Common Reaction Types in Heterocyclic Chemistry 17The preparation of heteroaromatic Grignard reagents using the halide and magnesium metal is usually diffi cult, how-
ever they can be easily prepared by reacting a halide with isopropylmagnesium chloride – this is especially important
for electron-defi cient systems such as pyridines. Grignard reagents have some advantages over lithium nucleophiles –
they can often be formed and used at room temperature and are more tolerant of functional groups.
Directed ortho Metallation (DoM)
Here, a substituent on the heteroaromatic ring activates an ortho proton, which is not otherwise ‘acidifi ed’, for abstrac-
tion by a strong base. This is in part due to coordination of the base to the directing group, bringing it into close prox-
imity to the proton. Many types of substituent will achieve this effect – important ones are CONR 2 , CONHR, NHCOR,
RO and Hal.
When a secondary amide is used, a second mole equivalent of the base is required to react with the N-hydrogen,
as shown.
The following examples are typical of the conditions that must be used to generate organolithium intermediates, which
are also typically then reacted with the electrophile at the low temperature. In the examples given in other chapters,
conditions such as these should be assumed, unless otherwise stated.
Dimethylformamide dimethyl acetal (DMFDMA)
Acidifi ed methylenes (CH 2 to a carbonyl, for example) react with hot DMFDMA to produce dimethylami-
nomethylene derivatives (enamines), that is to introduce a one-carbon unit at the oxidation level of an aldehyde
(see Common synthetic equivalents on page 19). The hot reagent is in equilibrium with MeO (which removes one