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. 2024 Jul 2;15(1):5552.
doi: 10.1038/s41467-024-49362-2.

Ligand-enabled ruthenium-catalyzed meta-C-H alkylation of (hetero)aromatic carboxylic acids

Xianglin Luo  1 , Peichao Hou  1 , Jiayi Shen  1 , Yifeng Kuang  1 , Fengchao Sun  1 , Huanfeng Jiang  1 , Lukas J Gooßen  2 , Liangbin Huang  3
Affiliations

Ligand-enabled ruthenium-catalyzed meta-C-H alkylation of (hetero)aromatic carboxylic acids

Xianglin Luo et al. Nat Commun. .

Abstract

Carboxylates are ideal directing groups because they are widely available, readily cleavable and excellent linchpins for diverse follow-up reactions. However, their use in meta-selective C-H functionalizations remains a substantial unmet catalytic challenge. Herein, we report the ruthenium-catalyzed meta-C-H alkylation of aromatic carboxylic acids with various functionalized alkyl halides. A bidentate N-ligand increases the electron density at the metal center of ortho-benzoate ruthenacycles to the extent that single-electron reductions of alkyl halides can take place. The subsequent addition of alkyl radicals is exclusively directed to the position para to the CAr-Ru bond, i.e., meta to the carboxylate group. The resulting catalytic meta-C-H alkylation extends to a wide range of (hetero)aromatic carboxylic acids including benzofused five-membered ring heteroarenes but no pyridine derivatives in combination with secondary/tertiary alkyl halides, including fluorinated derivatives. It also allows site-selective C5-H alkylation of 1-naphthoic acids. The products are shown to be synthetic hubs en route to meta-alkylated aryl ketones, nitriles, amides, esters and other functionalized products.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Carboxylate directed meta-C–H alkylation as an unmet catalytic challenge.
a Carboxylate groups directed C(sp2)-H functionalization into the ortho, not into the meta position. b N/P-containing group directed meta-C–H functionalization via Ru-catalyzed σ-bond activation. c This work: ligand-enabled meta-C–H alkylation of ArCO2H with alkyl halides.
Fig. 2
Fig. 2. The scope of the meta-alkylation of aromatic carboxylic acids.
[a]Reaction conditions: 1 (0.3 mmol), 2 (0.6 mmol), [Ru(p-cym)Cl2]2 (2.5 mol%), L6 (5.0 mol%), KOAc (2 equiv.), LiBr (30 mol%), tBuOH/HFIP = 9:1, 100 οC for 12 h under N2. Yields of the corresponding methyl esters after esterification with K2CO3 (2 equiv.) and MeI (5 equiv.) in NMP; [b]Isolated as the free acid; [c]1,4-dioxane instead of tBuOH/HFIP = 9:1; [d]1 (1.2 mmol), 2 (0.3 mmol), [Ru(p-cym)Cl2]2 (5.0 mol%), L5 (10.0 mol%), Na2CO3 (2 equiv.), AgOTf (20 mol%), tBuOH/HFIP = 20:1; [e][Ru(p-cym)Cl2]2 (5.0 mol%), L6 (10.0 mol%), AgOTf (20 mol%) instead of LiBr, tBuOH instead of tBuOH/HFIP.
Fig. 3
Fig. 3. The scope of C5-alkylation of 1-naphthoic acid.
[a]Reaction conditions: 1 (0.3 mmol), 2 (0.6 mmol), [Ru(p-cym)Cl2]2 (2.5 mol%), L5 (5.0 mol%), KOAc (2 equiv.), LiBr (30 mol%), tBuOH/HFIP = 9:1, 100 οC for 12 h under N2. Yields of the corresponding methyl esters after esterification with K2CO3 (2 equiv.) and MeI (5 equiv.) in NMP. [b]Isolated as the free acid. [c]1,4-dioxane instead of tBuOH/HFIP = 9:1.
Fig. 4
Fig. 4. Mechanistic studies.
A No reaction without ortho C–H or two meta substituents. B H/D exchange experiment. C Kinetic isotopic effect study. D Stoichiometric and catalytic reaction of Ru-A. E Trapping of intermediate with 1,1-diphenylethylene. F The rate of product 5ab formation w/wo L6. G Cyclic voltammograms for 1a, [Ru(p-cym)Cl2]2 + w/wo L6 and Ru-A + w/wo L6. H Reversible H/D exchange. I Plausible catalytic cycle.
Fig. 5
Fig. 5. Synthetic applications.
a Carboxylate directed ortho-C–H functionalization. b Decarbonylation of ArCO2H. c Reduction of ArCO2H. d Transformation of ArCO2H.
See this image and copyright information in PMC

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