Eu(OTf)₃‐Catalyzed Formal Dipolar [4π+2σ] Cycloaddition of Bicyclo‐[1.1.0]butanes with Nitrones: Access to Polysubstituted 2‐Oxa‐3‐azabicyclo[3.1.1]heptanes

Abstract

Herein, we have synthesized multifunctionalized 2‐oxa‐3‐azabicyclo[3.1.1]heptanes, which are considered potential bioisosteres for meta‐substituted arenes, through Eu(OTf)3‐catalyzed formal dipolar [4π+2σ] cycloaddition of bicyclo[1.1.0]butanes with nitrones. This methodology represents the initial instance of fabricating bicyclo[3.1.1]heptanes adorned with multiple heteroatoms. The protocol exhibits both mild reaction conditions and a good tolerance for various functional groups. Computational density functional theory calculations support that the reaction mechanism likely involves a nucleophilic addition of nitrones to bicyclo[1.1.0]butanes, succeeded by an intramolecular cyclization. The synthetic utility of this novel protocol has been demonstrated in the concise synthesis of the analogue of Rupatadine.

Catalytic Asymmetric Construction of Chiral Polysubstituted 3-Azabicyclo[3.1.1]heptanes by Copper-Catalyzed Stereoselective Formal [4π+2σ] Cycloaddition

“…Very recently, Deng achieved impressive work on Eu(OTf) 3catalyzed dipolar [4π+2σ] cycloaddition of BCBs with nitrones, resulting in the efficient synthesis of 2-oxa-3-aza-BCHeps. 14 Soon after, the silver-enabled strategy to synthesize polysubstituted 3-aza-BCHeps from BCBs and isocyanides was reported by Glorius. 15 In stark contrast to these advancements, the formations of BCBs to generate chiral frameworks remains extremely challenging.…”

“…Despite the notable progress, the exploration of aza-BCHeps as potential bioisosteres of pyridines has remained elusive due to the absence of a straightforward preparation method. Very recently, Deng achieved impressive work on Eu­(OTf) 3 -catalyzed dipolar [4π+2σ] cycloaddition of BCBs with nitrones, resulting in the efficient synthesis of 2-oxa-3-aza-BCHeps . Soon after, the silver-enabled strategy to synthesize polysubstituted 3-aza-BCHeps from BCBs and isocyanides was reported by Glorius .…”