Synthesis of Heterocyclic [3.3.3]Propellanes via a Sequential Four-Component Reaction

A highly chemoselective heteroannulation protocol for
the synthesis
of unreported polysubstituted heterocyclic [3.3.3]­propellanes has
been developed by sequential four-component reaction of ninhydrin,
malononitrile, primary amines, and dialkyl acetylenedicarboxylates
under mild conditions in water. To the best of our knowledge, there
are no previous reports for the synthesis of these classes of heterocyclic
[3.3.3]­propellanes. The merit of this sequential Knoevenagel condensation/enamine
formation/Michael addition/cyclization sequence is highlighted by
its high atom-economy, excellent yields, the use of water as reaction
media, and the efficiency of production without the use of any activator
or metal promoters. This synthesis serves as a nice addition to group-assistant-purification
(GAP) chemistry in which purification via chromatography and recrystallization
can be avoided, and the pure products were obtained simply by washing
the crude products with 95% ethanol.