12 Common Reaction Types in Heterocyclic Chemistry
The Vilsmeier reaction – formylation
In the Vilsmeier reaction, a nucleophilic molecule (in this book, a fi ve-membered aromatic heterocycle) is formylated,
that is a C-H is converted into C-CHO. The reagent is made in situ from the interaction of a formamide (most often
N,N-dimethylformamide (DMF)) and phosphoric trichloride (often referred to as phosphorus oxychloride, POCl 3 ).
The scheme shows the long sequence of steps, which starts with the amide oxygen acting as a nucleophile towards the
very electrophilic phosphorus and leads eventually to a chloro-iminium salt – this is the electrophile that attacks the
nucleophilic heterocycle.
When reaction with the heterocycle is complete, the reaction mixture is exposed to aqueous alkali, which brings about
a hydrolysis of the iminium product, revealing the aldehyde.
The Mannich reaction – dialkylaminomethylation
In the Mannich reaction, a nucleophilic molecule (fi ve-membered aromatic heterocycles in this book) is dialkylami-
nomethylated (most often dimethylaminomethylated), thus a C-H is converted for example into C-CH 2 NMe 2. The
reactive electrophilic species, for example [CH 2 =NMe 2 ], is most often generated in situ by the interaction of an alde-
hyde, a secondary amine and an organic acid, thus a mixture of dimethylamine, formaldehyde and acetic acid generates
[CH 2 =NMe 2 ]. These reaction mixtures are partly aqueous but the anhydrous salt [CH 2 =NMe 2 ] I (Eschenmoser’s
salt) is commercially available and can be used in a dry organic solvent. It is highly reactive and will react with sub-
strates that are resistant to the standard aqueous conditions.