Synthesis of Functionalized Arylacetamido-2-pyridones through ortho-C(sp²)–H-Activated Installation of Olefins and Alkynes

Abstract

We have identified different N-substituted 2pyridones as inbuilt directing groups for selective C−H-activated functionalization instead of deprotecting and/or throwing away the directing groups. A robust general method for external ligand-free Pd II -catalyzed C(sp 2 )−H olefination and alkynylation is established to access valuable phenylacetamido-2-pyridones. Diverse substrate scope has been demonstrated with 48 different examples with high yield and gram-scale synthesis. Adequate tolerance of valuable functional groups was also observed, such as olefins possessing esters, sulfone, amide, cyanide, and ketones, aromatic residues containing fluorine, chlorine, bromine, NO 2 , methyl, dimethyl, and methoxy, as well as 2-pyridone-N-bearing methyl, cyclopropyl methyl, cyclopentyl methyl, benzyl, phenyl, acetate, and acetamide groups, which smoothly produced the respective desired products. We used triisopropyl silane-substituted alkynes for the alkynylation reaction, which can easily be converted to several functional groups including terminal alkyne, heterocycle through click reaction, and others. Implementing our protocol, we have also demonstrated late-stage olefination and alkynylation of 2-pyridone, containing the CB2 agonist-type molecule with excellent yield. Considering N-substituted 2-pyridone acts as a biologically-active structural unit, this general method has the significance in terms of late-stage functionalization to access new molecular entities which can be employed in medicinal chemistry research through diverse C−H activation.

2-Pyridone-Directed CuII–Catalyzed General Method of C(sp2)-H Activation for C–S, C–Se, and C–N Cross-Coupling: Easy Access to Aryl Thioethers, Selenide Ethers, and Sulfonamides and DFT Study

“…While Cu-catalyzed aryloxylation is a known process using an N,O -directing group, the exploration of C–H thiolation reactions remains uncharted territory, especially when employing a relatively weaker coordinating N,O -directing group. As a part of our ongoing research on biologically relevant weak N,O -dented 2-pyridone directing group, we reported Pd-catalyzed 2-pyridone-directed C–H arylation, olefination, and alkynylation methodologies . In this study, we have demonstrated Cu(II)-catalyzed 2-pyridone-directed thiolation, selenylation, and sulfonamidation of the ortho C–H bond of benzoic acid derivatives.…”

Palladium-Catalyzed, Site-Selective C(sp2)8–H Halogenation and Nitration of 4-Quinolone Derivatives

“…In another exemplary work, the same group disclosed a compelling Rh(III) and Ru(II) catalyzed regioselective C5 and C2 alkynylation using ethynylbenzoiodoxolone (TIPS-EBX) reagent . Therefore, driven by the potential application of 4-quinolone motifs as well as our growing interests in developing general protocols toward carbon–carbon and carbon–heteroatom bonds via inert C–H bond activation, herein, we delineate an efficient palladium-catalyzed C8–H selective halogenations and nitration of 4-quinolone derivatives harnessing a strongly coordinating pyrimidine as a chelating removable auxiliary employing readily available N -halo succinimide (NXS, X = Cl, Br, I) and tert -butyl nitrite (TBN) as halogenating and nitrating agent, respectively (Figure ). To the best of our knowledge, no such report has been demonstrated until now.…”

Copper(II)-Mediated, Site-Selective C(sp2)–H Sulfonamidation of 1-Naphthylamines

“…Meanwhile, the reactivity of both amide-tethered oxazoline and pyrazole as an efficacious bidentate directing group was exploited with various sulfonamides (Figure ). With our continuous interest in developing general protocols toward carbon–carbon and carbon–heteroatom bonds, we envisaged that the Cu­(II)-mediated bidentate auxiliary-directed C8–H bond activation of naphthalene and the concomitant C–N bond-forming reaction with readily available sulfonamides could provide an easy entry to N -arylated sulfonamides. To the best of our knowledge, no such report exists for the selective C8–H sulfonamidation of 1-naphthylamine derivatives.…”