2j CF 20.5, CH 2 ), 36.9 (d, 2j CF 20.6, CH 2 ), 37.3 (d, 2j CF 21.0, CH2), 91.1 (d, ΪJcF 164.1, CHF), 94.4 (d, !jCF 166.4, CHF), 94.6 (d, IjCF 166.4, CHF), 95.8 (d, cF 166.1, CHF); m/z (EI+) 140 (M+-HF, 1%), 111 (9), 97 (22) , all isomers gave a similar result. Example 10 - Fluorination of Methyl Valerate By the same process as described above, methyl valerate (5.12 g, 44 mmol), elemental fluorine (220 mmol) and anhydrous acetonitrile (140 cm.3) gave a brown crude product mixture (10.02 g) which contained methyl valerate (52 area %), methyl 3- and 4-fluorovalerate (0.90 g, 21%, 66% conv.) (21 area %) in the ratio of 1.0 : 3.2 respectively, unidentified products (27 area %) and tar (7%). Purification of the crude product by preparative scale GC gave an isomeric mixture of methyl 3- and 4- fluorovalerate as a colourless liquid; (Found: M++NH4, 152.1092. C6H11FO2 requires: M + +NH4, 152.1087 -methyl valerate (<3%) present in the purified sample-) ; methyl 4-fluorovalerate δF (376 MHz) -176.07 (m); δπ (400 MHz) 1.31 (3 H, d, 3 JRH 6.4, 5-H), 1.78-1.90 (2 H, m, 3-H), 2.40 (2 H, m, 2-H), 3.62 (3 H, s, OCH3), 4.62 (1 H, dm, 2 J HF 49.2, 4-H); δc(100 MHz) 20.8 (d, 2 JcF 22.6, C-5), 29.6 (d, JCF 4.5, C-2), 31.9 (d, 2 J CF 21.4, C-3), 51.6 (s, OCH3), 89.9 (d, IjcF 166.2, C-4), 173.5 (s, C-l); m/z (EI+) 114 (M+-HF, 8%), 103 (27), 83 (20), 74 (23); methyl 3- fluorovalerate δF (376 MHz) -181.30 (m); δH (400 MHz) 0.98 (3 H, t, 3 JRH 7.2, 5- H), 1.65 (2 H, m, 4-H), 2.63 (2 H, m, 2-H), 3.65 (3 H, s, OCH3), 4.81 (1 H, dm, 2 J HF 48.4, 4-H); δc(100 MHz) 9.0 (s, C-5), 27.8 (d, 2j CF 21.0, C-4), 39.8 (d, J CF 24.1, C-2), 51.8 (s, OCH3), 91.4 (d, cF 170.9, C-3), 174.3 (s, C-l); m/z (EI+) 1 14 (M+- HF, 8%), 103 (27), 83 (20), 74 (23). Example 11 - Fluorination of Methyl Enanthate By the same process as described above, methyl enanthate (4.37 g, 30 mmol), elemental fluorine (91 mmol) and anhydrous acetonitrile (140 cm 3 ) gave a brown crude product mixture (7.25 g) which contained methyl enanthate (34 area %), methyl 3-, 4-, 5- and 6-fluoroenanthate (2.14 g, 68%, 64% conv.) (42 area %) in the ratio of 1.0 : 3.5 : 6.4 : 5.6 respectively, a trace amount of methyl 7-fluoroenanthate; δF(188 MHz) -217.23 (m) and, unidentified products (24 area %). Purification of the crude product by preparative scale GC gave an isomeric mixture of methyl 3-, 4-, 5- and 6- fluoroenanthate as a colourless liquid; (Found: C, 59.1 ; H, 9.3. C8H15FO2 requires: C, 59.2; H, 9.3%); δF (376 MHz) -173.14 (m), -180.08 (m), -182.84 (m), -183.62 (m); δH (400 MHz) 0.80-1.00 (1 H, m, CH2 and/or CH3), 1.27-1.65 (7 H, m, CH2 and/or CH3), 2.30-2.38 (3 H, m, CH2 and/or CH3), 3.67-6.68 (3 H, m, OCH3), 4.25- 5.02 (1 H, m, CHF); δc(100 MHz) 9.6 (d, JcF 4.9, CH3), 14.1 (s, CH3), 14.2 (s, CH3), 18.5 (s, CH2), 18.6 (s, CH2), 20.9 (d, JcF 4.1, CH2), 21.2 (d, J CF 22.9, CH3), 24.9 (d, JCF 5.0, CH2), 27.2 (d, JcF 4.2, CH2), 28.5 (d, 2 J CF 22.6, CH2CHF), 29.9 (d, JcF 4.2, CH2), 30.5 (d, 2 J CF 21.4, CH2CHF), 33.9 (s, CH2), 34.2 (d, J CF 21.0, CH2CHF), 34.8 (d, 2j CF 20.2, CH2CHF), 36.8 (d, J CF 20.6, CH2CHF-A), 37.4 (d, 2 JCF 20.6, CH2CHF), 40.5 (d, 2 J CF 24.0, CH2CHF), 51.7 (s, OCH3), 51.8 (s, OCH3), 51.8 (s, OCH3), 51.9 (s, OCH3), 90.6 (d, Ϊ JCF 169.4, CHF), 91.0 (d, !JCF 164.5, CHF), 92.4 (d, ! j CF 167.9, CHF), 95.4 (d, IjCF 167.5, CHF), 173.9 (s, CO), 174.1 (s, CO), 174.3 (s, CO), 174.6 (s, CO); m/z (CI+ NH3) 180 (M+ + 18, 100%), all isomers gave a similar result. Example 12 - Fluorination of Dimethyl pimelate By the same process as described above, dimethyl pimelate (2.09 g, 11 mmol), elemental fluorine (78 mmol) and anhydrous acetonitrile (140 cm3) gave a yellow crude product mixture (6.51 g) which contained dimethyl pimelate (2 area %), dimethyl 3- and 4-fluoroρimelate (1.22 g, 54%, 98% conv.) (71 area %) in the ratio of 1.0 : 1.7 respectively and, unidentified products (27 area %). Purification of the mixture by column chromatography on silica gel using 4:1 petroleum ether-ethyl acetate as the eluent gave a sample of dimethyl 3 -fluoropimelate (A) and 4- fluoropimelate (B) as an isomeric mixture and as a colourless liquid; Rf 0.64 (Found C, 52.5; H, 7.5. C9H15FO4 requires: C, 52.4; H, 7.3%); δF (376 MHz) -187.99 (m, A), -192.22 (m, B); δH (400 MHz) 1.60-1.99 (3.4 H, m, CH2), 2.26-2.88 (6.6 H, m, CH2), 3.66 (3.0 H, s, CH3-A), 3.67 (6.0 H, s, CH3-B), 3.70 (3.0 H, s, CH3-A), 4.53 (1.0 H, dm, 2 JHF 49.6, CHF-B), 4.93 (1.0 H, dm, 2 J H F 48.0, CHF-A); δc(100 MHz) 20.6 (d, 3j CF 4.2, CH2-A), 29.8 (d, 3j CF 4.5, COCH2-B), 30.7 (d, 2j CF 21.0, CH2CΗF-B), 33.6 (s, CH2CO-A), 34.3 (d, 2 J CF 20.9, CΗFCH2-A), 40.5 (d, 2 J CF 24.0, COCH2-A), 51.8 (s, CΗ3-A), 51.9 (s, CH3-B), 52.2 (s, CH3-A), 90.1 (d, cF 170.2, CHF-A), 92.5 (d, UcF 169.0, CH2-B), 170.7 (d, 3j CF 6.1, CO-2-A), 173.6 (s, CO-B), 173.8 (s, CO-8-A); m/z (CI+, NH3) 224 (M+ + NH4, 100%), all isomers gave a similar result. Example 13 - Fluorination of 1 -Chlorohexane By the same process as described above, 1 -chlorohexane (8.36 g, 69 mmol), elemental fluorine (208 mmol) and anhydrous acetonitrile (140 cm ) gave a dark yellow crude product mixture (9.02 g) which contained 1 -chlorohexane (54 area %) l-chloro-3-, 4- and 5-fluorohexane (1.51 g, 22%, 72% conv.) (30 area %) in the ratio of 1.0 : 1.8 : 1.9 respectively, a small amount of l-chloro-6-fluorohexane; δF(188 MHz) -217.49 (m), a large number of other unidentified products (16 area %) and tar (10%). Purification of the crude product by preparative scale GC gave an analytically pure sample of 1- chloro-5-fluorohexane and 1 -chloro-4-fluorohexane as an isomeric mixture and as a colourless liquid (Found: C, 51.8; H, 8.7. C6H12CIF requires: C, 52.0; H, 8.7%); δF (376 MHz) -173.29 (m, l-chloro-5-fluorohexane), -182.64 (m, l-chloro-4- fluorohexane); δH (400 MHz) 0.90-1.00 (4.7 H, m, CH2 and/or CH3), 1.29-2.10 (37.6 H, m, CH2 and/or CH3), 3.55 (11.4 H, m, CH2CI), 4.42 (1 H, dm, 2 J HF 49.5, CHF-1- chloro-4-fluorohexane), 4.68 (3.7 H, dm, 2 JHF 48.5, CHF-l-chloro-5-fluorohexane); l-chloro-5-fluorohexane δc(100 MHz) 21.0 (d, 2 J CF 20.9, C-6), 22.5 (d, 3 J CF 5.0, C-3), 32.3 (s, C-2), 36.1 (d, 2 J CF 21.0, C-4), 44.8 (s, C-l), 90.7 (d, cF 164.4, C-5); m/z (EI + ) no indicative peaks observed; 1 -chloro-4-fluorohexane δc(100 MHz) 9.3 (d, 3j CF 6.4, C-6), 28.1 (d, J CF 21.0, C-3 or C-5), 28.3 (d, 3 J CF 3.8, C-2), 32.0 (d, 2j C F 21.3, C-3 or C-5), 44.9 (s, C-l), 94.9 (d, !jCF 168.3, C-4); m/z (EI+) no indicative peaks observed.

Claims: Claims 1. A method of selectively fluorinating a carbon-hydrogen bond at an unactivated saturated sp hybridised carbon atom of an organic compound, the method including reacting the organic compound with elemental fluorine gas, characterised in that the reaction is carried out in the presence of a basic compound. 2. A method as in claim 1 wherein the basic compound contains a functional group having a lone pair of electrons. 3. A method as in claim 1 or 2 wherein the basic compound lacks any substantially acidic hydrogen atoms. 4. A method as in any of claims 1 to 3 wherein the basic compound contains a functional group selected from the group consisting of nitrile, ether, tertiary amine, nitro where the compound is Cj and amide where the compound is C[. 5. A method as in claim 4 wherein the basic compound is selected from the group consisting of acetonitrile, propanenitrile, diethyl ether, tetrahydrofuran, dimethylformamide and nitromethane. 6. A method as in any of claims 1 to 5 wherein the basic compound acts as a solvent for the compound. 7. A method as in any of claims 1 to 6 wherein the organic compound has a structure 1, 9, 10, 11, 12, 13 or 14 and the reaction involves converting the compound into the corresponding fluorinated compound 2, 3, 4, 5, 6, 7, 8 as follows: 10 11 14 wherein the groups R , R 3 , R 4 , R 5 , R 6 and R may be independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl and substituted aryl including those groups optionally containing hetero-atoms and n is an integer in the inclusive range from 1 to 8. 8. A method as in any of claims 1 to 7 wherein the reaction is carried out in a temperature range -60°C to +150°C. 9. A method as in claim 8 wherein the reaction is carried out in a temperature range from about 0°C to about +30°C. 10. A method as in any of claims 1 to 9 wherein the molar ratio of fluorine gas to organic compound is in the range 0.5 to 10 : 1. 11. A method of selectively fluorinating a carbon-hydrogen bond at an unactivated saturated sp 3 hybridised carbon atom of an organic compound substantially as herein described with reference to the Examples.

Inventors: CHAMBERS RICHARD DICKINSON, PARSONS MANDY, SANDFORD GRAHAM, CHAMBERS, RICHARD, DICKINSON
Applicants: CHAMBERS RICHARD DICKINSON, F2 CHEMICALS LTD, PARSONS MANDY, SANDFORD GRAHAM, CHAMBERS, RICHARD, DICKINSON, F2 CHEMICALS LTD.
Application year: 2000
Main classification: C07B39
IPC codes: C07B39, C07C17, C07C19, C07C23, C07C67, C07C69