Constructing Four-Membered Heterocycles by Cycloisomerization

Abstract

Four-membered heterocycles are highly sought after in modern drug discovery as they provide beneficial properties to the target molecules. Despite tremendous efforts by the synthetic research community, there is a need for a simple and new method to incorporate these motifs into the design molecules. Herein, we reveal a cycloisomerization strategy for the construction of oxetane and azetidine rings via metal hydride hydrogen atom transfer/ radical polar crossover, which is challenging both enthalpically and entropically. This method is suitable for synthesizing polysubstituted four-membered heterocycles. This mild and functionalgroup tolerant reaction has a broad substrate scope, including the spiro structure, which is an important motif in drug discovery research. Various four-membered heterocyclic building blocks can be synthesized by product derivatization. We also discuss the reaction mechanism, focusing on the four-membered ring formation, by deuterium experiments and DFT studies.

Electrocatalytic Access to Azetidines via Intramolecular Allylic Hydroamination: Scrutinizing Key Oxidation Steps through Electrochemical Kinetic Analysis

“…On the basis of literature reports ,,,− and our own observations, we envision the plausible mechanistic pathway (Figure B). The reaction is initiated by the first anodic event that involves the oxidation of Co­(II) catalyst 3 to concurrently form Co­(III)-hydride 22 upon rapid reaction with silane 4 .…”

“…For comparative purpose, a set of experiments was conducted under a series of conventionally employed chemical oxidants ( 11–21 ) and solvent systems without electrochemical input (see SI Figure S3 and pages S15–S17). The activated alkene precursor 9 that is prone to competitive hydrogenation was tested under previously employed catalytic systems in the alkene hydrofunctionalizations. ,,− Notably, reactions conducted under chemical oxidants predominantly yielded hydrogenated products (reduction by HAT) highlighting the crucial role of electricity in our reaction.…”

“…In addressing this issue, an elegant cycloisomerization strategy for the construction of oxetane and azetidine from homoallylic alcohols and amines has been reported recently. 68 Based on our diagnoses, we concluded that a regioselective and controllable generation of carbocationic intermediate via single electron transfer (SET) would circumvent the aforementioned limitations. In this article, we report the first intramolecular hydroamination of allylic amine derivatives via the electrochemical generation of carbocation equivalents that exclusively leads to azetidines (Figure 1C).…”

“…Finally, in assessing the nature of highly substituted internal alkenyl amines, alkene isomerization has been widely recognized, ,, and therefore, a method that can bypass undesired isomerization leading to terminal alkenes is pivotal. In addressing this issue, an elegant cycloisomerization strategy for the construction of oxetane and azetidine from homoallylic alcohols and amines has been reported recently …”

Photoinduced arylative formal 4-endo-dig cyclization of propargyl alcohols/amines to access strained heterocycles

“…We recently reported a method for the synthesis of fused oxetanes through Pd-catalyzed oxidative/annulative cyclization of propargyl alcohols with biphenyl amines. 12 Herein, 13 we demonstrate a totally contrasting and green approach for the synthesis of strained and small ring systems (oxetanes and azetidines) 14 via formal 4- endo-dig cyclization of propargyl alcohols/amines initiated by visible light-mediated annulation with benzoquinones. 15,16 The reaction does not require the assistance of any catalyst, reagent, or heat.…”