Diverse Applications of Nitrones for the Synthesis of Heterocyclic Compounds

Although best known for their [3+2]-dipolar cycloaddition reactivity and use in the preparation of isoxazolines and isoxazolidines, nitrones are versatile reagents that undergo a variety of transformations for the synthesis of a diverse array of heterocyclic compounds. The breadth of heterocycle synthesis using nitrone reagents includes: 1) stepwise [3+3]-cycloaddition reactions of nitrones with vinyl diazoacetates, transition-metal-coordinated cycloisomerization intermediates, trimethylene methanes, and cyclopropane diesters to form dihydro- and tetrahydro-1,2-oxazines; 2) internal redox cyclization reactions of alkyne-tethered nitrones to provide access to azabicyclooctanes, isoindoles, aminoindanones, and isoquinolones; 3) electrocyclizations of in situ generated N-allenylnitrones to form pyridines and azetidine-N-oxides, as well as metal-catalyzed cyclizations and rearrangements of nitrones to form azepine-N-oxides, spirocyclic isoxazolines, and α,β-epoxyimines; and 4) the use of [3+2]-cycloaddition reactions of nitrones to trigger cascade reactions for the formation of tetrahydrooxazepines, dihydrocarbazoles, and benzoindolizines. This Focus Review aims to highlight these diverse applications of nitrones for the synthesis of heterocycles to emphasize the broad utility of these reactive intermediates and to inspire their further development as important synthons beyond the scope of traditional [3+2]-dipolar cycloaddition reactions.