Cytosine fluorination

All of the direct fluorinations reported appear to be addition-elimination processes with solvent involvement (Scheme 42). A study of the mechanism and stereochemistry of uracil and cytosine fluorination using fluorine and acetyl hypofluorite has implicated a radical-cation mechanism (86JOC1466). The effect of acetate ion on the products proved to be important. In its absence both m-isomers (49) and trans-isomers (50) were observed in the reaction mixture, but only 50 [and 5-fluorouracil (51)] in its presence. The process has been rationalized in terms of the reaction diagram shown in Scheme 43. NMR studies have revealed that the acetate from the solution containing acetate ion, rather than the residue from acetyl hypofluorite, binds to the 6-position of uracil to form the intermediates (49 and 50). Acetate is a sufficiently strong base to induce trans-elimination of acetic acid from the cis-isomer (49). 5-Fluorouracil (51) was obtained in 45% yield from these reaction sequences (86CJC424). 

Because synthesis of l-(2-deoxy-2-fluoro-)S-D-arabinofuranosyl)cytosine (744, FAC), an elementary arabino type of nucleoside having a growth-inhibitory effect against L 1210 leukemia in mice, through direct introduction of a fluorine atom in the 2 - up (arabino) position was difficult, compound 744 was prepared by condensation of trimethylsilylated A -acetylcytosine with 3-0-acetyl-5-(7-benzoyl-2-deoxy-2-fluoro-D-arabin-ofuranosyl bromide (742), which had been prepared by periodate oxidation of 6-0-benzoyl-3-deoxy-3-fluoro-D-glucofuranose (741). Similar condensa-... 

Nucleosides Derived from Fluorinated Bases Many nucleosides have been synthesized from different fluoropyrimidines (uracil, thymidine, cytosine) or fluoropurine (adenine, guanine) bases, which are generally prepared by electro-... 

Fluorine addition with trifluoromethyl hypofluoritc to various uracil and cytosine bases and nucleosides has been extensively studied. Vicinal fluoro trifluoromethoxy or fluoro methoxy adducts, formed mainly by syn addition, are usually hydrolyzed thus resulting in fluoro-sub-stituted derivatives,42 48 e.g. formation of 24 and 25. 

Various uracil, cytosine and pyrimidine nucleosides, e.g. 22, have been successfully fluorinated by acetyl hypofluorite and also some labeled I8F derivatives synthesized.16- 18 34... 

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). 

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... 

The first direct synthesis of 5-fluorocytosine (15) was reported by Robins and Naik,21 in which cytosine (20) was reacted with trifluoromethyl hypofluorite followed by decomposition of the resulting adduct to provide 5-fluorocytosine in 85% yield. Some years later, Takahara disclosed that 15 could be prepared as its hydrofluoride salt in high purity when cytosine was reacted with fluorine gas in the presence of hydrogen fluoride, followed by treatment with methanol.22... 

To monitor tumor response to capecitabine therapy noninvasively, Zheng and co-workers, from the Indiana University School of Medicine, developed the synthesis of the fluorine- 18-labeled capecitabine as a potential radiotracer for positron emission tomography (PET) imaging of tumors.28 Cytosine (20) was nitrated at the C-5 position with nitric acid in concentrated sulfuric acid at 85°C, followed by neutralization to provide 5-nitrocytosine (27) in moderate yield. This nitro pyrimidine was then carried through the glycosylation and carbamate formation steps, as shown in the Scheme below, to provide the 6/s-protected 5-nitro cytidine 28 in 47% for the three-step process. Precursor 28 was then labeled by nucleophilic substitution with a complex of 18F-labeled potassium fluoride with cryptand Kryptofix 222 in DMSO at 150 °C to provide the fluorine-18-labe led adduct. This intermediate was not isolated, but semi-purified and deprotected with aqueous NaOH in methanol to provide [l8F]-capecitabine in 20-30% radiochemical yield for the 3-mg-scale process. The synthesis time for fluorine-18 labeled capecitabine (including HPLC purification) from end of bombardment to produce KI8F to the final formulation of [18F]-1 for in vivo studies was 60-70 min. 

In a process similar to the inhibition of thymidylate synthase by ffdUMP, fl5dC blocks (cytosine-5)-methyltransferase- (DCMtase)-catalyzed methylation of dC residues in DNA. In this case, a catalytic SH group on the enzyme adds to the 6-position of the pyrimidine. After transfer of a methyl group from AdoMet (( S)-adenosyl metionine) to the 5-position of this -enzyme-inhibitor complex, the presence of fluorine blocks the elimination of enzyme-SH (Figure 7)121. 

The fluorination of uracil (56) and cytosine (57) in a F AcOF/aq. AcOH system has been performed via a radical cation fluoride complex (58). This radical cation intermediate (58) is probably formed by an electron transfer due to the action of hypofluorite (AcOF) as shown in Scheme 5. ... 

Acetyl hypofluorite, prepared by reaction of fluorine gas with acetates, was introduced in 198111S. It reacts smoothly and quickly at -783C with many types of olefins to produce acetylatcd fluorohydrins. Electrophilic syn additions of this reagent across double bonds in unsaturated carbohydrates119,120, cytosine and uracil are described121. Other examples of stereoselective syn additions with this reagent include coumarin. stilbene and steroids118i l22. 

The fluorination of uracil and cytosine using fluorine and acetyl hypofluorite involves a radical-cation mechanism <86J0C1466>. 

---