An Application Of Rhodium Catalyst In Directed C-H Functionalization Of Quinoline N-Oxides

Over the past few decades, transition-metal-catalyzed C−H functionalization has emerged as a powerful strategy to synthesize complex molecules. The development of direct methods for activating the inactive C-H bonds to generate C-C bonds is more attractive but challenging due to the higher bond dissociation energy (BDE). Nevertheless, how to control the regioselectivity if the substrates have more than one reacting C−H bond remains a challenge. Therefore, the chelation-assisted transformation has become a common and powerful method for the regioselective functionalization of C–H bonds.

Quinoline is an important molecular skeleton in the medical industry, especially in many drugs and biologically active molecules. Accordingly, the development of efficient methods to produce substituted quinoline is of great significance. Recently, much effort has been made in the area of C−H functionalization of quinoline at different positions. N-oxide as a directing group has attracted significant attention, which has been used to achieve the desired regioselective control.

A significant number of methods exist for transition-metal-catalyzed functionalization at the C-2 position of quinoline N-oxides. By contrast, only a few examples have been reported for the selective C-8 functionalization of quinoline N-oxides. Organoboron reagents, especially alkyl boron reagents, have been used extensively in C−H functionalization.

Our research group (Prof. Liu’s group, SIMM, Shanghai, China) has focused on C-H bond functionalization. In a recent study, we have developed Rhodium(III)-catalyzed site-selective C–H alkylation and arylation of pyridones using organoboron reagents. Inspired by the previous work, we disclose a Rh(III)-catalyzed C-8 methylation and arylation of quinoline N-oxides with potassium trifluoroborate reagents.

After extensive optimization, the standard conditions for the Rh-catalyzed C-H functionalization reaction are: 5 mol% [RhCp*Cl₂]₂, 20 mol% AgSbF₆, 2 equiv of AgOAc, and 2 equiv of MeBF₃K in DME at 65 °C for 18 h under argon. C-8 methylated and arylated quinolines have been synthesized at good yields with the optimal reaction conditions. This finding has been utilized for the synthesis of selective agrochemical fungicide quinoxyfen derivatives.

The mechanism was proposed based on preliminary mechanistic experiments. The rhodacycle has been synthesized, isolated and characterized. The reaction could also proceed well with the synthesized rhodacycle, illustrating that this rhodacycle should be the active intermediate species in the catalytic cycle.

In summary, we developed a simple, highly efficient Rh(III)-catalyzed direct site-selective methylation and arylation of quinoline N-oxides at the C-8 Position using potassium trifluoroborates under mild conditions. This concise protocol and further chemical transformations of the products might have important applications in the synthesis of biologically active compounds.

This study, Cp*Rh(III)-Catalyzed Directed C-H Methylation and Arylation of Quinoline N-Oxides at the C-8 Position was recently published in the journal Advanced Synthesis & Catalysis.