52 Diazines
Radical substitution
The Minisci reaction (page 14) is particularly useful in the diazines because there are many situations where good
regioselectivity can be achieved.
C-Metallated diazines
Diazines undergo nucleophilic addition with many standard lithiating agents, however metallation and metal–
halogen exchange can be carried out, but require carefully controlled conditions, normally very low temperatures
and a hindered base (lithium tetramethylpiperidide; LiTMP), for deprotonations. The three parent diazines can be
lithiated adjacent to nitrogen (for pyrimidine at C-4, not C-2) and moderate to good yields of trapped products
can be obtained either by using very short lithiation times or by in situ trapping where the electrophile is added
before the metallating agent.
Lithiation of diazines with ortho-directing groups is straightforward and this strategy is used widely, for example,
2,4-dimethoxypyrimidine (a masked uracil) is lithiated at C-5 by LiTMP.
Metallation of pyrimidine-diones in nucleosides may not require protection of acidic N-hydrogen, the use of excess
lithiating agent being suffi cient. This is a particularly useful technique for ribosides, where the regioselectivity of
the reaction (C-5 versus C-6) can be controlled by the presence or absence of a protecting group on the 5'-hydroxy
group.