Cycloaddition of Fluorenone N-Aryl Nitrones with Methylenecyclopropanes and Sequential 1,3-Rearrangement: An Entry to Synthesis of Spirofluorenylpiperidin-4-ones

Abstract

A facile synthesis of various spirofluorenylpiperidin-4-ones has been achieved in good yields from fluorenone N-aryl nitrones and methylenecyclopropanes. This method involved an initial cycloaddition to form a 5-spirocyclopropane-isoxazoline, which underwent a highly selective 1,3-rearrangement to give the desired product. The stereochemistry of the spirofluorenylpiperidin-4-one could be controlled by the cycloaddition and sequential rearrangement strategy. Furthermore, the spirofluorenylpiperidin-4-ones could be not only prepared in one-pot procedure but also converted to useful scaffolds by reduction or oxidation conditions.

Synthesis of Spirofluorenyl‐β‐Lactams through Cycloaddition and Ring Contraction from N‐Aryl Fluorenone Nitrones and Methylenecyclopropanes

“…Temperature evaluation showed that the yield of 4 a dropped when the temperature was decreased or increased from 50 °C (Table , entries 13–17). However, above 70 °C, the by‐product piperidione 4 aa through [1,3]‐rearrangement reported by our previous work was observed and the yield of piperidione 4 aa was increased as the increased temperature (Table , entries 14–17). These results indicated that high temperature favored to form piperidinone motifs while acid promoted the formation of β ‐lactams at low temperature.…”

“…Recently, we have developed a [3+2] cycloaddition and sequential selective [1,3]‐rearrangement of N ‐aryl ketonitrones with methylenecyclopropanes to prepare spiropiperidinones . We found that N ‐aryl 9‐fluorenone nitrones reacted with methylenecyclopropanes to afford 5‐spirocyclopropane‐isoxazolidines, which then underwent a [1,3]‐rearrangement under thermal conditions, which was controllable because of the rigidity and steric hindrance of the fluorene . We surmised that addition of an acid to the 5‐spirocyclopropane‐isoxazolidine would afford spirofluorenyl‐ β ‐lactams containing a quaternary carbon by ring contraction (Scheme ‐C).…”

Computational Investigation of the Selective Cleavage of Diastereotopic Cyclopropane Bonds in 5-Spirocyclopropane Isoxazolidines Rearrangement

“…The Brandi–Guarna rearrangement , of 5-spirocyclopropane isoxazolidines 1 has been widely applied in the synthesis of polycyclic heterocycles and natural products (Scheme ). − It consists of a thermal-induced ring opening of isoxazolidines 1 , leading to the formation of tetrahydropyridones 2 (Scheme ). This type of skeleton, that is, a piperidine ring-containing framework, is widely diffused in alkaloids and bioactive molecules. − …”

Yb(OTf)3‐Catalyzed Cycloaddition/[3,3]‐Rearrangement of N‐Vinyl‐α,β‐Unsaturated Ketonitrones with Methylenecycloprop‐anes: Stereoselective Synthesis of Nine‐Membered Nitrogen Heterocycles

“…[12] During studies on nitrones and their cycloadditions, [13] we recently developed a novel strategy for the highly diastereoselective synthesis of nine-membered ring scaffolds though a [3 + 2] cycloaddition and sequential [3,3]-rearrangement cascade strategy from N-vinyl-α,β-unsaturated ketonitrones and various electrophiles, including arynes, isocyanates, and activated alkynes (Scheme 1-A). [15,16] The cyclopropane unit, especially in spirocyclopropanes, is a design element frequently used in biologically active compounds to increase metabolic stability and rigidity. [15,16] The cyclopropane unit, especially in spirocyclopropanes, is a design element frequently used in biologically active compounds to increase metabolic stability and rigidity.…”

“…[14] To construct three stereocenters in the nine-membered rings, we proposed that N-vinyl-α,β-unsaturated ketonitrones and methylenecyclopropanes (MCPs) would undergo cycloaddition and sequential [3,3]-rearrangement to afford formal [7 + 2] cycloaddition products containing three stereocenters (Scheme 1-B). [15,16] The cyclopropane unit, especially in spirocyclopropanes, is a design element frequently used in biologically active compounds to increase metabolic stability and rigidity. [17] Herein, we report a Yb(OTf) 3 -catalyzed formal [7 + 2] cycloaddition of N-vinyl-α,β-unsaturated ketonitrones with MCPs for the preparation of nine-membered Nheterocycles bearing three stereocenters with high diastereoselectivity.…”