Facile Synthesis of Azetidine Nitrones and Diastereoselective Conversion into Densely Substituted Azetidines

Abstract

An electrocyclization route to azetidine nitrones from N-alkenylnitrones was discovered that provides facile access to these unsaturated strained heterocycles.R eactivity studies showed that these compounds undergo av ariety of reduction, cycloaddition, and nucleophilic addition reactions to form highly substituted azetidines with excellent diastereoselectivity.T aken together,t hese transformations provide af undamentally different approacht oa zetidines ynthesis than traditional cyclization by nucleophilic displacement and providen ovel access to av ariety of underexplored strained heterocyclic compounds. Scheme 2. Cycloaddition and reduction of azetidine nitrones. THF = tetrahydrofuran, Tf = trifluoromethanesulfonyl.

Substituent and Solvent Effect Studies of N‐Alkenylnitrone 4π Electrocyclizations**

“…Similar reactivity trends were also observed for cyclooctenyl nitrone 1 y and the synthesis of azetidine nitrone 2 y proceeded smoothly in HFIP. Treatment of 2 w with DMAD gave an analogous dipolar cycloaddition product to those previously reported for 2 a and further supported the application of these mechanistic trends to advance the use of this method for complex azetidine synthesis (Scheme 6B) [10,13,20,25] . In contrast to 1 c , 1 d , and 1 w – 1 y , fluorenyl nitrones 1 z and 1 aa were resistant to electrocyclization at 40 °C in HFIP but heating 1 z to 60 °C provided 2 z in moderate yield.…”

A general synthesis of azetidines by copper-catalysed photoinduced anti-Baldwin radical cyclization of ynamides

“…1d ) 24 , 25 . Due to the unique 3D shape of these small nitrogen heterocycles and the range of biological activities they display, azetidines have been extremely studied as active pharmaceutical ingredients recently and their synthesis has been therefore intensively reinvestigated in recent years 26 – 30 .…”

Synthesis and Transformations of Nitrones for Organic Synthesis

“…98,99 Similarly, Cu(OAc) 2promoted reactions of malonate-derived oximes with vinylboronic acids give N-alkenylnitrones, which undergo 4πelectrocyclization to form azetidine nitrones (Scheme 5). 100 Copper-catalyzed reaction of oximes with cyclopropenes using chiral phosphines gives chiral N-cyclopropylnitrones (eq 26). 101 Copper-catalyzed reaction of (E)-O-propargylic arylaldoximes gives four-membered cyclic nitrones.…”