Divergent Functionalizations of Azetidines and Unsaturated Azetidines

Abstract

Azetidines are unusual heterocyclic motifs that comprise key components of biologically active molecules and provide desirable structural properties for drug discovery. While a variety of methods have been designed for the synthesis of azetidines, screening and optimization studies often require systematic and versatile strategies for varying structural characteristics. With this need in mind, this review surveys methods for the divergent preparation of substituted azetidines from starting materials that contain a 4-membered azacycle. The scope and tolerance of azetidine functionalization reactions are described including approaches such as lithiation and electrophilic trapping, nucleophilic displacement, and transition metal catalysis. To complement this discussion, opportunities for using unsaturated azetidines as precursors to functionalized saturated analogues are also examined as an emerging alternative tactic towards the diversity-oriented preparation of these strained heterocycles. The aim of this Minireview is to identify recent advances, as well as areas where further development is needed, to continue to inspire innovative solutions to the divergent synthesis of functionalized azetidines.[a] T.

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

“…Azetidine [76,77] has attracted less attention than aziridines, pyrrolidines and piperidines, among small and medium size aza-heterocycles, because there are no general methods for their preparation. However, four-membered nitrogen-containing heterocycles have recently found applicability in pharmacy as highly biological active compounds.…”

Strain-release arylations for the bis-functionalization of azetidines

“…Strained sp 3 -rich heterocycles have emerged as important scaffolds in medicinal chemistry over recent years, as they can help tune pharmacokinetic properties. 1 Among those, azetidines have received particular attention. They have been used in numerous occasions as phenyl isosteres or to rigidify amine structures.…”

Synthesis of Azetidine Nitrones and Exomethylene Oxazolines through a Copper(I)-Catalyzed 2,3-Rearrangement and 4π-Electrocyclization Cascade Strategy

“…In 2017, Anderson and co-workers pioneered the report that N -alkenylnitrones generated by Chan–Lam coupling reaction of malonate-derived oximes and alkenylboronic acids easily underwent a 4π-electrocyclization to prepare a variety of azetidine nitrones in good yields, and the azetidine nitrones could be converted to various densely substituted azetidines by further simple transformations (Scheme B) . Azetidine derivatives have also been not only investigated as important synthetic intermediates but also found in several biologically active natural products . Many elegant strategies have been developed to prepare azetidine derivatives, including [2 + 2] or [3 + 1] cycloadditions, β-lactam reduction, and C–H bond functionalizations .…”