Azetidines, Azetines and Azetes: Monocyclic

Abstract

The four-membered azaheterocycles, azetidines and azetidin-2-ones are thermally stable and easy to handle. Structures of many compounds have been established by X-ray crystallography. Azetidines react with electrophiles and nucleophiles. The ring opening affords useful amides, alkenes, and amines. Cyclic products such as piperidines, pyrrolidines, and pyrroles have been synthesized from azetidines. Oxidation of 3-hydroxyazetidines forms azetidin-3-ones. Azetidines are synthesized from acyclic precursors like γ-haloamines, γ-aminoalcohols, and β-aminoallenes. Reactions of 1,3-dielectrophiles with primary amines and cycloadditions are also used in the synthesis of azetidines. Reduction of β-lactams affords azetidines. Heterocycles like aziridines, oxetanes, and azabicyclobutanes are transformed into azetidines. Azetidin-2-ones (β-lactams) are precursors of β-amino acids, amides, 3,3-dichloroazetidines, and many other heterocyclic compounds. The syntheses of β-lactams involve cyclizations of β-amino acids, β-amino esters, β-functionalized amides, and cyclocondensations of isocyanates and alkenes, imines and enolates, imines and ketenes, and nitrones and alkynes. The application of chiral auxiliaries and catalysts has made considerable progress in asymmetric synthesis. Applications of microwaves and polymer supports are reported. Although β-lactams are mainly antibacterials, many compounds have been tested and shown promising results as cholesterol absorption inhibitors (CAIs), enzyme inhibitors, anticancer agents, and hypoglycemic agents. A monocyclic azetidin-2-one (ezetimibe) is now in clinical use as CAI. Azetines and azetes comprise a rare class of constrained azaheterocycles. Only a few stable compounds belonging to these classes are known. Azetines undergo ring opening and cycloaddition reactions. Azetines are synthesized by photochemical cyclization of amides and by partial reduction of azetes. Tri- t -butylazete is a kinetically stabilized compound, which undergoes reduction, cycloaddition, and cycloreversion. It is synthesized by photolysis of pyridazines, and by thermolysis or photolysis of Dewar pyridazines.