Additive-Free, Pd-Catalyzed 3-Amino-1-methyl-1H-pyridin-2-one-Directed C(sp²)–H Arylation and Methylation in Water

Abstract

Small molecules containing a 2-pyridone unit received much attention due to their significance in medicinal chemistry. In this regard, development of novel methodologies via metal-catalyzed carbon–carbon bond formation by chelation-assisted C–H activation will be an attractive method to achieve therapeutically important 2-pyridone analogues and arylated acid synthons. We report our studies on a Pd­(II)-catalyzed coupling reaction between methyl, aryl, heteroaryl iodides, and sp2 carbons both at β- and γ-positions using 3-amino-1-methyl-1H-pyridin-2-one as an efficient, built-in bidentate N,O-directing group (DG) toward the synthesis of pyridone derivatives. The effect of temperature, solvent, reagent equivalence, and substrate has been investigated for this DG-mediated late-stage functionalization reactions along with the crystal structure of a selected analogue. Moreover, this DG has been successfully applied for ortho-selective C­(sp2)–H activation in aqueous medium in high yields to demonstrate the practicability of this present methodology.

Revolutionizing C–H Activation Reactions: Harnessing Green Solvents for Sustainable Catalysis

“…A research on Pd(II)-catalyzed C(sp 2 )-H arylation and methylation of methyl, aryl, heteroaryl iodides, and sp 2 carbons at both β-and γ-positions was done by Roy et al in 2019. 29 As part of the study, they used 3-amino-1-methyl-1H-pyridin-2-one as a bidentate N,O-directing group (DG) in water to synthesize to synthesize pyridine and arylated acid synthons. (See Scheme 7 for details).…”

Transition‐Metal‐Catalyzed Directed C−H Functionalization in/on Water

“…Although only a few examples are presented using water as a solvent and Pd(OAc) 2 as a catalyst, yet the arylation of sp 2 carbons could be achieved with aryl iodide as coupling partners in good yields (Scheme 6). [18] The bidentate pyridone based DG can be removed using BF 3 ‐OEt 2 in MeOH at 90 °C for 24 h, furnishing methyl ester in good yield. Later, the arylation of aryl acetic and acrylic acid derivatives 8 has been accomplished using 8‐aminoimidazopyridine as a potential bidentate removable auxillary in presence of the Pd‐catalysis (Scheme 7).…”

Installing the “magic methyl” – C–H methylation in synthesis

“…Additionally, methyl iodide was used by Roy & Kundu in their ortho methylation of arenes bearing a 2-pyridone unit (Scheme 4C). 33 In this instance, water was used as the solvent.…”