Fluorination of dicarbonyl compounds

#The present application is a 35 U.S.C. § 371 National Phase Application of International Application Serial No. PCT/GB03/00761, filed Feb. 19, 2003 and published in English as PCT Publication No. WO 03/070677 on Aug. 28, 2003, which claims priority to Great Britain Patent Application Serial No. 0203953.5, filed Feb. 20, 2002, the disclosures of each of which are incorporated herein by reference in their entireties.

#The present invention relates to the preparation of dicarbonyls, in particular dicarbonyl compounds which are 2-fluoro- and 2,2-difluoro-1,3-diketones and -ketoesters.

#The use of elemental fluorine for the site specific fluorination of aliphatic compounds is rarely satisfactory due to the high reactivity of the element which leads to unspecific multiple substitution, carbon-carbon bond cleavage and oxidation. Because of the growing importance of fluorinated organic compounds in applications such as in biochemical systems (see, for example Biomedical Aspects of Fluorine Chemistry, R Filler, Y Kobayashi (editors), Elsevier Biomedicinal Press, New York, 1982 and J T Welch, Tetrahedron, 1987, 43, (14), 3123) in recent years considerable effort has gone into finding ways of introducing fluorine into specific sites within molecules to provide building blocks for the preparation of biologically active compounds which have more complex structures. In this context, the replacement of the 2-hydrogen in 1,3-diketones and 1,3-ketoesters is just one transformation that has aroused much interest since the mono- and/or di-fluorinated products can be useful intermediates in the preparation of bio-active molecules. This transformation has been carried out either by treating the 1,3-diketone or 1,3-ketoester, or their metal enolates, with one of several “electrophilic fluorinating agents” that have been developed recently. For example, 1,3-diketones and 1,3-ketoesters have been treated with acetyl hypofluorite (S Rozen and O Lerman, J. Org. Chem., 1983, 48, 724), N-fluoro-pyridinium salts with or without a Lewis Acid catalyst (T Umemoto et al, J. Amer. Chem. Soc., 1990, 112, 8563), xenon difluoride (B Zajc and M Zupan, J. Chem. Soc., Chem. Commun., 1980, 759), lamellar C19XeF6 (H B Kagan, S S Yemul and R Setton, Tetrahedron Letts., 1980, 21, 277), and N-fluorobis[(perfluoroalkyl) sulphonyl]imides (G Resnati and D D Desmarteau, J. Org. Chem., 1992, 57, 4281; Z Xu, D D Desmarteau and Y Gotoh, J. Fluroine Chem., 1992, 58, 71; G Resnatti and D D Desmarteau; J. Org. Chem., 1991 56, 4925; Z Xu, D D Desmarteau and Y Gotoh, J. Chem. Soc., Chem. Commun., 1991, 179) and their metal enolates have been treated with acetyl hypofluorite, as disclosed by Rozen and Lerman, and with N-fluoro-pyridinium salts, according to the method of Umemoto et al.

#A solution of methyl 3-oxopentanoate (13.0 g, 0.1 mole) in methanol (100 ml) was stirred in an FEP (perfluoropolymer) reactor at −5° C. A gaseous mixture of 10% fluorine in nitrogen was passed through it at 100 ml/min for 28 hrs giving a total of 0.7 moles or 7 equivalents of fluorine.

#The reaction solution was drowned into 500 ml water and extracted with 3×50 ml of methylene chloride. The combined organic solutions were dried over magnesium sulphate and rotary evaporated to give 13.9 g of crude product. This was distilled to give 9.1 g of methyl 2-fluoro-3-oxopentanoate, 1.1 g of the starting material and left 1.1 g of residues. This represents a yield of 70% based on consumed starting material at 92% conversion with 9% tar.

#A similar procedure to example 1 was carried out except the solvent was a mixture of methanol (90 ml) and water (10 ml). The crude weight of product was 13.2 g, which was distilled to give 7.9 g methyl 2-fluoro3-oxopentanoate and 2.9 g starting material, leaving 1.3 g of residue. This represents a yield of 71% at 78% conversion and 12% tar.