Strain-release arylations for the bis-functionalization of azetidines

Trauner, Florian; Reiners, Felix; Apaloo-Messan, Kodjo-Edmond; Nißl, Benedikt; Shahbaz, Muhammad; Jiang, Dongfang; Aicher, Julian; Didier, Dorian

doi:10.1039/d1cc07053c

Cited by 7 publications

(4 citation statements)

References 33 publications

(17 reference statements)

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“…Strained, internal C−N bond of ABB have been exploited for introducing different functional groups at nitrogen and at the bridgehead carbon (Scheme 1b). Strong nucleophiles (e.g., thiol, turbo‐amide, Grignard reagent or organocuprates) can add directly to bridgehead carbon of ABB without any definitive N‐activation and in conjunction to such C3 functionalization, strategies like S N Ar, Buchwald–Hartwig coupling or acylation/sulfonylation were used to leverage subsequent N1 functionalization [8d–h] . Recently, the Aggarwal group disclosed a suite of transformations using tailored C3‐substituted ABB derivatives (Scheme 1c), [9a–d] wherein a distinct nitrogen activation led to intramolecular rearrangement or annulation at C3 involving functional group(s) present at that position—affording N1/C3‐functionalized azetidines in tandem fashion.…”

Section: Methodsmentioning

confidence: 99%

Cation‐Promoted Strain‐Release‐Driven Access to Functionalized Azetidines from Azabicyclo[1.1.0]butanes

et al. 2023

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Access to 1,3‐functionalized azetidines through a diversity‐oriented approach is highly sought‐after for finding new applications in drug‐discovery. To this goal, strain‐release‐driven functionalization of azabicyclo[1.1.0]‐butane (ABB) has generated significant interest. Through appropriate N‐activation, C3‐substituted ABBs are shown to render tandem N/C3‐fucntionalization/rearrangement, furnishing azetidines; although, modalities of such N‐activation vis‐à‐vis N‐functionalization remain limited to selected electrophiles. This work showcases a versatile cation‐driven activation strategy of ABBs. And capitalizes on the use of Csp3 precursors amenable to forming reactive (aza)oxyallyl cations in situ. Herein, N‐activation leads to formation of a congested C−N bond, and effective C3 activation. The concept was extended to formal [3+2] annulations involving (aza)oxyallyl cations and ABBs, leading to bridged bicyclic azetidines. Besides the fundamental appeal of this new activation paradigm, operational simplicity and remarkable diversity should engender its prompt use in synthetic and medicinal chemistry.

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Section: Methodsmentioning

confidence: 99%

Cation‐Promoted Strain‐Release‐Driven Access to Functionalized Azetidines from Azabicyclo[1.1.0]butanes

et al. 2023

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“…In 2022, a strain-release arylation approach was exploited by Didier and coworkers for the efficient preparation of 1,3-bisarylated azetidines, which are scarcely explored motifs in the literature. 18 At first, the C3 functionalization of ABB through nucleophilic ring-opening with aryl Grignard reagents was examined. In comparison with previous reports, the ABB system was generated by using the less nucleophilic n-BuLi as the lithiation agent instead of PhLi to suppress the by-product 25 derived from the addition of the organolithium reagent to the ABB system.…”

Section: Synthesis Of 13-bisarylazetidines From Abbsmentioning

confidence: 99%

Synthesis and strain-release reactions of 1-azabicyclo[1.1.0]butanes: an update

Liuisi¹,

Musci²,

Colella³

et al. 2022

Arkivoc

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Azabicyclo[1.1.0]butanes (ABBs) are important synthetic tools for the preparation of functionalized azetidines. The transformations of azabicyclo[1.1.0]butanes generally involve the C3-N bond cleavage, which allows for the functionalization of the azacycles in the 1,3 positions. Recently, important advances in the field have led to the preparation of novel strained compounds from ABBs. Diverse spirocyclic and heterocyclic-substituted azetidines could be prepared, also harnessing enabling technologies. This review aims to discuss the most recent reports regarding the synthesis and transformations of ABBs as versatile synthons for the construction of pharmaceutically relevant heterocycles.

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“…Recent step-economic strategies towards substituted azetidines include the work of Baran and Gianatassio on strain-release amination [5] and alkylation [6] of 1-azabicyclo[1.1.0]butanes (ABB) that provide an elegant route to 3-subsituted structures, as well as our contribution on 1,3-bisarylations. [7] The group of Aggarwal reported the strain-release of ABB through boron-homologations for the synthesis of 3,3-bisfunctionalized azetidines. [8] Cyclobutanes were similarly obtained from metalated bicyclo[1.1.0]butanes.…”

Section: Introductionmentioning

confidence: 99%

Stereoselective Polar Radical Crossover for the Functionalization of Strained-Ring Systems

Didier,

Trauner,

Ghazali

et al. 2024

Preprint

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Radical-polar crossover of organoborates is a poweful tool that enables the creation of two C-C bonds simultaneously. Small ring systems have become essential motifs in drug discovery and medicinal chemistry. However, step-economic methods for their selective functionalization remains scarce. Here we present a one-pot strategy that merges a simple preparation of strained organoboron species with the recently popularized polar radical crossover of borate derivatives to stereoselectively access tri-substituted azetidines, cyclobutanes and five-membered carbo- and heterocycles.

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Strain-release arylations for the bis-functionalization of azetidines

Abstract: The addition of nucleophilic organometallic species onto in situ generated azabicyclobutanes enables the selective formation of 3-arylated azetidine intermediates through strain-release. Single pot strategies were further developed for the N-arylation...

Cited by 7 publications

References 33 publications

Cation‐Promoted Strain‐Release‐Driven Access to Functionalized Azetidines from Azabicyclo[1.1.0]butanes

Cation‐Promoted Strain‐Release‐Driven Access to Functionalized Azetidines from Azabicyclo[1.1.0]butanes

Synthesis and strain-release reactions of 1-azabicyclo[1.1.0]butanes: an update

Stereoselective Polar Radical Crossover for the Functionalization of Strained-Ring Systems

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