Unified Approach to the Chemoselective α-Functionalization of Amides with Heteroatom Nucleophiles

Abstract

Functionalization at the α-position of carbonyl compounds has classically relied on enolate chemistry. As a result, the generation of a new C–X bond, where X is more electronegative than carbon requires an oxidation event. Herein we show that, by rendering the α-position of amides electrophilic through a mild and chemoselective umpolung transformation, a broad range of widely available oxygen, nitrogen, sulfur, and halogen nucleophiles can be used to generate α-functionalized amides. More than 60 examples are presented to establish the generality of this process, and calculations of the mechanistic aspects underline a fragmentation pathway that accounts for the broadness of this methodology.

An α‐Cyclopropanation of Carbonyl Derivatives by Oxidative Umpolung

“…Furthermore, we were pleased to find that 2‐norbornyl amides undergo oxidative cyclopropanation through amide umpolung chemistry using 2‐iodo pyridine, trifluoromethanesulfonic anhydride, and pyridine‐ N ‐oxide (PNO) subsequently . Even though a pyridine base is used for this approach, elimination towards the norbornene derivative 36 represents only a minor reaction pathway (Scheme ).…”

“…Furthermore, we were pleased to find that 2-norbornyl amides undergo oxidative cyclopropanation through amide umpolung chemistry using 2-iodo pyridine, trifluoromethanesulfonic anhydride, and pyridine-N-oxide (PNO) subsequently. [84][85][86][87] Even though a pyridine base is used for this approach, elimination towards the norbornene derivative 36 represents only a minor reaction pathway (Scheme 7). This result showcases the aforementioned tenet of non-classical In conclusion, we have demonstrated that 2-electron oxidative umpolung is a valuable concept for the metal-free construction of cyclopropanes.…”

A Novel Class of 7‐Membered Heterocyclic Compounds

“…[2] In doing so, the amide is transformed into an α-trifloxyenamine 2, which resides in a biased equilibrium with the keteniminium salt 3. The latter, a highly electrophilic species, can be intercepted by several nucleophiles, including nucleophilic oxidants, [3][4][5][6][7] and enables a range of unconventional reactivity profiles for the atoms surrounding the original amide functionality. [8][9][10][11][12] The capture of the central electrophilic atom of the keteniminium by modestly nucleophilic entities such as alkenes (in formal [2+2] cycloaddition reactions [13,14] or other ring-forming events) [15] or ethers [16,17] is a well-documented phenomenon.…”

Chemoselective γ‐Oxidation of β,γ‐Unsaturated Amides with TEMPO

“…In comparison to this plethora of methods for α‐functionalisation,[ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ] accessing remote positions has remained largely an unexplored area in amide activation. Two examples of γ‐aminoxylation were reported for conjugated acyloxazolidinone (imide) Ti‐enolates by Romea and Urpi (Scheme 1 a ).…”