The Azomethine Ylide Route to Amine C–H Functionalization: Redox-Versions of Classic Reactions and a Pathway to New Transformations

Abstract

ConspectusRedox-neutral methods for the functionalization of amine α-C–H bonds are inherently efficient because they avoid external oxidants and reductants and often do not generate unwanted byproducts. However, most of the current methods for amine α-C–H bond functionalization are oxidative in nature. While the most efficient variants utilize atmospheric oxygen as the terminal oxidant, many such transformations require the use of expensive or toxic oxidants, often coupled with the need for transition metal catalysts.Redox-neutral amine α-functionalizations that involve intramolecular hydride transfer steps provide viable alternatives to certain oxidative reactions. These processes have been known for some time and are particularly well suited for tertiary amine substrates. A mechanistically distinct strategy for secondary amines has emerged only recently, despite sharing common features with a range of classic organic transformations. Among those are such widely used reactions as the Strecker, Mannich, Pictet–Spengler, and Kabachnik–Fields reactions, Friedel–Crafts alkylations, and iminium alkynylations. In these classic processes, condensation of a secondary amine with an aldehyde (or a ketone) typically leads to the formation of an intermediate iminium ion, which is subsequently attacked by a nucleophile. The corresponding redox-versions of these transformations utilize identical starting materials but incorporate an isomerization step that enables α-C–H bond functionalization. Intramolecular versions of these reactions include redox-neutral amine α-amination, α-oxygenation, and α-sulfenylation. In all cases, a reductive N-alkylation is effectively combined with an oxidative α-functionalization, generating water as the only byproduct.Reactions are promoted by simple carboxylic acids and in some cases require no additives. Azomethine ylides, dipolar species whose usage is predominantly in [3 + 2] cycloadditions and other pericyclic processes, have been identified as common intermediates. Extension of this chemistry to amine α,β-difunctionalization has been shown to be possible by way of converting the intermediate azomethine ylides into transient enamines.This Account details the evolution of this general strategy and the progress made to date. Further included is a discussion of related decarboxylative reactions and transformations that result in the redox-neutral aromatization of (partially) saturated cyclic amines. These processes also involve azomethine ylides, reactive intermediates that appear to be far more prevalent in condensation chemistry of amines and carbonyl compounds than previously considered. In contrast, as exemplified by some redox transformations that have been studied in greater detail, iminium ions are not necessarily involved in all amine/aldehyde condensation reactions.

Stereoselective Monoamine Oxidase‐Catalyzed Oxidative Aza‐Friedel–Crafts Reactions of meso‐Pyrrolidines in Aqueous Buffer

“…However, in this case one would expect to find identical ee values for 5a – d . Another plausible explanation is a post‐oxidation racemization by an internal redox‐neutral hydride transfer mechanism, as commonly observed for cyclic iminium ions 23. This racemization has been described to proceed through an azomethine ylide intermediate as depicted in Scheme .…”

Intramolecular Redox‐Mannich Reactions: Facile Access to the Tetrahydroprotoberberine Core

“…Conditions that were shown previously to be applicable to a wider range of amine redox transformations were examined next, namely, the use of toluene as the solvent and carboxylic acids as additives (Table 1). 6a Exposure of 3 a and pyrrolidine (1.3 equiv) to heating at reflux in toluene in the absence of any additives led to the consumption of 3 a within 12 h (entry 1). As before, a complex mixture of unidentified polar materials was observed.…”

Redox‐Neutral C1 Functionalization of Unprotected Tetrahydroisoquinolines with Diazo Carbonyl Compounds

“…Havingo ptimizedt he reaction conditions, we then explored the scope and limitationo ft he present Ag-catalyzed C1 functionalization process with avariety of THIQs, diazo compounds, and 2,6-dimethylbenzaldehyde (Scheme 3). The reaction was found to be not significantly affected by the substituents on the aromatic ring of THIQs;b oth electron-donating groups (8,9)a nd electron-withdrawingg roup (10)w ere well tolerated. When 4-methyl THIQ was used as the substrate, the reaction gave the desired three-component couplingp roduct 11 in 72 %y ield with 1:2d iastereoselectivity.S imilarly,t wo inseparable diastereomers wereo btained in ar atio of 1:1.2 by using 4-phenylT HIQ as the substrate.…”

“…In the past years, the redox-neutral a-CÀHb ond functionalizations of secondary amines involving exo/endo-iminiumi somerization have been reportedb yS eidel and other research groups. [8][9][10][11][12][13][14][15] The transition of exo-iminium ion 4 into endo-iminiumi on 6 is proposed to be accomplished by iminium deprotonation/reprotonation via an azomethine ylide intermediate. Carboxylica cids [11][12][13][14][15] and transition-metals such as Cu, [9a-c] Ag, [9e, 12a] and Au, [9d] have been developedt op romote this process.…”