Non-Aromatic Heterocycles 155Ring synthesis
From bifunctional acyclic precursors
Five- and six-membered saturated rings can be prepared by reduction of the corresponding heteroaromatic com-
pound, but the most general method for making all ring sizes is by cyclisation of an -substituted amine, alcohol,
or thiol via an intramolecular nucleophilic displacement – an ‘exo-tet’ ring closure. The rate of cyclisation of
-halo-amines goes through a minimum at the four-membered ring size; the fi ve- and six-membered rings are by
far the easiest to make.
As examples of this strategy, oxetanes and oxiranes can be prepared by cyclisation of 1,3-halo-alcohols or of 1,2-halo-
alcohols (‘halohydrins’), respectively.
Aziridines can be prepared by alkali-promoted cyclisation of 2-halo-amines or of a 2-hydroxy-amine hydrogen sulfate ester.
Azetidines can be obtained by cyclisations of 3-halo-amines. Even the highly strained 1-azabicyclo[1.1.0]butane can
be made by this strategy.
Reversing the sense of cyclisation, N-chloroamines, with a suitable C-H-acidifying substituent, can be ring closed
effi ciently producing N-alkylaziridines.
Thietanes, tetrahydrothiophenes and tetrahydrothiapyrans can all be prepared by the reaction of the appropriate
1,-dihalide with sulfi de anion: the sodium salt of a 1,-halo-hydrosulfi de is the intermediate.
Cyclisations involving hetero-atom attachment to an alkene via -complexes with cations, such as Br, I, Hg and
Pd, are useful methods because they give products with functionalised side-chains for further transformations – such
closures are nominally ‘exo-trig’.