Fluorination pyrimidinones

Chlorotrifluoroethylene was converted in one step using nBuLi to dieth-ylfluoromalonate, which was a useful precursor for 5-fluorouracil (84CL1573). Fluorinated pyrimidinones can also be obtained from a,fi-unsaturated carboxylic acid derivatives prepared from 1-phosphonyloxy-perfluoroalkyl-l-alkenephosphonates (86TL2879). 

In the previous sections discussing synthesis of chain-fluorinated diazines by heterocyclizations, there were many examples of formation of di-, tetra- and hexahydropyrimidines - so-called hydrates (or other solvates) - instead of the corresponding aromatic products. This situation was quite common for the preparation of chain-fluorinated pyrimidinones or fused pyrimidines possessing an additional electron-withdrawing group, as well as Biginelli-type adducts (Fig. 30, see also Sect. 7 of this chapter). 

Direct 5-fluorination can be effected on activated pyrimidines for example, F2 in HOAc or anhydrous HF have been used for the preparation of 5-fluoro-2(lH)-pyrimidinones (77CCC2694), and for 5,5-difluorination of 6-O-cyclouridines (83TL1055). Uracil and cytosine are 5-fluorinated by the same procedure (80TL4605,82CPB887). 

Electrochemical (anodic) fluorinations can be carried out, but may be difficult to control and over-fluorination and/or fluorination of substituents often results. The mechanism involves conversion of the substrates into radical cations, which are then trapped by fluoride, rather than electrophilic fluorination. Again, the method is more suited to robust systems such as pyrimidinones and purines. 

Fluoro and 2,4-difluoropyrimidines have also been prepared in good yields directly from pyrimidinones by the use of anhydrous potassium fluoride in tetraglyme-18-crown-6 at elevated temperature <85JHC145>. Synthesis of fluorinated pyrimidines via diazonium salts appears to be inferior to other methods <85JHC145>. 

Further annelation to pyrimidine ring based on substitution of fluorine at 5-position was used in patent literature. Alantos Pharmaceuticals in a course of matrix metaUoprotease inhibitors development described an efficient pyrazole annelation to pyrimidine. The synthesis of key intermediate - pyrimidine dicarbox-ylic acid 188 was accomplished in 3 step bromination - carbonylation - oxidation sequence from pyrimidinone 185. The acid was converted to the corresponding... 

Braun T, Foxon SP, Perutz RN, Walton PH (1999) Nickel-assisted carbon-fluorine bond activation of 2,4,6-trifluoropyrimidine synthesis of new pyrimidine and pyrimidinone derivatives. Angew Chem Int M 38 3326-3329... 

Driscoll JS, Marquez VE, Plowman J, Liu PS, KeUey JA, Barchi JJ (1991) Antitumor properties of 2(lJ/)-pyrimidinone riboside (zebularine) and its fluorinated analogs. J Med Chem 34 3280-3284... 

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