Heteroatom substituted pyrimidines

The availability of different metal ion binding sites in 9-substituted purine and pyrimidine nucleobases and their model compounds has been recently reviewed by Lippert [7]. The distribution of metal ions between various donor atoms depends on the basicity of the donor atom, steric factors, interligand interactions, and on the nature of the metal. Under appropriate reaction conditions most of the heteroatoms in purine and pyrimidine moieties are capable of binding Pt(II) or Pt(IV) [7]. In addition, platinum binding also to the carbon atoms (e.g. to C5 in 1,3-dimethyluracil) has been established [22]. However, the strong preference of platinum coordination to the N7 and N1 sites in purine bases and to the N3 site in pyrimidine bases cannot completely be explained by the negative molecular electrostatic potential associated with these sites [23], Other factors, such as kinetics of various binding modes and steric factors, appear to play an important role in the complexation reactions of platinum compounds. 

Fluorouracil (5FU) is 5-fluoropyridrimidine-2,4(1/7, 3H)-dione. Its structure is illustrated in Figure 11. The hydrogen in the naturally occurring pyrimidine, uracil, is substituted by fluorine in the 5 position. The presence of the heteroatoms in the structure imparts hydrophilicity to the compound as they are capable of hydrogen bonding. 

There is, for example, no end-of-text chapter entitled Heterocyclic Compounds. Rather, heteroatoms are defined in Chapter 1 and nonaromatic heterocyclic compounds introduced in Chapter 3 heterocyclic aromatic compounds are included in Chapter 11, and their electrophilic and nucleophilic aromatic substitution reactions described in Chapters 12 and 23, respectively. Heterocyclic compounds appear in numerous ways throughout the text and the biological role of two classes of them—the purines and pyrimidines—features prominently in the discussion of nucleic acids in Chapter 27. 

There is no satisfactory method for heteroatom arylation of oxygenated pyrimidines. (9-Alkylation of hydroxypyrimidines competes with the favored 7V-alkylation hard electrophiles may move the selectivity in favor of O-alkylation. Therefore, both (9-arylation and 0-alkylation are best effected in the electrophilic positions by substitution reactions on the chlorides, sulfides, and oxidized sulfides using a metal salt of the phenol or alcohol. In the 5-position, the options are vigorous reaction conditions for substitution of a bromine substituent, and (9-alkylation in competition with A-alkylation. 

Nitrogen can be incorporated in the macroring by inclusion of a small-ring nitrogen heterocycle such as pyridine or pyrimidine. Three approaches should be noted. If the pyridyl unit is incorporated as a 2,6-bis(methyleneoxy)pyridine derived from lutidine, the precursor will normally be a lutidine dihalide or diol. In the case of sulfur, the diol would be a dithiol. If the pyridyl unit is to be attached by 2,6-aminomethyl groups, amide formation followed by reduction is a possibility. In the event that the heterocycle will be attached directly to a macroring heteroatom, nucleophilic aromatic substitution may be useful. 

---