Regiocontrollable [2 + 2] benzannulation of γ,δ-C(sp3)–H bonds with dihaloarenes using palladium catalysis

Abstract

Methylene-selective C−H functionalization at distal positions is a challenge that remains to be addressed in the field of Pd(II) catalysis. We have previously reported a ligand enabled β, γ-C–H coupling with dihaloarenes for the synthesis of benzocyclobutenes (BCBs) as a promising class of scaffolds in drug discovery. Herein, we report a Pd(II)-catalyzed γ, δ-methylene C–H activation of free aliphatic acids and subsequent coupling with dihaloarenes, which offers an efficient route for the synthesis of diversely functionalized benzocyclobutenes (BCBs). The development of a carboxyl-pyridone ligand is crucial for the remote C(sp³)−H activation. Notably, previous γ, δ-methylene C–H activation reactions of mono-aliphatic acids are uniformly limited to carbocyclic substrates. The site selective activation of γ, δ-C–H bonds allows the installation of the BCB pharmacophores that are one more carbon further away from the carboxyl group which could serve as hydrogen bond donor or acceptor. Such alternation of distance between two interactions can significantly impact bioactivity.

Aliphatic carboxylic acids are diverse in structural variability and readily available via simple preparative methods. Their common occurrence in natural products and bioactive molecules compounds underscores the significance of these molecules.¹ In recent years, transition-metal-catalyzed C−H functionalization has emerged as an efficient strategy for transforming unreactive aliphatic C–H bonds into a diverse range of C–C bonds and other functional groups.^2–4 However, the functionalization of free carboxylic acids has been mostly limited to β-position, which restricts the range and practicality of applications for aliphatic acids.^5–9 Activating distal C–H bonds, such as those in the γ-position of the carboxylic acid, is more challenging as this requires the formation of a less thermodynamically stable six-membered metallacycle. 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.¹⁰ Catalytic γ-C–H activation of methyl C–H bonds has led to the development of a diverse range of reactions such as arylation, heteroarylation and olefination.^11–15 Recently, our group developed a transannular γ-methylene C–H arylation of cycloalkane carboxylic acids with quinuclidine-pyridone ligands (Fig. 1A).¹⁶ Later in 2024, our group reported an enantioselective δ-methylene C−H arylation of cycloalkane carboxylic acids with chiral bifunctional oxazoline-pyridone ligands (Fig. 1A).¹⁷ The above mentioned γ, δ-methylene C-H activation reactions of mono-aliphatic acids are uniformly limited to carbocyclic substrates. Thus, the selective functionalization of γ, δ-methylene C–H bonds in free carboxylic acids remains a significant challenge.

Fig. 1. Ligand-enabled [2+2] Benzannulation of Free Aliphatic Acids.

The benzocyclobutene (BCB) motif is an important bicyclic scaffold found in natural products and marketed drugs.^18–22 In addition, the propensity of BCBs to undergo thermal electrocyclic ring opening, leading to the formation of reactive diene fragments also makes them important building blocks in organic synthesis.²³ Consequently, this chemistry has been widely utilized in natural product synthesis and extensively explored in the field of polymer and materials science.^24–26 Currently, the [2+2] cycloaddition of alkenes and benzynes is one of the most common synthetic routes to BCBs.²⁷ However, the challenge of controlling the regioselectivity in this cycloaddition reaction remains unresolved. In addition, existing BCB synthesis methods are limited in scope and efficiency due to the requirement for the preinstallation of reactive functional groups such as double or triple bonds.^28–35 In 2022, Zhu reported an efficient synthesis of benzocyclobutenes by Pd(II)-catalyzed formal [2+2] annulation between arylboronic acids and alkenes. ³⁵ However, they were unable to obtain γ, δ-BCB using the corresponding alkene. Very recently, our group reported successful Pd-catalyzed β, γ-BCB synthesis through the annulation of aliphatic acids with dihaloarenes enabled by amide-pyridone ligands (Fig. 1B).³⁶ This reaction prompted us to investigate whether this strategy could be exploited to promote γ, δ-methylene functionalization in the absence of β-C−H bonds, thereby enabling the synthesis of γ, δ-BCB acids, which are distinct from the β, γ-BCB acids as protein binders. Herein, we report the first Pd(II)-catalyzed distal methylene C(sp³)–H activation of [2+2] annulation between aliphatic acids and dihaloarenes by using bidentate carboxyl-pyridone ligands (Fig. 1C). Exclusive regioselectivity in the BCB formation is achieved through the differentiation between the aryl iodide and bromide sites.

We began our efforts by testing a range of ligands for the Pd(OAc)₂-catalyzed reaction of a model substrate, 3,3-dimethylheptanoic acid (1a, 1.0 equiv.), with a dihaloarene coupling partner 1-bromo-4-chloro-2-iodobenzene (2a, 2.0 equiv.) (Fig. 2). No desired product was obtained in the absence of ligand. Similarly, a representative monodentate pyridine-type ligand (L1), a mono-dentate pyridone ligand (L2) and an N-acetyl amino acid (MPAA) ligand (L3), also failed to deliver the desired product. We then turned our attention to pyridone-based bidentate ligands. Recent findings from our group have demonstrated that these types of bidentate ligands can promote methylene C−H activation reactions of free carboxylic acids. Unfortunately, less than 5% yield of desired product was obtained when we employed pyridone-based bidentate ligands L4-L7, which forms a five membered chelates. We next aimed to accelerate the C–H bond cleavage through changing the ligand bite angle. Pleasingly, the desired BCB product was formed in a modest 18% yield when we employed pyridine-pyridone ligand L8. Encouraged by this result, we surveyed a range of six-member pyridine-pyridone bidentate ligands, but efforts to modify the substitution on the ligand backbone did not enhance reactivity (L9-L11), We next moved to investigate other pyridone-based bidentate ligands. Amide-pyridone ligand (L12), which was previously demonstrated to be an efficient ligand for the C–H functionalization of two adjacent methylene units in carboxylic acids in the synthesis of β, γ-BCBs, afforded the desired γ, δ-BCB in 35% desired product. To our delight, replacing the amide functionality in the ligand with a carboxylate (L13) improved the yield of 3a to 68%, which was observed to be a single regioisomer, the structure of which was conclusively determined by single-crystal x-ray diffraction analysis (see the Supporting Information for details). Other recently developed classes of bidentate pyridone ligands such as sulfonamide pyridones and quinuclidine-pyridones (L14-L15) were also tested but proved less effective than L13. Using optimal ligand L13, we moved on to screen other parameters of reaction conditions. In particular, HFIP was found optimal which similar to our previous palladium-catalyzed C(sp³)−H functionalization reactions.⁹ (See SI for detailed information)

Fig. 2. Investigation of Ligands for The [2+2] Benzannulation via Stitching of γ,δ-C–H Bonds with Dihaloarenes.

^aConditions: 1 (0.1 mmol), dihaloarenes 2a (0.2 mmol), Pd(OAc)₂ (10 mol%), ligand (20 mol%), K₂HPO₄ (1.5 equiv), AgCO₃ (2.0 equiv), HFIP (1.0 mL), 110 °C, 48 h. ^bIsolated yields.

With the optimal ligand and reaction conditions in hand, a range of aliphatic acids were tested (Fig. 3). The presence of functionality such as phenyloxy (1l) and aryl groups (1h-1i) in the acid substrate was tolerated by the reaction. Aliphatic acids bearing β-gem-dimethyl groups (1a-1l) or a single methyl group together with a longer alkyl substituent (1m) were also compatible despite the presence of β-methyl C−H bonds that are generally more reactive. Moreover, five-membered cyclic aliphatic acids were also compatible to afford desired BCB products (3n-3p). Notably, in all cases, the product was observed as a single regio- and diastereomer. When aliphatic acids containing β-C−H bonds were subjected to standard conditions, β, γ-dehydrogenation occurred to give the olefin as the major products (see the Supporting Information for details).

Fig. 3. Aliphatic Acids Scope for The [2+2] Benzannulation Reaction of Free Aliphatic Acids.

^aConditions: 1a (0.1 mmol), dihaloarenes 2a (0.2 mmol), Pd(OAc)₂ (10 mol%), ligand (20 mol%), K₂HPO₄ (1.5 equiv), AgCO₃ (2.0 equiv), HFIP (1.0 mL), 110 °C, 48 h. ^bIsolated yields. ^cL10 was used instead of L13.

Subsequently, a wide range of bromoiodoarenes were tested (4a-4p). Substituents at various positions were compatible with this reaction(4b-4d). Halogens including fluorine (4e-4f), chlorine (4g), and bromine (4h-4i) were found to be compatible, affording the desired BCBs in moderate yields. Reactions employing electron-withdrawing bromoiodoarenes proved particularly effective (4j-4p), while bromoiodoarenes containing electron-rich groups tended to result in low yields (see supporting information for details). Interestingly, arenes containing amide functionality (4o-4p), which is widely used in C–H activation as a directing group, were also effective in this transformation. Furthermore, dibromoarenes (4a, 4q-4s) were also found to be effective in this reaction, producing the desired BCBs with slightly reduced yields. Compounds containing hetero-BCBs have numerous applications in many functionalized materials in biomedical implants and pharmaceuticals chemistry.²³ Gratifyingly, quinoline (4t), and thiophene (4u) derivatives were also competent in this process, affording the desired hetero-BCBs in 43% and 44% yield. Dihaloarenes bearing bioactive structures such as menthol and galactose were also tolerated, leading to products 4v and 4w.

Finally, we turned our attention to the synthetic applications of the γ, δ-BCB acids product. Heating a mixture of 3a and N-methylmaleimide in toluene at 200°C for 16 h afforded o-quinodimethanes 5 via an electrocyclic cyclobutane opening followed by a Diels−Alder reaction (Fig. 5). Compound 3a could be readily converted to the important amine 6 through a Curtius rearrangement. Moreover, the patented bioactive compound 10 can be efficiently synthesized using our method in a two-step procedure. ³⁷

Fig. 5.

Synthetic Applications

Control experiments were performed to provide mechanistic insights into this Pd-catalyzed [2+2] benzannulation reaction. First, deuterium incorporation experiments were carried out using deuterated solvents. Deuteration was observed only at γ-methyl positions in isolated product 3d under the optimized conditions (Fig. 6A), while no deuterium incorporation was observed in absence of L13 (Fig. 6B). This observation suggests that L13 promotes activation of both methyl and methylene C−H bonds. The β-H elimination step following γ-methylene C−H activation outcompetes γ-methyl C−C or C−O bond formation, resulting in the observed exclusive γ, δ-methylene C−H functionalization selectivity. (For detailed discussion, see SI) Next, the reaction of 1k was monitored by ¹H NMR. A trace of γ, δ-dehydrogenation product 11 (5% yield) was observed under the standard reaction conditions without dihaloarene coupling partner (Fig. 6C). However, dehydrogenation intermediate 11 was not formed under the ligandless conditions (Fig. 6D), indicating ligand L13 is crucial for the C–H activation step. Next, using dehydrogenation product 11 as the substrate, the desired BCB product 3k could be obtained in 23% yield (Fig. 6E). In the absence of ligand, the BCB product 3k was formed from the alkene in similar yield (Fig. 6F), indicating ligand is not required for this process.

Fig. 6. Mechanistic Studies.

Based on the above control experiments, we propose that our transformation proceeds via a Pd(II)/Pd(0)/Pd(II)/Pd(IV) catalytic cycle as depicted in Fig. 7. Initially, Pd(II) coordinates with carboxPyridone ligand to generate int-I which subsequently reacts with the substrate to form intermediate int-II through the cleavage of the γ-methylene C–H bond. Int-II then undergoes a β-hydride elimination, producing int-III as a Pd(0) species. In addition, int-I can also react with substrate to form int-VII for the cleavage of γ-methyl C−H bond. However, the activation of the methyl C–H bond is reversible, and the β-hydride elimination pathway predominates over the methyl C−C or C−O reductive elimination, resulting in exclusive chemoselectivity of γ, δ-methylene C−H functionalization. After an intermolecular oxidative addition of the Pd(0) into the aryl-iodo bond, int-IV is formed as a Pd(II) species. Then, it goes through a carbopalladation to form int-V. Subsequently, an intramolecular oxidative addition of the Pd(II) into the aryl-bromo bond generates int-VI as a Pd(IV) species. Finally, reductive elimination from int-VI delivers the desired product, regenerating the Pd(II) species to complete the catalytic cycle.

Fig. 7. Proposed Mechanism.

In summary, we have developed a palladium-catalyzed distal methylene C(sp³)–H activation of free carboxylic acids for the efficient assembly of γ, δ-BCB acids and derivatives. This methodology affords a novel disconnection for preparing diverse BCBs from simple starting materials. The key to the success of this method was the use of a bidentate carboxyl-pyridone ligand. Further studies on the reaction mechanism are underway.

Methods:

General procedure for the synthesis of benzocyclobutenes

A 2-dram vial equipped with a magnetic stir bar was charged with Pd(OAc)₂ (2.2 mg, 10 mol%) and L13 (3.6 mg, 20 mol%), the appropriate carboxylic acid substrate (0.10 mmol), dihaloarene (0.2 mmol), Ag₂CO₃ (55.0 mg, 0.2 mmol), K₂HPO₄ (26.1 mg, 0.15 mmol) was then added in HFIP (1.0 ml). Subsequently the vial was capped and closed tightly. The reaction mixture was then stirred at the rate of 300 rpm at 110 °C for 48 h. After being allowed to cool to room temperature, the mixture was acidified with 0.1 ml of formic acid and stirred for 30 seconds and then diluted with ethyl acetate. The mixture was passed through a pad of Celite with ethyl acetate as the eluent to remove any insoluble precipitate. The resulting solution was concentrated, and the residual mixture was dissolved with a minimal amount of acetone and loaded onto a preparative TLC plate. The pure product was then isolated using preparative TLC with ethyl acetate and hexane with 1% acetic acid as the eluent.

Fig. 4. Dihaloarene Scope for The [2+2] Benzannulation Reaction of Free Aliphatic Acids.

^aConditions: 1a (0.1 mmol), dihaloarenes 2 (0.2 mmol), Pd(OAc)₂ (10 mol%), ligand (20 mol%), K₂HPO₄ (1.5 equiv), AgCO₃ (2.0 equiv), HFIP (1.0 mL), 110 °C, 48 h. ^bIsolated yields. ^cAliphatic acid (0.2 mmol), dihaloarene (0.1 mmol).