Ligand-Enabled Pd(II)-Catalyzed β-Methylene C(sp³)–H Arylation of Free Aliphatic Acids

Abstract

Ligand development has enabled rapid advances in Pd(II)-catalyzed β-methyl C(sp³)–H activation of free carboxylic acids. However, there are only a handful of reports of free-acid directed β-methylene C(sp³)–H activation, all of which are limited to intramolecular reactions. Herein, we report the first Pd(II)-catalyzed intermolecular β-methylene C(sp³)–H arylation of free aliphatic acids, which is enabled by bidentate pyridine-pyridone ligands. The bite angle of this ligand has been discovered to play a key role in promoting β-methylene C–H activation of free carboxylic acid. This new transformation provides a disconnection for alkylation of arenes with simple aliphatic acids. A variety of free aliphatic acids, including the antiasthmatic drug seratrodast were compatible with the reported protocol.

Graphical Abstract

In recent years, transition-metal-catalyzed C–H functionalization has emerged as an efficient strategy for the construction of carbon-carbon and carbon-heteroatom bonds.¹ In particular, the β-C(sp³)–H functionalization of carboxylic acid derivatives using carefully designed exogenous DGs has been extensively developed as potential alternative disconnections for conjugate addition.^2–3 Notably, methylene C–H functionalization often requires the installation of bidentate directing groups as exemplified by the Daugulis amino-quinoline DG.⁴ In order to develop ligand-accelerated C–H activation reactions, our group reported a ligand-enabled strategy for the arylation of β-methylene C(sp³)–H bonds using simple monodentate amide auxiliaries.⁵ However, despite the impressive disconnections they enable, the synthetic efficiency of these methodologies are limited by the need to install and remove the DGs they require (Scheme 1A). Thus, the direct C−H arylation of free carboxylic acids would be highly desirable due to its superior atom and step economies.

Scheme 1.

Pd(II)-Catalyzed β-Methylene C−H Arylation of Free Aliphatic Acids

Over the past decade, our group has focused on ligand-enabled C–H activation reactions directed by native functional groups such as free carboxylic acids, free aliphatic amines, and native amides.⁶ Catalytic β-C–H activation of methyl C–H bonds has led to the development of a diverse range of reactions such as arylation,^7a–7f olefination,^7g acetoxylation,^7h,7j and lactonization⁷ⁱ (Scheme 1B).⁷ However, methylene C–H arylation of free acid remains to be demonstrated despite our early report of methyl C–H arylation of free acid.^7a–7f Recently, our group developed a pair of Pd(II)-catalyzed α,β-dehydrogenation reactions of free carboxylic acids through β-methylene C−H activation, delivering α,β-unsaturated carboxylic acids or γ-alkylidene butenolides.⁸ Later in 2022, Our group achieved site-selective β- and γ-methylene C−H lactonization of dicarboxylic acids (Scheme 1B).⁹ However, this chemistry was limited to intramolecular functionalization of the methylene C(sp³)–H bond. Intermolecular reactions offer the potential to rapidly expand molecular diversity, thus, we considered the expansion of this chemistry to enable intermolecular functionalization of β-methylene C(sp³)–H bonds to be a particularly important goal. Herein, we report the first Pd(II)-catalyzed β-methylene C(sp³)–H arylation of free aliphatic acids (Scheme 1C). A wide range of aliphatic carboxylic acids can be directly arylated through activation of methylene C–H bonds.

We began our efforts by testing a range of ligands for the Pd(OAc)₂-catalyzed reaction of model substrate butyric acid (1a, 1.0 equiv.) with aryl iodide (4-iodotoluene, 2.0 equiv.) (Table 1). No desired product was obtained in the absence of ligand. Similarly, a representative monodentate pyridine-type ligand (L2), a mono-dentate pyridone ligand (L3) and an N-acetyl amino acid（MPAA） ligand (L4), also failed to deliver any product. We then turn our attention to pyridone-based bidentate ligands. Recent findings from our group have demonstrated that these types of bidentate ligands can promote carboxylic acid directed β-methylene C−H cleavage.⁸ Pleasingly, the β-methylene arylated product was formed in a modest 21% yield when we employed pyridine-pyridone ligand L5, which forms a six membered bidentate chelate. Encouraged by this result, we next screened a range of other six-member pyridone-based bidentate ligands, but all 6-membered chelates tested gave low yields (See SI for detailed information). We next aim to accelerate C−H cleavage through changing the ligand bite angle (L7) based on the structure of L5.⁸ To our delight, the five-member quinoline-pyridone bidentate ligand improved the yield to 62% (L7). Encouraged by this result, we next started modifying the electronic and/or steric properties of L7. However, efforts to modify the substitution on the ligand backbone didn’t further enhance the reactivity (L8-L14). In addition, ligand bearing an isoquinoline moiety only gave 22% yield (L15).

Table 1.

Investigation of Ligands for the β-Methylene C(sp³)–H Arylation of Free Aliphatic Acids^a,b

^aConditions: 1 (0.1 mmol), aryl iodide 2a (0.2 mmol), Pd(OAc)₂ (10 mol%), ligand (12 mol%), Na₂HPO₄ (1.0 equiv.), AgOAc (2.0 equiv.), Ag₂CO₃ (0.5 equiv.), HFIP (1.0 mL), 100 °C, 48 h.

^bIsolated yields.

With the optimal ligand and reaction conditions in hand, a wide range of aryl iodides were tested (Table 2). Reactions employing electron-neutral or electron-rich aryl iodides (3a-3f) proved particularly effective, while aryl iodides containing electron-withdrawing groups tended to result in slightly lower yields (3g-3l). Additionally, both meta-substituted and ortho-substituted aryl iodides reagents were viable coupling partners (3m-3r). Furthermore, the reaction worked well with 3,5-disubstituted aryl iodide, giving the arylated product in 56% yield (3s). In addition to substituted phenyl iodides, heteroaryl iodides are also tolerated by this reaction (3t-3u).

Table 2.

Aryl Iodide Scope for the β-Methylene C(sp³)–H Arylation of Free Aliphatic Acids^a,b

^aConditions: 1 (0.1 mmol), aryl iodide 2 (0.2 mmol), Pd(OAc)₂ (10 mol%), L7 (12 mol%), Na₂HPO₄ (1.0 equiv.), AgOAc (2.0 equiv.), Ag₂CO₃ (0.5 equiv.), HFIP (1.0 mL), 100 °C, 48 h.

^bIsolated yields.

Subsequently, arylation of a wide range of free carboxylic acids with β-methylene C–H bonds was carried out under the optimized reaction conditions (Table 3). Simple linear and branched aliphatic acids, such as naturally occurring caprylic acid and 4-methyloctanoic acid performed well, affording the desired arylated products 4a to 4e in high yields. Substrates containing sterically hindered alkyl groups at the β position were also tolerated, albeit with a slight reduction in the yields of the corresponding products (4f−4h). Acids containing isopropyl, cyclohexyl and cyclohexylmethyl moieties at the γ positions were also successfully arylated to the desired products (4i−4k). In addition, phenyl propanoic acids bearing chloro- and trifluoromethyl- substituents were converted to β-arylated products in high yields (4m−4o). Furthermore, phenylbutyric acid and phenylvaleric acid underwent smooth arylation to provide the corresponding products in good yields (4p−4q). 4-tBu substituted cyclohexane carboxylic acid was also viable substrate (4r). Notably, the β-methylene arylation reaction was also found to be selective for carboxylic acids in the presence of enolizable ketones and esters, affording the desired products in moderate yields (4r−4u). Fatty acids were also found to be compatible with this transformation, providing the β-arylated products in up to 72% yield (4v−4x). To illustrate the utility of this transformation, the antiasthmatic drug seratrodast was subjected to the standard reaction conditions, delivering the desired product in 52% yield (4y).

Table 3.

Aliphatic Acid Scope for the β-Methylene C(sp³)–H Arylation of Free Aliphatic Acids^a,b,c,d,e

^aConditions: 1 (0.1 mmol), aryl iodide 2 (0.2 mmol), Pd(OAc)₂ (10 mol%), L7 (12 mol%), Na₂HPO₄ (1.0 equiv.), AgOAc (2.0 equiv.), Ag₂CO₃ (0.5 equiv.), HFIP (1.0 mL), 100 °C, 48 h.

^bIsolated yields.

^c4-Iodotoluene was used instead of 4-Iodoanisole.

^dcis-4-(tert-butyl)cyclohexane carboxylic acid as starting material

^eThe reaction was run at 110 °C.

In summary, we have developed the first protocol for Pd(II)-catalyzed β-methylene C(sp³)–H arylation of free aliphatic acids without requiring the use of an exogenous directing group. The key to the success of this method was the use of a bidentate pyridine-pyridone ligand. This new methodology affords a novel disconnection for preparing diverse arylated carboxylic acids from simple starting materials.