Alkynyl Triazenes as Fluoroalkyne Surrogates: Regioselective Access to 4-Fluoro-2-pyridones by a Rh(III)-Catalyzed C–H Activation–Lossen Rearrangement–Wallach Reaction

Abstract

Fluorinated pyridones are an important scaffold displaying relevant biological activities. Efficient assembly strategies of pyridones are transition metal-catalyzed C–H annulations with alkynes. The inaccessibility and extreme lability of fluoro alkynes render any direct utilization in catalysis futile. We report a highly regioselective synthesis of 4-fluoro-2-pyridones using 1-alkynyl triazenes as a convenient fluoroalkyne surrogates. The protocol comprises an alkenyl C–H annulation with 1-alkynyl triazenes followed by a treatment with HF·pyridine smoothly delivering a broad range of 4-fluoro-2-pyridones in a one-pot fashion in 90 min at 23–60 °C. Notably, a rare Lossen rearrangement occurs during the C–H functionalization part of the transformation, allowing selective access to the less-available 4-fluoro-2-pyridone framework. Furthermore, the triazenyl intermediate was elaborated into additional fluorine-containing substituents like fluorinated alkoxy and trifluoromethyl groups.

Vinyl and Alkynyl Triazenes: Synthesis, Reactivity, and Applications

“…Besides oxidative C−H activation reactions, alkynyl triazenes have been used as substrates in redox‐neutral annulation reactions with N ‐(pivaloyloxy)acrylamides [29] . The Cp*Rh III ‐catalyzed reactions were found to proceed with Lossen rearrangement to give 4‐triazenyl‐2‐pyridones with high selectivity.…”

Divergent rhodium-catalyzed electrochemical vinylic C–H annulation of acrylamides with alkynes

“…1a , left side) 17 , 18 . Inspired by these seminal works, various transition metal-catalyzed vinylic C–H annulation reactions with alkynes have been developed to prepare α-pyridones or α-pyrones, including ones catalyzed by Rh 19 – 24 , Ru 25 – 29 , Co 30 – 33 , Pd 34 – 36 , and Fe 37 , 38 catalysts. Despite these advances, important challenges remain, including: (1) typically high reaction temperatures (100–120 °C); (2) stoichiometric transition metal oxidants such as Cu(OAc) 2 or AgOAc are generally required to regenerate catalysts; (3) a highly selective divergent synthesis of α-pyridones and cyclic imidates (Fig.…”

“…1a, left side) 17,18 . Inspired by these seminal works, various transition metalcatalyzed vinylic C-H annulation reactions with alkynes have been developed to prepare α-pyridones or α-pyrones, including ones catalyzed by Rh [19][20][21][22][23][24] , Ru [25][26][27][28][29] , Co [30][31][32][33] , Pd [34][35][36] , and Fe 37,38 catalysts. Despite these advances, important challenges remain, including: (1) typically high reaction temperatures (100-120°C);…”

Divergent Rhodium-Catalyzed Electrochemical Vinylic C–H Annulation of Acrylamides with Alkynes

“…3 Subsequently, the groups of Li and Rovis reported Rhcatalyzed vinylic C-H annulation of acrylamides with alkynes to afford a-pyridones under elevated temperature using stoichiometric transition metal oxidants (Scheme 1A, left side). 4 Inspired by these seminal works, various transition metal-catalyzed vinylic C-H annulation reactions with alkynes have been developed to prepare -pyridones or -pyrones, including ones catalyzed by Rh, 5 Ru, 6 Co, 7 Pd, 8 and Fe 9 catalysts. Despite these advances, important challenges remain, including: 1) typically high reaction temperatures (100-120 °C); 2) stoichiometric transition metal oxidants such as Cu(OAc)2 or AgOAc are generally required to regenerate catalysts; 3) a highly selective divergent synthesis of -pyridones and cyclic imidates (Scheme 1A, right side) from acrylamides is still lacking.…”