Copper-Catalyzed Radical C–C Bond Cleavage and [4+1] Annulation Cascade of Cycloketone Oxime Esters with Enaminothiones

Abstract

Carbon–carbon bond formation is among the most important reactions in organic synthesis. Reconstruction of a carbon–carbon bond through ring-opening C–C bond cleavage of a strained carbocycle usually occurs via a thermodynamically preferable pathway. However, carbon–carbon bond formation through thermodynamically less favorable C–C bond cleavage has seldom been documented. Herein, we disclose an unusual C–C bond cleavage of cycloketone oxime esters for [4+1] annulation. Under anaerobic copper­(I) catalysis, cycloketone oxime esters underwent regioselective, thermodynamically less favorable radical C–C bond cleavage followed by annulation with enaminothiones; that is, α-thioxo ketene N,S-acetals efficiently affording 2-cyanoalkyl-aminothiophene derivatives. Cyclobutanone, -pentanone, -hexanone, and -heptanone oxime esters could act as the effective C1 building blocks in the annulation reaction. An iminyl radical mechanism is proposed for the rare C–C bond cleavage/[4+1] annulation cascade.

ZnCl2‐Catalyzed [4+1] Annulation of Alkylthio‐Substituted Enaminones and Enaminothiones with Sulfur Ylides

“…We recently found that alkylthio‐substituted enaminones and enaminothiones, that is, α‐oxo (thioxo) ketene N,S‐acetals, could undergo carbene insertion reactions to establish O‐ and S‐heterocycles under copper(II) catalysis or metal‐free conditions (Scheme a), and cycloketone oxime esters were also used as the C1 building blocks to react with enaminothiones in the presence of a copper(I) catalyst to give thiophene derivatives (Scheme b) . Thus, we envisioned that sulfur ylides might also act as the suitable C1 building blocks to react with alkylthio‐substituted enaminones and enaminothiones to execute [4+1] annulation to afford multisubstituted furan and thiophene derivatives (Scheme c).…”

Iminyl-Radical-Triggered C–C Bond Cleavage of Cycloketone Oxime Derivatives: Generation of Distal Cyano-Substituted Alkyl Radicals and Their Functionalization

“…Yu and co-workers reported a copper-catalyzed [4+1] annulation of cycloketone oxime esters 12 with -thioxo ketene N,S-acetals 134 to access 2-cyanoalkyl-3-aminothiophene derivatives 135 (Scheme 35). 53 The five-membered S-heterocycle was constructed through the abstraction of hydrogen adjacent to the S-atom in intermediate 137 by the carboxylate anion followed by addition to the in situ generated iminium ion. This is the first example with cycloketone oxime esters as the C1 building blocks in an annulation reaction.…”

Recent Developments in Radical Cross‐Coupling of Redox‐Active Cycloketone Oximes

“…In 2019, Yu and co‐workers demonstrated an efficient copper(I)‐catalyzed [4+1] annulation of cycloketone oxime esters with enaminothiones 90 for the synthesis of 2‐cyanoalkyl‐3‐aminothiophene derivatives 91 , where cycloketone oximes esters served as C1 building blocks (Scheme 31). [43] With CuCl as the catalyst, various substituted enaminothiones were treated with symmetrical and asymmetrical cycloketone oxime esters to afford cyanoalkylated thiophenes in moderate to good yields. Interestingly, an unusual and thermodynamically less favorable ring cleavage of 2‐substituted cycloketone oximes was observed.…”