Silver-Catalyzed Direct Synthesis of Trifluoromethylated Enaminopyridines and Isoquinolinones Employing Trifluorodiazoethane

Abstract

This Letter reports a Ag-catalyzed three-component approach for the N-alkenylation of 2-aminopyridines employing aldehydes and trifluorodiazoethane. Unlike the known reactions of trifluorodiazoethane with imines, which generate Mannich adducts, aziridines, or triazolines depending on the substrates and conditions, this reaction, after Mannich addition, proceeds via a carbene formation and 1,2-aryl migration sequence to afford (E)-enaminopyridines. This surprising selectivity, which is effective for a wide range of aldehydes and 2-aminopyridines, has been subsequently explored to access trifluoromethylated isoquinolinones.

Recent advances in transition metal-mediated trifluoromethylation reactions

“…Recently in 2021, Mohanan's group further developed a facile methodology for Ag-catalyzed three-component synthesis of trifluoromethylated enaminopyridines and isoquinolinones, by employing 2-aminopyridine, trifluorodiazoethane and aldehydes (Scheme 50). 105 The authors hypothesized that this reaction was initiated by in situ generation of Schiff base 50f by the reaction of aldehyde 50a and 2-aminopyridine 50b . In the presence of a silver salt, CF 3 CHN 2 generated silver trifluorodiazoethylide 50e , which subsequently endured Mannich addition with 50f to generate adduct 50g , that upon nitrogen elimination formed silver–carbenoid intermediate 50h .…”

Trifluorodiazoethane: A versatile building block to access trifluoromethylated heterocycles

“…Very recently, a three‐component synthesis of biologically relevant trifluoromethylated isoquinolinones 92 was unraveled by our group using 2‐aminopyridine 91 , trifluorodiazoethane, and 2‐carboxybenzaldehyde 90 (Scheme 44) [61]. The multicomponent reaction involves in situ generation of imine from 2‐carboxybenzaldehyde and 2‐aminopyridine followed by Ag‐catalyzed addition of trifluorodiazoethane, and then 1,2‐migratory aryl insertion to produce enamine 93 .…”

Ruthenium(ii)-catalyzed synthesis of CF3-isoquinolinones via C–H activation/annulation of benzoic acids and CF3-imidoyl sulfoxonium ylides

“…7 In addition, 3-CF 3 isoquinolinones could not be prepared via direct C(sp 2 )–H trifluoromethylation of isoindolinone cores using TMSCF 3 under oxidative conditions, due to the fact that trifluoromethylation occurs at the electron-rich C4 position (Scheme 1c). 10…”