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

Trisha Mitra (TCGLS Member), Brindaban Roy and Mrinalkanti Kundu (TCGLS Member)

The Journal of organic chemistryJournal; Article; (JOURNAL ARTICLE), 2019

DOI: 10.1021/acs.joc.9b02122

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 sp(2) 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(sp(2)​)​-​H activation in aqueous medium in high yields to demonstrate the practicability of this present methodology.