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

Over the past few decades, transition-metal-catalyzed C鈭扝 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鈭扝 bond remains a challenge. Therefore, the chelation-assisted transformation has become a common and powerful method for the regioselective functionalization of C鈥揌 bonds.

Quinoline is an important molecular聽skeleton in the medical聽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鈭扝 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.

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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鈭扝 functionalization.

Our research group (Prof. Liu鈥檚 group, SIMM, Shanghai, China) has focused on C-H bond functionalization.聽In a recent study, we have developed Rhodium(III)-catalyzed site-selective C鈥揌 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 掳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.

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

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