Direct fluorination process for preparing high purity alpha-fluoro-beta-dicarbonyl compounds

Abstract: β-Dicarbonyls are directly fluorinated with fluorine in the presence of a radical scavenger, preferably oxygen, to form the corresponding α-fluorinated-β-dicarbonyl compounds. The process has particular application to β-diketones and β-ketoesters having the formula: where R 1 is H, alkyl or alkoxy, R 2 is H, alkyl or perfluoroalkyl, and R 3 is H, Cl, Br, I or alkyl. Typically, the product is 90-96% pure and contains radical fluorination impurity levels which are 10-20% lower than when a radical scavenger is not used.

Description: This invention relates to processes for fluorinating β-dicarbonyls to form the corresponding α-fluorinated-β-dicarbonyl compounds. Previously, β-dicarbonyls, such as β-diketones and β-ketoesters having the formula: where R 1 is H, alkyl or alkoxy, R 2 is H, alkyl or perfluoroalkyl, and R 3 is H, Cl, Br, I or alkyl, have been fluorinated directly with fluorine in acidic solvents or in polar solvents containing acidic, or weakly basic, polar additives. See, e.g., US-A-5,569,778 (Umemoto et al.) and WO-A-95/14646 (Chambers et al.). This technology has proven reasonably selective for those diketones and ketoesters which are stabilised in the enol form under the chosen solvent conditions. Even with substrate loadings of only 5-10 wt.%, however, the desired monofluorinated products still contain 10-15% radical fluorination impurities (the term "radical fluorination impurities" refers to products resulting from fluorination at R 1 and/or R 2 in Formula I above). EP-A-0891962 (Nukui et al.) discloses a process for preparing fluorinated dicarbonyl compounds comprising reacting dicarbonyl compounds and fluorine gas without any solvent and in the presence of at least one acid selected from trifluoromethanesulphonic acid (i.e., triflic acid), methanesulphonic acid, hydrofluoric acid, sulphuric acid, trifluoroacetic acid, boron trifluoride and sulphonated polymers. Nukui et al. discloses in Example 1 that methyl-3-oxopentanoate can be fluorinated in the absence of solvent with triflic acid as an additive, to give only 16% fluorination impurities, including 2,2-difluorinated impurity. The yield was reported to be high only when 2.5 equivalents of fluorine were added. US-A-4036864 (Barton et al) discloses a process for the electrophilic fluorination of a saturated organic compound containing a hydrogen atom bound to a tertiary carbon atom which comprises reacting together the organic compound with an electrophilic fluorinating agent (such as molecular fluorine) substantially homogeneously dispersed in a liquid medium in the presence of a free radical inhibitor (such as oxygen, e.g. in the presence of air). Examples are restricted to the mono-fluorination of adamantane and derivatives thereof and of steroid derivatives. Ketoesters containing perfluoroalkyl groups are only effectively fluorinated in nonpolar solvents. Under these conditions, 30% radical fluorination is observed. For all of the dicarbonyl substrates, fluorinated impurities are often difficult to separate and many of them are carried forward in subsequent chemical steps. A further problem in direct fluorinations using formic acid, trifluoroacetic acid and/or triflic acid, has been that fluorine use has been inefficient. Between 1.6 and 4 times the stoichiometric amount of fluorine has been required to obtain high conversions with these acid additives. Accordingly, it is desired to directly fluorinate β-dicarbonyl compounds by a process that does not suffer from the foregoing deficiencies in the art. The present invention provides a process for providing an α-fluorinated-β-dicarbonyl compound by directly fluorinating a β-dicarbonyl compound with fluorine, wherein the direct fluorination is conducted in a medium comprising oxygen. The oxygen is a radical scavenger that inhibits side reactions between fluorine and acid additives. Preferably dilute oxygen is used as a radical scavenger for the direct fluorination of β-dicarbonyl compounds, as shown in the following reaction scheme I: where R 1 is H, alkyl or alkoxy, R 2 is H, alkyl or perfluoroalkyl, and R 3 is H, Cl, Br, I or alkyl. The products of the inventive process (e.g., 2-ftuoro-1,3-dicarbonyls) are important precursors to fluorinated heterocycles used in the pharmaceutical industry. Conventional processes of direct fluorination typically provide fluorinated carbonyl products which are only 75-85% pure and contaminated with radical fluorination byproducts, which are difficult to separate. Use of oxygen in the fluorine stream can slightly lower the overall isolated yield, but after washing with water, yields a product which is 90-96% pure and containing radical fluorination impurity levels which are 5-20% lower than when oxygen is not used. Use of oxygen in the fluorine stream inhibits side reactions between fluorine and acid additives used in direct fluorination (e.g., using formic acid, trifluoroacetic acid, and/or triflic acid) so that less fluorine is required to give high substrate conversion. In embodiments of the inventive process, F 2 /N 2 mixtures are diluted with air to give dilute F 2 /O 2 /N 2 mixtures, which are sparged into solutions of the substrate in an acidic solvent, preferably anhydrous hydrofluoric acid, trifluoroacetic acid, formic acid or triflic acid (for ketoesters where R 2 is perfluoroalkyl, the solvent usually is CFCl 3 ). The gas mixture can suitably comprise 1 to 50% F 2 , 0.1% % to 50% O 2 and 0 to 99% N 2 , preferably 5 to 25% F 2 , 1 to 25% O 2 and 50 to 95% N 2 , more preferably 10 to 20% F 2 , 10 to 20% O 2 and 60 to 80% N 2 . At high conversions, less than 5% radical fluorination byproducts are observed. The amount of fluorine present in the reaction can be less than 2.5 equivalents of fluorine per equivalent of the β-dicarbonyl compound. The process of the invention proceeds satisfactorily when the amount of fluorine is less than 1.6 equivalents, or even less than 1.3 equivalents, per equivalent of said β-dicarbonyl compound. Surprisingly, when oxygen is added during the fluorination, ketoesters where R 2 is perfluoroalkyl can be fluorinated selectively without a solvent. When fluorinated neat in the absence of oxygen, these compounds char, giving only a small amount of the desired product. The process, therefore, offers the advantage of significantly higher product purity obtained at much higher reaction loadings. The invention will be illustrated in more detail with reference to the following Examples, but it should be understood that the present invention is not deemed to be limited thereto. Example 1 Methyl-3-oxopentanoate was fluorinated in neat HF using 10%F 2 /10%O 2 /80%N 2 in accordance with the following procedure. A 300 mL Parr reactor was charged with 55.1 g (424 mmol) methyl-3-oxo-pentanoate. The reactor was externally cooled to about -35°C and 150 mL anhydrous HF were condensed in under static vacuum. This corresponds to a substrate loading of 27 wt.%. About 1.04 equivalents (442 mmol) of F 2 were sparged as a 10%F 2 /10%O 2 /80%N 2 stream into the reactor at -30°C at 800 mL/min, allowing the effluent to pass through a soda-lime scrubber. After addition of F 2 , HF solvent was evacuated through a soda-lime scrubber. The reactor was then opened and 100 mL H 2 O were added. The mixture was then neutralised with NaHCO 3 . The product was extracted with ether. Analysis of the product by 1 H and 19 F NMR showed 100% conversion. The isolated yield was 81 wt.% of 92% pure methyl-2-fluoro-3-oxopentanoate. Radical fluorination impurities in the isolated product totalled 5%. Example 2 Methyl-3-oxopentanoate was fluorinated in neat HF using 20%F 2 /20%O 2 /60%N 2 in accordance with the following procedure. A 2 L Parr reactor was charged with 325 g (2.50 mol) methyl-3-oxo-pentanoate. The reactor was externally cooled to about -50°C and 1.150 L anhydrous HF were condensed in under static vacuum. This corresponds to a substrate loading of 22 wt.%. About 1.1 equivalents (2.75 mol) of F 2 were sparged as a 20%F 2 /20%O 2 /60%N 2 stream into the reactor at -30°C at 800 mL/min, allowing the effluent to pass through a soda-lime scrubber. After addition of F 2 , HF solvent was evacuated through a soda-lime scrubber. The reactor was then opened and 500 mL H 2 O were added. The mixture was then neutralised with NaHCO 3 . The product was extracted with ether. Analysis of the product by 1 H and 19 F NMR showed 100% conversion. The isolated yield was 90 wt.% of 94% pure methyl-2-fluoro-3-oxopentanoate. Radical fluorination impurities in the isolated product totalled 4%. Example 3 Methyl-3-oxopentanoate was fluorinated in neat HF using 10%F 2 /40%O 2 /50%N 2 in accordance with the following procedure. A 300 mL Parr reactor was charged with 54.3 g (418 mmol) methyl-3-oxo-pentanoate. The reactor was externally cooled to about -35°C and 155 mL anhydrous HF were condensed in under static vacuum. This corresponds to a substrate loading of 26 wt.%. About 1.07 equivalents (449 mmol) of F 2 were sparged as a 10%F 2 /40%O 2 /50%N 2 stream into the reactor at -30°C at 800 mL/min, allowing the effluent to pass through a soda-lime scrubber. After addition of F 2 , HF solvent was evacuated through a soda-lime scrubber. The reactor was then opened and 100 mL H 2 O were added. The mixture was then neutralised with NaHCO 3 . The product was extracted with ether. Analysis of the product by 1 H and 19 F NMR showed 100% conversion. The isolated yield was 78 wt.% of 93% pure methyl-2-fluoro-3-oxopentanoate. Radical fluorination impurities in the isolated product totalled 5%. Example 4 (Comparative Example) Methyl-3-oxopentanoate was fluorinated in neat HF using 10%F 2 /90%N 2 in accordance with the following comparative example. A 300 mL Parr reactor was charged with 59.5 g (458 mmol) methyl-3-oxo-pentanoate. The reactor was externally cooled to about -35°C and 155 mL anhydrous HF were condensed in under static vacuum. This corresponds to a substrate loading of 28 wt.%. About 1.06 equivalents (484 mmol) of F 2 were sparged as a 10%F 2 /90%N 2 stream into the reactor at -30°C at 800 mL/min, allowing the effluent to pass through a soda-lime scrubber. After addition of F 2 , HF solvent was evacuated through a soda-lime scrubber. The reactor was then opened and 100 mL H 2 O were added. The mixture was then neutralised with NaHCO 3 . The product was extracted with ether. Analysis of the product by 1 H and 19 F NMR showed 99% conversion. The isolated yield was 91 wt.% of 81% pure methyl-2-fluoro-3-oxopentanoate. Radical fluorination impurities in the isolated product totalled 15%. Example 5 (Comparative Example) Methyl-3-oxopentanoate was fluorinated in neat HF using 10%F 2 /90%N 2 in accordance with the following comparative example. A 60 mL Parr reactor was charged with 5.17 g (39.8 mmol) methyl3-oxo-pentanoate. The reactor was externally cooled to about -35°C and 20 mL anhydrous HF were condensed in under static vacuum. This corresponds to a substrate loading of 20 wt.%. About 1.11 equivalents (484 mmol) of F 2 were sparged as a 10%F 2 /90%N 2 stream into the reactor at -30°C at 200 mL/min, allowing the effluent to pass through a soda-lime scrubber. After addition of F 2 , HF solvent was evacuated through a soda-lime scrubber. The reactor was then opened and 100 mL H 2 O were added. The mixture was then neutralised with NaHCO 3 . The product was extracted with ether. Analysis of the product by 1 H and 19 F NMR showed 96% conversion. The isolated yield was 87 wt.% of 86% pure methyl-2-fluoro-3-oxopentanoate. Radical fluorination impurities in the isolated product totalled 9.4%. Example 6 Methyl-3-oxopentanoate was fluorinated in neat HF using 10%F 2 /1%O 2 /89%N 2 in accordance with the following procedure. A 60 mL FEP reactor was charged with 4.64 g (35.6 mmol) methyl-3-oxo-pentanoate. The reactor was externally cooled to about -50°C and 20 mL anhydrous HF were condensed in under static vacuum. This corresponds to a substrate loading of 19 wt.%. About 1.13 equivalents (40.2 mmol) of F 2 were sparged as a 10%F 2 /1%O 2 /89%N 2 stream into the reactor at -30°C at 200 mL/min, allowing the effluent to pass through a soda-lime scrubber. After addition of F 2 , HF solvent was evacuated through a soda-lime scrubber. The reactor was then opened and 30 mL H 2 O were added. The mixture was then neutralised with NaHCO 3 . The product was extracted with ether. Analysis of the product by 1 H and 19 F NMR showed 100% conversion. The isolated yield was 80 wt.% of 95% pure methyl-2-fluoro-3-oxopentanoate. Radical fluorination impurities in the isolated product totalled 3%. Example 7 Methyl-3-oxopentanoate was fluorinated in neat HF using 10%F 2 /0.1%O 2 /89.9%N 2 in accordance with the following procedure. A 60 mL FEP reactor was charged with 4.08 g (31.4 mmol) methyl-3-oxo-pentanoate. The reactor was externally cooled to about -50°C and 20 mL anhydrous HF were condensed in under static vacuum. This corresponds to a substrate loading of 17 wt.%. About 1.13 equivalents (40.2 mmol) of F 2 were sparged as a 10%F 2 /0.1%O 2 /89.9%N 2 stream into the reactor at -30°C at 200 mL/min, allowing the effluent to pass through a soda-lime scrubber. After addition of F 2 , HF solvent was evacuated through a soda-lime scrubber. The reactor was then opened and 30 mL H 2 O were added. The mixture was then neutralised with NaHCO 3 . The product was extracted with ether. Analysis of the product by 1 H and 19 F NMR showed 100% conversion. The isolated yield was 80 wt.% of 95% pure methyl-2-fluoro-3-oxopentanoate. Radical fluorination impurities in the isolated product totalled 3%. Example 8 Methyl-3-oxopentanoate was fluorinated in neat HF using 10%F 2 /10%O 2 /80%N 2 in accordance with the following procedure. A 100 mL FEP reactor was charged with 25.6 g (197 mmol) methyl-3-oxo-pentanoate. The reactor was externally cooled to about -50°C and 42 mL anhydrous HF were condensed in under static vacuum. This corresponds to a substrate loading of 38 wt.%. About 1.10 equivalents (217 mmol) of F 2 were sparged as a 10%F 2 /10%O 2 /80%N 2 stream into the reactor at -30°C at 300 mL/min, allowing the effluent to pass through a soda-lime scrubber. After addition of F 2 , HF solvent was evacuated through a soda-lime scrubber. The reactor was then opened and 30 mL H 2 O were added. The mixture was then neutralised with NaHCO 3 . The product was extracted with ether. Analysis of the product by 1 H and 19 F NMR showed 100% conversion. The isolated yield was 80 wt.% of 85% pure methyl-2-fluoro-3-oxopentanoate. Radical fluorination impurities in the isolated product totalled 11%. Example 9 Methyl-3-oxopentanoate was fluorinated in neat HF using 10%F 2 /10%O 2 /80%N 2 in accordance with the following procedure. A 100 mL FEP reactor was charged with 15.3 g (118 mmol) methyl-3-oxo-pentanoate. The reactor was externally cooled to about -50°C and 23 mL anhydrous HF were condensed in under static vacuum. This corresponds to a substrate loading of 40 wt.%. About 1.02 equivalents (120 mmol) of F 2 were sparged as a 10%F 2 /10%O 2 /80%N 2 stream into the reactor at -45°C at 300 mL/min, allowing the effluent to pass through a soda-lime scrubber. After addition of F 2 , HF solvent was evacuated through a soda-lime scrubber. The reactor was then opened and 30 mL H 2 O were added. The mixture was then neutralised with NaHCO 3 . The product was extracted with ether. Analysis of the product by 1 H and 19 F NMR showed 96% conversion. The isolated yield was 87 wt.% of 90% pure methyl-2-fluoro-3-oxopentanoate. Radical fluorination impurities in the isolated product totalled 6%. Example 10 Methyl-3-oxopentanoate was fluorinated in trifluoroacetic acid (TFA) using 10%F 2 /10%O 2 /80%N 2 in accordance with the following procedure. A 100 mL FEP reactor was charged with 5.2 g (40 mmol) methyl-3-oxo-pentanoate and 29 g TFA. This corresponds to a substrate loading of 18 wt.%. About 1.2 equivalents (48 mmol) of F 2 were sparged as a 10%F 2 /10%O 2 /80%N 2 stream into the reactor at -15°C at 300 mL/min, allowing the effluent to pass through a soda-lime scrubber. After addition of F 2 , TFA solvent was evacuated through a soda-lime scrubber. The reactor was then opened and 30 mL H 2 O were added. The mixture was then neutralised with NaHCO 3 . The product was extracted with ether. Analysis of the product by 1 H and 19 F NMR showed 95% conversion. The isolated product was 84% pure methyl-2-fluoro-3-oxopentanoate. Radical fluorination impurities in the isolated product totalled 7%. Example 11 (Comparative Example) Methyl-3-oxopentanoate was fluorinated in TFA using 10%F 2 /90%N 2 in accordance with the following comparative example. A 100 mL FEP reactor was charged with 5.2 g (40 mmol) methyl-3-oxo-pentanoate and 26 g TFA. This corresponds to a substrate loading of 20 wt.%. About 1.5 equivalents (60 mmol) of F 2 were sparged as a 10%F 2 /90%N 2 stream into the reactor at -20°C at 300 mL/min, allowing the effluent to pass through a soda-lime scrubber. After addition of F 2 , TFA solvent was evacuated through a soda-lime scrubber. The reactor was then opened and 30 mL H 2 O were added. The mixture was then neutralised with NaHCO 3 . The product was extracted with ether. Analysis of the product by 1 H and 19 F NMR showed 85% conversion. The isolated product was 60% pure methyl-2-fluoro-3-oxopentanoate. Radical fluorination impurities in the isolated product totalled 12%. Example 12 Methyl-3-oxopentanoate was fluorinated in formic acid using 10%F 2 /10%O 2 /80%N 2 in accordance with the following procedure. A 100 mL FEP reactor was charged with 7.2 g (55 mmol) methyl-3-oxo-pentanoate and 26 g formic acid. This corresponds to a substrate loading of 22 wt.%. About 1.06 equivalents (59 mmol) of F 2 were sparged as a 10%F 2 /10%O 2 /80%N 2 stream into the reactor at 5°C at 300 mL/min, allowing the effluent to pass through a soda-lime scrubber. After addition of F 2 , the reactor was opened and 30 mL H 2 O were added. The mixture was then neutralised with NaHCO 3 . The product was extracted with ether. Analysis of the product by 1 H and 19 F NMR showed 98% conversion. The isolated product was 75% of 88% pure methyl-2-fluoro-3-oxopentanoate. Radical fluorination impurities in the isolated product totalled 7%. Example 13 (Comparative Example) Methyl-3-oxopentanoate was fluorinated in formic acid using 10%F 2 /90%N 2 in accordance with the following comparative example. A 100 mL FEP reactor was charged with 7.0 g (54 mmol) methyl-3-oxo-pentanoate and 25 g formic acid. This corresponds to a substrate loading of 22 wt.%. About 1.04 equivalents (56 mmol) of F 2 were sparged as a 10%F 2 /90%N 2 stream into the reactor at 5°C at 300 mL/min, allowing the effluent to pass through a soda-lime scrubber. After addition of F 2 , the reactor was opened and 30 mL H 2 O were added. The mixture was then neutralised with NaHCO 3 . The product was extracted with ether. Analysis of the product by 1 H and 19 F NMR showed 69% conversion. The isolated product was 77% of 55% pure methyl-2-fluoro-3-oxopentanoate. Radical fluorination impurities in the isolated product totalled 8%. Example 14 Methyl-3-oxopentanoate was fluorinated in triflic acid using 10%F 2 /10%O 2 /80%N 2 in accordance with the following procedure. A 60 mL FEP reactor was charged with 8.27 g (63.6 mmol) methyl-3-oxo-pentanoate and 1.08 g triflic acid. This corresponds to a substrate loading of 88 wt.%. About 1.21 equivalents (77 mmol) of F 2 were sparged as a 10%F 2 /10%O 2 /80%N 2 stream into the reactor at 0°C at 100 mL/min, allowing the effluent to pass through a soda-lime scrubber. After addition of F 2 , triflic acid solvent was evacuated through a soda-lime scrubber. The reactor was then opened and 30 mL H 2 O were added. The mixture was then neutralised with NaHCO 3 . The product was extracted with ether. Analysis of the product by 1 H and 19 F NMR showed 86% conversion. The isolated product was 72% pure methyl-2-fluoro-3-oxopentanoate. Radical fluorination impurities in the isolated product totalled 13%. Example 15 Ethyl acetoacetate was fluorinated in HF using 10%F 2 /10%O 2 /80%N 2 in accordance with the following procedure. A 100 mL FEP reactor was charged with ethyl acetoacetate (80 mmol). The reactor was externally cooled to about -50°C and 40 mL anhydrous HF were condensed in under static vacuum. This corresponds to a substrate loading of 20 wt.%. About 1.1 equivalents of F 2 were sparged as a 10%F 2 /10%O 2 /80%N 2 stream into the reactor at -30°C at 300 mL/min, allowing the effluent to pass through a soda-lime scrubber. After addition of F 2 , HF solvent was evacuated through a soda-lime scrubber. The reactor was then opened and 30 mL H 2 O were added. The mixture was then neutralised with NaHCO 3 . The product was extracted with ether. Analysis of the product by 1 H and 19 F NMR showed 96% conversion. The isolated product was 91% pure ethyl-2-fluoroacetoacetate. Radical fluorination impurities in the isolated product totalled 4%. Example 16 (Comparative Example) Ethyl acetoacetate was fluorinated in HF using 10%F 2 /90%N 2 in accordance with the following comparative example. A 60 mL FEP reactor was charged with ethyl acetoacetate (40 mmol). The reactor was externally cooled to about -50°C and 20 mL anhydrous HF were condensed in under static vacuum. This corresponds to a substrate loading of 20 wt.%. About 1.1 equivalents of F 2 were sparged as a 10%F 2 /90%N 2 stream into the reactor at -30°C at 300 mL/min, allowing the effluent to pass through a soda-lime scrubber. After addition of F 2 , HF solvent was evacuated through a soda-lime scrubber. The reactor was then opened and 30 mL H 2 O were added. The mixture was then neutralised with NaHCO 3 . The product was extracted with ether. Analysis of the product by 1 H and 19 F NMR showed 90% conversion. The isolated product was 73% pure ethyl-2-fluoroacetoacetate. Radical fluorination impurities in the isolated product totalled 16%. Example 17 2,4-pentanedione was fluorinated in HF using 10%F 2 /10%O 2 /80%N 2 in accordance with the following procedure. A 60 mL FEP reactor was charged with 2,4-pentanedione (25 mmol). The reactor was externally cooled to about -50°C and 15 mL anhydrous HF were condensed in under static vacuum. This corresponds to a substrate loading of 20 wt.%. About 1.1 equivalents of F 2 were sparged as a 10%F 2 /10%O 2 /80%N 2 stream into the reactor at -65°C at 300 mUmin, allowing the effluent to pass through a soda-lime scrubber. After addition of F 2 , HF solvent was evacuated through a soda-lime scrubber. The reactor was then opened and 30 mL H 2 O were added. The mixture was then neutralised with NaHCO 3 . The product was extracted with ether. Analysis of the product by 1 H and 19 F NMR showed 98% conversion. The isolated product was 95% pure 3-fluoro-2,4-pentanedione. Radical fluorination impurities in the isolated product totalled 3%. Example 18 (Comparative Example) 2,4-pentanedione was fluorinated in HF using 10%F 2 /90%N 2 in accordance with the following comparative example. A 60 mL FEP reactor was charged with 2,4-pentanedione (25 mmol). The reactor was externally cooled to about -50°C and 15 mL anhydrous HF were condensed in under static vacuum. This corresponds to a substrate loading of 20 wt.%. About 1.1 equivalents of F 2 were sparged as a 10%F 2 /90%N 2 stream into the reactor at -65°C at 300 mL/min, allowing the effluent to pass through a soda-lime scrubber. After addition of F 2 , HF solvent was evacuated through a soda-lime scrubber. The reactor was then opened and 30 mL H 2 O were added. The mixture was then neutralised with NaHCO 3 . The product was extracted with ether. Analysis of the product by 1 H and 19 F NMR showed 96% conversion. The isolated product was 93% pure 3-fluoro-2,4-pentanedione. Radical fluorination impurities in the isolated product totalled 3%. Example 19 Ethyl-4,4,4,-trifluoroacetoacetate was fluorinated in CFCl 3 using 10%F 2 /10%O 2 /80%N 2 in accordance with the following procedure. A 60 mL FEP reactor was charged with ethyl-4,4,4,-trifluoroacetoacetate (20 mmol) and 15 g CFCl 3 . This corresponds to a substrate loading of 15 wt.%. About 1.0 equivalent of F 2 was sparged as a 10%F 2 /10%O 2 /80%N 2 stream into the reactor at -25°C at 300 mL/min, allowing the effluent to pass through a soda-lime scrubber. After addition of F 2 , CFCl 3 solvent was evacuated through a soda-lime scrubber. The reactor was then opened and 30 mL H 2 O were added. The mixture was then neutralised with NaHCO 3 . The product was extracted with ether. Analysis of the product by 1 H and 19 F NMR showed 85% conversion. The isolated product was 80% pure ethyl-2,4,4,4,-tetrafluoroacetoacetate. Radical fluorination impurities in the isolated product totalled 3%. Example 20 (Comparative Example) Ethyl-4,4,4,-trifluoroacetoacetate was fluorinated in CFCl 3 using 10%F 2 /90%N 2 in accordance with the following comparative example. A 60 mL FEP reactor was charged with ethyl-4,4,4,-trifluoroacetoacetate (20 mmol) and 15 g CFCl 3 . This corresponds to a substrate loading of 15 wt.%. About 1.0 equivalent of F 2 was sparged as a 10%F 2 /90%N 2 stream into the reactor at -25°C at 300 mL/min, allowing the effluent to pass through a soda-lime scrubber. After addition of F 2 , CFCl 3 solvent was evacuated through a soda-lime scrubber. The reactor was then opened and 30 mL H 2 O were added. The mixture was then neutralised with NaHCO 3 . The product was extracted with ether. Analysis of the product by 1 H and 19 F NMR showed 80% conversion. The isolated product was 45% pure ethyl-2,4,4,4,-tetrafluoroacetoacetate. Radical fluorination impurities in the isolated product totalled 30%. Example 21 Ethyl-4,4,4,-trifluoroacetoacetate was fluorinated using 2%F 2 /18%O 2 /80%N 2 in accordance with the following procedure. A 60 mL FEP reactor was charged with ethyl-4,4,4,-trifluoroacetoacetate (20 mmol). About 1.0 equivalent of F 2 was sparged as a 2%F 2 /18%O 2 /80%N 2 stream into the reactor at -30°C at 300 mL/min, allowing the effluent to pass through a soda-lime scrubber. The reactor was then opened and 30 mL H 2 O were added. The mixture was then neutralised with NaHCO 3 . The product was extracted with ether. Analysis of the product by 1 H and 19 F NMR showed 75% conversion. The isolated product was 65% pure ethyl-2,4,4,4,-tetrafluoroacetoacetate. Radical fluorination impurities in the isolated product totalled 5%. Example 22 (Comparative Example) Ethyl-4,4,4,-trifluoroacetoacetate was fluorinated using 2%F 2 /98%N 2 in accordance with the following comparative example. A 60 mL FEP reactor was charged with ethyl-4,4,4,-trifluoroacetoacetate (20 mmol). About 1.0 equivalent of F 2 was sparged as a 2%F 2 /98%N 2 stream into the reactor at -40°C at 300 mL/min, allowing the effluent to pass through a soda-lime scrubber. The reactor was then opened and 30 mL H 2 O were added. The mixture was then neutralised with NaHCO 3 . The product was extracted with ether. Analysis of the product by 1 H and 19 F NMR showed 80% conversion. The isolated product was less than 5% pure ethyl-2,4,4,4,-tetrafluoroacetoacetate. Radical fluorination impurities in the isolated product totalled 80%. The results from the foregoing Examples are summarised in the following table (along with an example from Nukui et al.): While the invention has been described in detail and with reference to specific examples thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the scope thereof as defined in the following claims.

Claims: A process for providing an α-fluorinated-β-dicarbonyl compound, said process comprising directly fluorinating a β-dicarbonyl compound with fluorine to provide said α-fluorinated-β-dicarbonyl compound, wherein said direct fluorination is conducted in a medium comprising oxygen. A process as claimed in Claim 1, wherein said oxygen is a radical scavenger that inhibits side reactions between fluorine and acid additives. A process as claimed in Claim 1 or Claim 2, wherein said process further comprises contacting said β-dicarbonyl compound with a gas mixture comprising 1 to 50% F 2 , 0.1 to 50% O 2 and 0 to 99% N 2 . A process as claimed in Claim 3, wherein said gas mixture comprises 5 to 25% F2, 1 to 25% O 2 and 50 to 95% N 2 . A process as claimed in Claim 4, wherein said gas mixture comprises 10 to 20% F 2 , 10 to 20% O 2 and 60 to 80% N 2 . A process as claimed in any one of the preceding claims , wherein the fluorination is conducted in an acidic solvent or a polar solvent containing acidic polar additives. A process as claimed in any one of Claims 1 to 5, wherein an oxygen-containing gas is sparged into a solution of the β-dicarbonyl compound in an acidic solvent selected from anhydrous hydrofluoric acid, trifluoroacetic acid, formic acid, triflic acid and, when the β-dicarbonyl compound is a ketoesters containing a perfluoroalkyl moiety, trichlorofluoromethane. A process as claimed in any one of Claims 1 to 5, wherein the β-dicarbonyl compound is a ketoester containing a perfluoroalkyl group, and the process is conducted without a solvent or acid additive. A process as claimed in any one of the preceding claims, wherein less than 2.5 equivalents of fluorine are present per equivalent of said β-dicarbonyl compound. A process as claimed in Claim 9, wherein less than 1.6 equivalents of fluorine are present per equivalent of said β-dicarbonyl compound. A process as claimed in Claim 10, wherein less than 1.3 equivalents of fluorine are present per equivalent of said β-dicarbonyl compound. A process as claimed in any one of the preceding claims, wherein the β-dicarbonyl compound is selected from β-diketones and β-ketoesters. A process as claimed in Claim 12, wherein a 1,3-diketone is fluorinated to a 2-fluoro-1,3-diketone. A process as claimed in any one of the preceding claims, wherein the β-dicarbonyl compound is of the formula: where R 1 is H, alkyl or alkoxy, R 2 is H, alkyl or perfluoroalkyl, and R 3 is H, Cl, Br, I or alkyl. A process as claimed in Claim 14, wherein R 3 is H, Cl, Br or I. A process as claimed in Claim 15 wherein R 3 is H. A process as daimed in any one of Claims 14 to 16, wherein said β-dicarbonyl compound is other than methyt-3-oxopentanoate. The use of oxygen as a radical scavenger in the direct fluorination of a β-dicarbonyl compound with fluorine to provide an α-fluorinated-β-dicarbonyl compound. A use as claimed in Claim 18, wherein the fluorination is as defined in any one of Claims 1 to 17.

Inventors: BAILEY WADE H III, CASTEEL WILLIAM JACK JR, BAILEY, WADE H., III, CASTEEL, WILLIAM JACK, JR.
Applicants: AIR PROD & CHEM, AIR PRODUCTS AND CHEMICALS, INC.
Application year: 2000
Main classification: C07C45
IPC codes: C07C69, C07C49, C07C45, C07C67