Solvent‐Controlled Rhodium‐Catalyzed C6‐Selective C−H Alkenylation and Alkylation of 2‐Pyridones with Acrylates

Abstract

A solvent-controlled rhodium-catalyzed C6-selective alkenylation and alkylation of 2-pyridones with acrylates via a pyridine-directed CÀ H cleavage was developed. Using DMF as solvent, the CÀ H alkenylation with acrylates selectively occurs to deliver the corresponding C6-alkenylated 2-pyridones in good yields. On the other hand, the C6-alkylated products are predominantly formed in a more polar and protic solvent, HFIP. Thus, a single set of starting substrates can be divergently transformed to C6-functionalized 2-pyridones, which are of potent interest in medicinal and pharmaceutical chemistry.[a] S.

Emerging unconventional organic solvents for C–H bond and related functionalization reactions

“…Using these starting materials, several literature precedents have described chemodivergent reactivity depending on the reaction conditions: hydroarylation vs. oxidative annulation (Scheme 2b). 7,8 These reactivity patterns represented an ideal test case for investigating the role of HFIP since, a priori, it could play opposite effects. In both cases, the authors discovered that the addition of HFIP enables the use of milder conditions for obtaining the corresponding product in almost quantitative yields, but presumably due to different reasons.…”

“…Miura and co-workers have demonstrated the selective C-H alkenylation and alkylation of 2-pyridones with acrylates, depending on the employed solvent (Scheme 3a). 7 Using DMF, the authors observed the expected formation of the C6-alkenylated product. In sharp contrast, HFIP promoted the alkylation processes due to its capability to act as a proton source.…”

Recent Progress in Nitro-Promoted Direct Functionalization of Pyridones and Quinolones

“…Among the large number of aza-heterocycles available, pyridones and quinolones, both of which have a common six-membered aza-framework, exhibit a wide range of pharmacologically important activities ( Figure 1) [6][7][8][9][10]. Therefore, various methods for the preparation of structurally diverse pyridones and quinolones have been studied in detail [6,[11][12][13][14][15][16][17][18][19][20][21].…”

“…Among the large number of aza-heterocycles available, pyridones and quinolones, both of which have a common six-membered aza-framework, exhibit a wide range of pharmacologically important activities ( Figure 1) [6][7][8][9][10]. Therefore, various methods for the preparation of structurally diverse pyridones and quinolones have been studied in detail [6,[11][12][13][14][15][16][17][18][19][20][21]. Conventional strategies for the synthesis of aza-heterocycles involve (1) construction of azaheterocycle frameworks from prefunctionalized starting materials, (2) ring transformation leading to Conventional strategies for the synthesis of aza-heterocycles involve (1) construction of aza-heterocycle frameworks from prefunctionalized starting materials, (2) ring transformation leading to aza-heterocycle frameworks, and (3) direct functionalization of aza-heterocycle frameworks, which are supplementary to each other ( Figure 2) [22].…”

“…The nitro group is also a good leaving group, which is often involved in addition-elimination reactions [31,32]. To the best of our knowledge, the currently used methods for direct functionalization of the quinolone and pyridone scaffolds are mainly focused on transition-metal-catalyzed cross-coupling and C-H activation reactions [6,[11][12][13][14][15][16][17][18][19][20][21]. However, most of these methods suffer from some limitations, such as the use of potentially poisonous and expensive noble metals, along with harsh reaction conditions.…”