Fluoropyrimidine

The aminodefluorination occurs to a considerably lesser extent according to the Sn(ANRORC) mechanism (40%) apparently, the competitive addition on C-2, leading to the Sn(AE) substitution, is more favored. This preference for Sn(AE) reactions is characteristic of the fluoro atom it has been also observed in aminodefluorinations of 2-fluoropyrimidines (Section II,C,l,c). 

Fluoro-5-phenyl-l,2,4-triazine (109, X = F) reacts much faster than the 3-chloro-, 3-bromo-, or 3-iodo-compound. Moreover, the reaction mixture obtained is cleaner than that from the corresponding 3-chloro- or 3-bromo compounds 3-amino-5-phenyl-l,2,4-triazine (110) is formed in good yield. This conversion takes place to only a small extent (18%) via the ANRORC process the main part of the aminodefluorination seems to involve the Sn(AE) mechanism. This result is consistent with the observation that the aminodefluorination of 4,6-diphenyl-2-fluoropyrimidine follows the Sn(AE) process, whereas 2-fluoro-4-phenylpyrimidine (position 6 is vacant for addition of the nucleophile) reacts for the most part according to the Sn(ANRORC) mechanism (see Section II,C,l,c). 

Fluoropyrimidines do radiosensitize by causing redistribution of cells into a relatively sensitive phase of the cell cycle (early S). 

Fluoropyrimidines and Other Fluorine-Substituted Six-Membered Ring Heterocycles... 

The fluorine chemical shifts for fluoropyrimidines, 2-fluoropyrazine, 2-fluoro quinoxaline, 4-fluoroquinazaline, 5-fluorouracil, 5-fluoro-cytosine, and cyanuric fluoride are provided in Scheme 3.82. The fluorine of 2-fluoropyrimidine is considerably deshielded relative to... 

Ruckman J, Green LS, Beeson J, Waugh S, Gillette WL, Henninger DD, Claesson-Welsh L, Janjic N, 2 -Fluoropyrimidine RNA-based aptamers to the 165-amino acid form of vascular endothelial growth factor (VEGF165), J. Biol. Chem., 273 20556-20567, 1998. 

Furthermore, 2-fluoropyrimidine can be obtained in 27% yield from pyrimidin-2-amine using the same procedure. - ... 

The displacement of fluoride from 2-fluoropyrimidine by aliphatic amines is about 100 times as fast as the displacements of the corresponding chloride or bromide, and reactions can be carried out at room temperature. Aryl-amines are umeactive under these conditions, but do react in the presence of trifluoro-acetic acid or boron trifluoride. These mild conditions allow the use of the fluoro-compound in solid phase synthesis (using excess of the fluoropyrimidine to ensure complete conversion). ... 

High reactivity of 2-fluoropyrimidme was used for the amines, anilines and ami-noacids decoration on solid support. In this case among halopyrimidines only 2-fluoropyrimidine is appropriate as reagent and in a case of aminoacids gave corresponding in high preparative yields (Scheme 30) [76, 153,154]... 

Scheme 30 Solid-supported decoration of amino acids by 2-fluoropyrimidine...

The reactions with P-nucleophiles are even more rare than with C-nucleophiles. Recently such reaction was used for the synthesis of polysubstimted pyrimidi-nylphosphonic acid 172. Microwave-assisted Michaehs-Arbuzov reaction of triisopropyl phosphite with the corresponding 2-fluoropyrimidine 170, followed by deprotection of the phosphonate group using TMSBr in acetonitrile gave the desired add 172 in 66 % total yield. The derivative 172 exhibits anti-influenza virus A activity in the middle micromolar range (Scheme 37) [177]. 

Bremer M (1995) Liquid crystals based on 2-fluoropyrimidine and -pyridine synthesis, dielectric anisotropy and phase behavior. Adv Mater 9 803-807... 

Shkurko OP, Baram SG, Mamaev VP (1974) Pyrimidines - XXXI. Preparation of 4 (6)-substituted 2-fluoropyrimidines. Chem Heterocycl Comp 8 1159-1162... 

Svirskaya PI, Yedidia V, Leznoff CC, Miller JM (1985) Huorinated heterocychc compounds. 2. 2,4-difluoro and 4-amino-2-fluoropyrimidines, nucleoside base analogs. J Heterocycl Chem 22 149-153... 

Gibson C, Kessler H (2000) 2-Fluoropyrimidine as an efficient reagent in solid-phase synthesis of N-aryl- and N-aUtyl-N-pyrimidin-2-ylamines. Tetrahedron Lett 41 1725-1728... 

Fig. 1 Bond lengths (nm) and angles for 2-fluoropyridine, 2-fluoropyrimidine and 2-fluoro-...

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