4-(Dimethylamino)pyridine as Multivalent Catalyst in Organic Synthesis

4-(Dimethylamino)pyridine (DMAP) is an common and well-known catalyst in organic synthesis.([1,2]) It has basic and nucleophilic character, commonly exploited in reactions.([3,4]) DMAP has moderate aqueous solubility, which allows it to be used in aqueous reactions for green chemistry.([5,6]) Despite being toxic, DMAP is a versatile and inexpensive catalyst, able to promote different types of reactions with an emphasis on heterocycle synthesis,([7-15]) cycloadditions,([7,8]) multicomponent reactions (MCRs),([10,13,14,16,17]) and acylation reactions.([1,18-21]) It is also worth noting its growing use as a catalyst in stereoselective reactions.([7,22,23]) There are several methods for DMAP synthesis.([24,25]) An efficient protocol that provides DMAP (1) (Scheme 1) in high yield involves nucleophilic aromatic substitution (SNAr) of 4-chloropyridine hydrochloride (2) and dimethylamine in 1,4-dioxane and sodium hydroxide at 70 degrees C under pressure.([24]) Other methods such as continuous flow, which is a fast and economical protocol,([26]) can lead to successful DMAP synthesis. In this SNAr protocol,([25]) a nucleophile is formed through a reaction between DMF and NH3, which is then added to 4-chloropyridine hydrochloride (1) at high temperature and pressure to synthesize DMAP in 78% yield (Scheme 1).([25])