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

Abstract

Access to 1,3-functionalized azetidines through 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 appeal. 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 a selected set of electrophiles. Current work showcases a versatile cation-driven activation strategy of ABB. This process is capitalized on the use of Csp3-precursors amenable to form reactive (aza)oxyallyl cation in situ. Herein, N-activation that translates into forming a congested C-N bond, stipulates effective C3 activation. The concept can be further extended to formal [3+2]-annulation involving azaoxyallyl cation and ABB, leading to bridged bicyclic-azetidines. Besides fundamental appeals to this new activation paradigm, operational simplicity and remarkable diversity should engender its prompt use in synthetic and medicinal chemistry.