Synthesis of Spirocyclic 1‐Pyrrolines from Nitrones and Arynes through a Dearomative [3,3′]‐Sigmatropic Rearrangement

Abstract

A dearomative [3,3′]‐sigmatropic rearrangement that converts N‐alkenylbenzisoxazolines into spirocyclic pyrroline cyclohexadienones has been developed by using the dipolar cycloaddition of an N‐alkenylnitrone and an aryne to access these unusual transient rearrangement precursors. This cascade reaction affords spirocyclic pyrrolines that are inaccessible through dipolar cycloadditions of exocyclic cyclohexenones and provides a fundamentally new approach to novel spirocyclic pyrroline and pyrrolidine motifs that are common scaffolds in biologically‐active molecules. Diastereoselective functionalization processes have also been explored to demonstrate the divergent synthetic utility of the unsaturated spirocyclic products.

Synthesis of Spirocyclic 1‐Pyrrolines from Nitrones and Arynes through a Dearomative [3,3′]‐Sigmatropic Rearrangement

“…[15] Surprisingly, when benzyne is generated in the presence of N-cyclohexenylnitrones derived from benzoylformate esters (see 1 p), spirocyclic pyrrolines 4 are not observed and dihydrobenzofurans 5 a-5 c are isolated in good yield (Scheme 5 A). [13,17] This result is consistent for analogous nitrones with linear alkyl-substituted N-alkenyl groups (see 5 d), although pyrroline formation is favored for malonatederived nitrones and N-styrenylnitrones (see Scheme 3, 4 e, 4 g and 4 n). Evidence of pyrroline 4 u was not observed during reaction monitoring but computational studies suggest that a transition state for the rearrangement of 4 u to 5 a is accessible.…”

“…The product was verified by X-ray crystal structure analysis and both solution and solid-state characterization data were consistent with the proposed formation of 4 a through a boat-like [3,3']-sigmatropic rearrangement of dipolar cycloaddition intermediate 3 a (Scheme 2 B). [13,14] Computational studies suggest that the transition state for the conversion of 3 a into 4 a is accessible at ambient temperature and that formation of the new CÀC and C=O bonds exceeds the cost of the weak N À O bond and the loss of aromaticity (Scheme 2 B). [15] Optimization of reaction conditions for the formation of 4 a was achieved by examining solvent and additive effects (Scheme 2 A).…”

“…The favored diastereomer of 4 n was verified by X-ray crystallography. [13] In contrast, the aryl ketone and ester substituents of 4 o demonstrated competing preferences for controlling the facial selectivity of CÀC bond formation. These experiments established the breadth of the new cascade process in terms of the nitrone component for the preparation of spirocyclic pyrrolines 4.…”

Nitrone and Alkyne Cascade Reactions for Regio‐ and Diastereoselective 1‐Pyrroline Synthesis

“…[18] Thei solation of 12 h-12 j are noteworthy since analogous cascade reactions between N-alkenylnitrones derived from benzoylformate esters and benzyne give dihydrobenzofurans through ap roposed spontaneous rearomatization process. [12] Further attempts at controlling stereochemical information using ac hiral non-racemic ester substituent on the nitrone showed only moderate selectivity (12 k) suggesting that the stereochemical information is likely too far removed from the initial C À Cb ond forming event to be influential. To the best of our knowledge,s pirocyclic1pyrrolines 12 are new compounds that have not previously been reported in the literature.T he only exception is 12 b, which was reported by our group via the hydrogenation of 10.…”

“…Recently,w ec ommunicated ad ipolar cycloaddition and dearomative rearrangement cascade reaction for the synthesis of spirocyclic 1-pyrrolines (Scheme 2A). [12] This transformation is proposed to proceed via a[ 3+ 2]-dipolar cycloaddition of an N-alkenylnitrone and an aryne to give Nalkenylbenzisoxazoline intermediate 9,w hich spontaneously undergoes aformal dearomative [3,3']-sigmatropic rearrangement to give the corresponding spirocyclic 1-pyrrolines 10. [13] These studies provided proof of principle for the utility of Nalkenylisoxazoline cascade intermediates as retrosynthetic alternatives for 1-pyrroline synthesis and were facilitated by our previous discovery of the use of the Chan-Lam reaction for preparing N-alkenylnitrones from oximes.…”