Perspectives on Intermolecular Azomethine Ylide [3+2] Cycloadditions with Non-Electrophilic Olefins

Abstract

Our interest in the synthesis of compact nitrogen heterocycles from abundant sources has motivated a critical analysis of the status in azomethine ylide chemistry. Despite the outstanding developments in catalytic enantioselective [3+2] cycloadditions, these are still limited to electron-poor olefins. Only a few examples can be found in the literature that report on cycloadditions using non-electrophilic alkenes and those are compiled herein. With this account we aim to extract lessons and challenges that will inspire future breakthroughs in this area.

Direct and Stereospecific [3+2] Synthesis of Pyrrolidines from Simple Unactivated Alkenes

“…Encouraged by this result, we optimized this system using challenging aliphatic α‐olefin 2 b as a model substrate (Scheme c). This class of alkenes have never been observed to participate in [3+2] cycloadditions . We observed that the lithium anion Li‐ A was not able to promote the cycloaddition (0 % yield), while the Me 2 Al‐derived anion Me 2 Al‐ B furnished the cycloadduct 3 ab (52 % yield).…”

“…Remarkably, electron‐rich olefins like butyl vinyl ether and N ‐vinylcarbazole also engage in this cycloaddition ( 3 ai , aj ). To the best of our knowledge, these are the first nucleophilic olefins to participate in this reaction . Although electron‐deficient olefins are beyond the scope of this report, an acrylate substrate was found to seamlessly engage in this cycloaddition as well (see the Supporting Information).…”

“…Moreover, 3 av is primed for heterogenization through ring‐opening metathesis polymerization (ROMP), and 3 a 2 v leads to interesting C−H oxidation catalysts (Scheme d). To put these results in perspective, we should emphasize that even strained and conventional cycloalkanes were specifically declared unreactive in azomethine ylide [3+2] cycloadditions before our work ,. Importantly, these polar pyrrolidines can be decorated with unprotected amines ( 3 ac , aj , au ), alcohols ( 3 ad ), nitriles ( 3 ae , ak ), ethers ( 3 af , ai ), ketals ( 3 ap ), esters ( 3 at ), silanes ( 3 ag , ah ), or other olefins ( 3 am , av ).…”

“…We have recently reviewed the current state‐of‐the‐art in azomethine ylide [3+2] cycloadditions involving non‐electrophilic olefins . Lithium 2‐aza‐allyl anions (Li‐ A ), which were introduced by Kauffmann and popularized by Pearson, can engage the least activated olefins thus far, namely styrenes, vinylsulfides, and vinylsilanes . These intermolecular reactions often display modest scope (alkyl and cycloalkyl olefins are unreactive), moderate selectivity, and even reversible behavior .…”

“…Lithium 2‐aza‐allyl anions (Li‐ A ), which were introduced by Kauffmann and popularized by Pearson, can engage the least activated olefins thus far, namely styrenes, vinylsulfides, and vinylsilanes . These intermolecular reactions often display modest scope (alkyl and cycloalkyl olefins are unreactive), moderate selectivity, and even reversible behavior . Preliminary experiments (Scheme b; top) revealed that imines featuring N‐heterocycles are particularly difficult substrates, as could be expected from the electrophilic character of these heteroaromatics .…”