Pyridone Functionalization: Regioselective Deprotonation of 6‐Methylpyridin‐2(1H)‐ and ‐4(1H)‐one Derivatives

Abstract

Selective functionalization at the α‐methyl group of 1‐substituted pyridin‐2(1H)‐ and 4(1H)‐ones (2‐ and 4‐pyridones) can be achieved by appropriate choice of base. n‐Butyllithium was found to effect clean 6(2)‐methyl deprotonation of 1‐benzyl‐2‐ and ‐4‐pyridone derivatives, while potassium hexamethyldisilazide (KHMDS) was the preferred reagent for methyl deprotonation of the corresponding 1‐methyl‐2‐ and ‐4‐pyridones. Deprotonation proceeds smoothly at –78 °C, and the resulting anions react readily with a wide range of electrophiles (aldehydes, ketones, alkylating reagents, and an azo compound) under precise temperature control to form usefully functionalized 2‐ and 4‐pyridones and quinolizinones.

Non-Palladium-Catalyzed Approach to the Synthesis of (E)-3-(1,3-Diarylallylidene)Oxindoles

“…Based on the fact that the functional handle of the methyl group was located at the γ-position of the α,β-unsaturated carbonyl moiety, we assumed that aldol reaction may be feasible. In addition, several examples of similar aldol reactions were found in the literature [24][25][26]. According to the results of base screening, only n-BuLi could provide the desired aldol product, 8aa, in good yield (Scheme 4).…”

The Construction of Polycyclic Pyridones via Ring-Opening Transformations of 3-hydroxy-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,8-diones

“…The chemistry of these heterocycles is actively developed not only for the design of biologically important compounds [ 7 , 8 , 9 ], but also for effective preparation in the industry [ 1 , 2 , 3 , 10 , 11 , 12 , 13 , 14 , 15 ]. At the same time, there is a need to search for new multifarious pyridone building blocks [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ] and convenient synthetic tools for the construction of polycyclic pyridones [ 1 , 2 , 3 , 15 ], including CH functionalization [ 26 ].…”

Selective C(sp3)–H Cleavage of Enamides for Synthesis of 2-Pyridones via Ligand-Enabled Ni–Al Bimetallic Catalysis

“…However, most of these reactions occurred at vinylic C­(sp 2 )–H sites, wherein electron-rich π bonds were crucial to C­(sp 2 )–H bond functionalization toward high-valent transition metals or electrophiles (Scheme a, left). By contrast, rare examples have been reported for catalytic β′-C­(sp 3 )–H bonds of enamides (Scheme a, right), because vinylic C­(sp 2 )–H bonds displayed higher reactivity than C­(sp 3 )–H bonds, and their reactions often dominated in most cases . In the year 2010, Glorius and co-workers devised a smart strategy to address this challenge.…”