38 Pyridines
However, more use has been made of halogen exchange reactions for the generation of pyridine organometallic nucle-
ophiles. All three isomeric bromopyridines can be converted into lithio derivatives at low temperature. Particularly
signifi cant is the conversion of halopyridines into Grignard reagents by reaction with isopropylmagnesium chloride at
room temperature, avoiding the very low temperatures required for the generation of organolithium species (tempera-
tures of around –70 °C have to be used in exchange reactions with n-butyllithium in order to avoid nucleophilic addi-
tion of the reagent to the heterocycle, cf. pages 35–36). Grignard reagents are also more tolerant of functional groups
in a reaction partner than are organolithium species. Selectivity in Grignard formation and halogen–metal exchange is
for a -halogen over an - or -halogen.
Another, very widely used protocol is metallation ortho to directing groups (DoM: Directed ortho Metallation). In the
examples shown, a 4-carbamate or 4-chlorine allows lithiation at C-3 and a 3-fl uorine leads to lithiation at C-4 – in
general, when a directing group is located at pyridine C-3, lithiation usually takes place at C-4, not C-2. Note: Either
n-butyllithium or lithium diisopropylamide can be used in these metallations/deprotonations, but only n-butyllithium
will serve in metal–halogen exchange reactions.