Recyclable Ruthenium Catalyst for Distal meta-C-H Activation.

We disclose the unprecedented hybrid-ruthenium catalysis for distal meta-C-H activation. The hybrid-ruthenium catalyst was recyclable, as was proven by various heterogeneity tests, and fully characterized with various microscopic and spectroscopic techniques, highlighting the physical and chemical stability. Thereby, the hybrid-ruthenium catalysis proved broadly applicable for meta-C-H alkylations of among others purine-based nucleosides and natural product conjugates. Additionally, its versatility was further reflected by meta-C-H activations through visible-light irradiation, as well as para-selective C-H activations.

Introduction

Methods for achieving position‐selective functionalizations of specific C−H bonds have surfaced as transformative tools for molecular science. Thus, a plethora of ortho‐selective arene C−H functionalizations has been accomplished by proximity‐induced C−H activation through chelation assistance. In sharp contrast, distal C−H functionalizations continue to be challenging with considerable momentum gained by steric control, template assistance, weak hydrogen bonding, or transient mediator (Figure 1 aI–IV). Recently, Greaney, Frost, and Ackermann among others developed site‐selective homogeneous C−H functionalization via ruthenium‐catalyzed σ‐activation, allowing meta‐ and para‐functionalization to the metal center (Figure 1 aV). In spite of recent notable progress, the realm of C−H functionalizations was thus far considerably limited to homogeneous catalysis. This approach impedes challenging catalyst separation and reuse, directly translating into trace metal impurities in the target molecules. While classical heterogeneous catalysts—metal catalysts dispersed on solid surfaces—have been previously reported for C−H functionalizations, hybrid catalysts —homogeneous catalysts immobilized with organic linkers on solid supports—add unique properties to the design of the reusable catalysts. Thereby, numerous heterogenized homogeneous catalysts, namely hybrid catalysts, have been devised particularly by Jones and Sawamura among others. In sharp contrast to this advance in hybrid catalysis, recyclable polymer‐based hybrid‐ruthenium catalyst for remote C−H alkylations via σ‐activation has as of yet unfortunately proven elusive.

Figure 1

Towards heterogeneous distal C−H functionalization.

Within our program on sustainable C−H activation, we have now unraveled an unprecedented recyclable hybrid‐ruthenium catalyst for remote C−H alkylations in a biomass‐derived solvent, on which we report herein (Figure 1 b). Salient features of our strategy include a) the first hybrid‐ruthenium catalysis for distal C−H alkylations, b) robust hybrid‐ruthenium catalyst for meta‐C−H functionalization, c) full characterizations of the recyclable hybrid‐ruthenium catalyst for remote C−H alkylation, d) expedient position‐selective C−H alkylations with ample scope, ranging from purine‐based nucleosides to natural product conjugates with the aid of typical heterocyclic groups and alkylating reagents in an eco‐friendly solvent, and e) experimental and computational mechanistic insights.

Results and Discussion

We initiated our studies by probing various reaction conditions for the envisioned recyclable ruthenium‐catalyzed meta‐C−H alkylation of arene 1 a (Table 1). The amount of ruthenium in the hybrid‐ruthenium catalysts were determined by detailed inductive coupled plasma‐optical emission spectrometry (ICP‐OES) analysis.

Table 1

Establishing meta‐C−H functionalization by hybrid‐ruthenium catalyst.

	Deviation from above	Yield [%][a]
		1st run	2nd run
1	none	66	64
2	RuCl2PPh3(p‐cymene) instead of Hybrid‐Ru I	81	0
3	hybrid‐Ru II instead of Hybrid‐Ru I	70	69
4	without Hybrid‐Ru I	0	–
5	only Hybrid‐support	0	–
6	1,4‐dioxane instead of 2‐MeTHF	63	–
7	PhCMe3 instead of 2‐MeTHF	45	–
8	80 °C instead of 60 °C	61	–
9	Ru@SiO2 [b] instead of Hybrid‐Ru I	0	–

[a] Reaction conditions: 1 a (0.25 mmol), 2 a (0.75 mmol), catalyst (10 mol %), KOAc (2 equiv), 2‐MeTHF (2.0 mL), 60 °C, 24 h, isolated yield. [b] See the reference [22]. “–” indicates that the reaction is not performed.

–

–

–

–

–

–

After considerable experimentations, we were delighted to obtain the meta‐alkylated product 3 aa with KOAc as the base in biomass‐derived 2‐MeTHF at 60 °C, and observe the reusability of hybrid‐ruthenium catalysts (entries 1 and 2). Fine‐tuning the hybrid‐ruthenium catalyst by changing the arene ligands highlighted the pivotal role of the designable hybrid catalysts, giving a higher yield and improved reusability (entry 3). Control experiments confirmed the essential role of the recyclable hybrid‐ruthenium catalyst, suggesting a simple electrophilic aromatic substitution less likely to be operative (entries 4 and 5). Furthermore, conventional solvents for meta‐C−H alkylation proved to be less effective, while an elevated reaction temperature gave unsatisfactory results (entries 6–8). Having shown slightly higher reactivity and recyclability than the Hybrid‐Ru I, Hybrid‐Ru II was chosen as a better candidate for distal C−H functionalizations and further characterizations to elucidate its mode of action. Notably, one heterogeneous catalyst was reported for meta‐C−H bromination. However, the previously employed catalyst fell short in delivering the desired meta‐alkylated product (entry 9).

To obtain detailed understanding of the hybrid‐ruthenium‐catalyst, we became intrigued to further probe its reusable nature (Scheme 1). We were hence delighted to observe that the hybrid‐ruthenium featured excellent reusability, enabling practical access to meta‐C−H alkylated arenes (Scheme 1 a). Practitioners in pharmaceutical, agrochemical and chemical industries performing large scale reactions or flow applications in homogeneous catalysis are mainly concerned with the removal of metal impurities, which are detrimental to synthetic and economic efficiency, while well‐designed heterogeneous catalysts help to avoid additional process by a simple separation. It is noteworthy that less than 8 ppm of ruthenium was detected by detailed ICP‐OES studies of the reaction mixture, reflecting negligible leaching of the transition metal. The sustainable feature of the hybrid‐ruthenium catalysis was also mirrored by a gram‐scale reaction, maintaining high efficiency along with position‐selectivity and reusability of hybrid‐ruthenium catalyst (Scheme 1 b).

Scheme 1

Reusability and recyclability of hybrid‐ruthenium catalyst.

As the reusability and recyclability of the hybrid‐ruthenium catalyst were demonstrated, we became attracted to further delineating its heterogeneous nature (Scheme 2). A hot‐filtration test demonstrated that the physical removal of the hybrid‐ruthenium catalyst completely inhibited the hybrid catalysis for meta‐C−H alkylations (Scheme 2 a). In addition, we performed a poisoning test with SMOPEX®‐105, of which the role was clearly shown to inhibit the homogeneous ruthenium catalysis. In contrast, the hybrid catalysis occurred in the presence of the metal scavenger (Scheme 2 b). Furthermore, a three‐phase test clearly illustrated the heterogeneous mode of the hybrid‐ruthenium catalyst, rendering homogeneous catalysis unlikely to be operative (Scheme 2 c).

Scheme 2

Heterogeneity tests.

Given the unique features of recyclable and reusable hybrid‐ruthenium catalyst, we sought to determine its chemical and physical properties. It is noteworthy that the hybrid‐ruthenium catalyst has not yet been characterized by any means of spectroscopic or microscopic tools, whereas a reactivity was reported. To shed light on the characteristic features, we firstly conducted detailed solid‐state NMR spectroscopic studies of the Hybrid‐support, RuCl2PPh3(p‐cymene), Hybrid‐Ru II and reused Hybrid‐Ru II (Figure 2 a and 2b). Interestingly, 13C and 31P‐NMR spectra showed similar chemical shifts among RuCl2PPh3(p‐cymene), the Hybrid‐Ru II, and the reused Hybrid‐Ru II, providing strong evidence that coordination of the ruthenium by phosphorus remained stable during the course of the hybrid‐ruthenium catalysis. X‐ray photoelectron spectroscopy (XPS) was also employed to determine the oxidation state of ruthenium from hybrid‐ruthenium catalyst and the reused one (Figure 2 c). The peak of Ru 3d5/2 at 281.1 eV from the surface of both catalysts corresponds to ruthenium(II) species. Furthermore, the powder X‐ray powder diffraction (PXRD) patterns of the Hybrid‐Ru II identified two very wide peaks around 10° and 20° showing the amorphous support, whereas the formation of crystalline ruthenium compounds such as ruthenium oxide was not detected (Figure 2 d). The PXRD patterns from the reused Hybrid‐Ru II confirmed crystalline KBr (JCPDS 730 381) as an insoluble byproduct in 2‐MeTHF while the residue was proven to be innocuous to the reusability of the hybrid‐ruthenium catalyst.

Figure 2

Characterizations of the hybrid‐ruthenium catalysts.

Additionally, we performed detailed microscopic studies including scanning electron microscopy (SEM), transmission electron microscopy (TEM) and transmission electron microscopy energy‐dispersive X‐ray spectroscopy (TEM‐EDX) studies of the Hybrid‐Ru II and the reused one (Figure 3). SEM analysis of the Hybrid‐Ru II revealed non‐aggregated spheres up to 100 μm in diameter with relatively smooth surface (Figure 3 a). The reused Hybrid‐Ru II in SEM studies showed innocent KBr on the surface previously detected by PXRD. TEM analysis of the Hybrid‐Ru II and the reused Hybrid‐Ru II revealed that both hybrid catalysts have homogeneous non‐porous amorphous morphology (Figure 3 b). This reflected the durability of hybrid catalyst, enabling outstanding reuses in meta‐C−H functionalization. TEM‐EDX mapping studies also confirmed the excellent stability of coordination between phosphorus (yellow) and ruthenium (red) with homogeneous dispersion (Figure 3 c).

Figure 3

Detailed microscopic analysis of the hybrid‐ruthenium catalysts.

The thus established reactivity and recyclability together with full characterization of hybrid‐ruthenium catalyst allowed us to explore its unique catalytic performance. We commenced the exploration by hybrid‐ruthenium‐catalyzed meta‐C−H functionalization with a set of representative arenes (Scheme 3). The robust heterogeneous meta‐C−H alkylations were not limited to pyridinyl arenes, but arenes having pyrimidine, oxazoline, pyrazole, and purine groups were also found to be viable. Also, differently substituted arenes 1 bearing electron‐deficient and electron‐rich functional groups were position‐selectively transformed to the desired meta‐functionalized products 3. Distal meta‐C−H alkylation by the Hybrid‐Ru II tolerated various alkyl bromides 2, including valuable functional groups, featuring halides, ethers, esters, and amides, while natural product derivatives were converted without racemization.

Scheme 3

Robustness of hybrid‐ruthenium catalysis for meta‐C−H functionalization.

Hence, the Hybrid‐Ru I was identified as a powerful hybrid‐ruthenium catalyst for meta‐C−H alkylations, showing comparable reactivities (3 aa, 3 ag, 3 ga, 3 ia, 3 ma, and 3 pa). It is noteworthy that the robust nature of the hybrid‐ruthenium catalysis was mirrored by the gram‐scale meta‐C−H functionalization of purine (3 sa). In contrast, alternative attempted alkylating reagents led thus far to less satisfactory results.

As photocatalysis enables valuable chemical transformations, particularly in the realm of homogeneous ruthenium‐catalyzed C−H functionalization, but heterogeneous ruthenium catalysis has not been explored yet. Interestingly, experiments with hybrid‐ruthenium catalyst provided meta‐C−H alkylated products at room temperature in a reusable manner (Scheme 4 a). While accessing para‐selective C−H functionalization was typically achieved by the substrate's inherent substitution pattern or template‐based directing groups, homogeneous ruthenium catalysts enabled distal functionalization of arenes.[ , , ] Delightfully, hybrid‐ruthenium catalyst also efficiently accomplished para‐C−H alkylation under slightly modified reaction condition (Scheme 4 b). Indeed, the robust and versatile hybrid‐ruthenium‐catalyst allowed for distal C−H transformation with excellent level of site‐selectivity, exclusively leading to functionalization at the meta or para position in both thermal and mild light‐induced conditions. Importantly, the versatile hybrid‐ruthenium catalysis set the stage for novel position‐selectivity as compared to the homogeneous ruthenium catalysis.

Scheme 4

Versatility of hybrid‐ruthenium catalysis.

Furthermore, we performed mechanistic studies to elucidate the hybrid‐ruthenium catalyst's mode of action (Scheme 5). Notably, we made mechanistic observations comparable to those of our homogeneous catalysis, reflecting that hybrid catalysis is characterized by predictable reactivity and selectivity that are in accordance with the homogeneous realm.

Scheme 5

Experimental key mechanistic findings.

To this end, an intermolecular competition experiments revealed that the electron‐rich arene 1 i was preferentially reacted (Scheme 5 a). meta‐C−H activations in the presence of isotopically labelled CD3OD provided strong support for facile and reversible C−H activation solely at the ortho position (Scheme 5 b), while kinetic experiments indicated a secondary isotope effect, being suggestive of C−H cleavages at the ortho and meta position are not kinetically relevant (Scheme 5 c). Furthermore, we examined a SET‐type regime by the use of the typical radical scavengers TEMPO, Galvinoxyl free radical, and 1,1‐diphenylethylene, resulting in a significant inhibition of meta‐C−H alkylation catalyzed by the Hybrid‐Ru I (Scheme 5 d). Kinetic studies demonstrated similar initial rates of the hybrid catalyst Hybrid‐Ru II upon reuse, albeit featuring an extended induction period (Scheme 5 e). Additionally, free p‐cymene was observed by 1H NMR spectroscopy and gas chromatographic study.

Additionally, the positional selectivity of the hybrid‐ruthenium‐catalyzed meta‐C−H functionalization was further probed by means of radical Fukui indices for 1 a, A, and the ruthenacycle complexes B and B at the PBE0‐D3(BJ)/def2‐TZVP,SDDAll(Ru)+SMD(THF)//TPSS‐D3(BJ)/def2‐SVP,SDDAll(Ru) level of theory and with PPh3 (Figure 4 a). While the intermediate A, ruthenium(II) complex B, and 1 a did not show site‐selectivity, we could observe that ruthenium(III) complex B only showed a significant meta‐selectivity, providing support for a SET oxidation process on the ruthenium(II) center for meta‐selectivity through σ‐activation by ortho‐C−H metalation.

Figure 4

Computational mechanistic studies.

Furthermore, we carried out detailed orbital analysis for the singlet and the triplet state of complex (C and C) at the same level of theory (Figure 4 b). The triplet state C bears single occupied ligand and metal orbitals whereas the singlet state C has a double occupied metal orbital and a vacant ligand orbital, showing a clear evidence of stabilization of the singlet state by the charge transfer from the ligand to the metal.

On the basis of our detailed experimental and computational mechanistic studies along with the spectroscopic and microscopic characterization of the hybrid‐ruthenium catalyst, a plausible catalytic cycle for the heterogeneous meta‐C−H alkylation was proposed (Scheme 6). The mechanistic rationale commences by a carboxylate‐assisted C−H ruthenation. Subsequently, ruthenium(III) intermediate is generated via single electron transfer from the ruthenium(II) complex B to the alkyl halide 2. The alkyl radical attacks aromatic moiety at the position para to ruthenium, rendering intermediate C. Thereafter, protodemetallation followed by aromatization delivers the desired meta‐alkylated product 3 and regenerates the catalytically active ruthenium(II) complex A as confirmed by various characterization of reused hybrid‐ruthenium catalyst.

Scheme 6

Proposed catalytic cycle.

Conclusions

In summary, we have reported on a recyclable catalyst for remote C−H functionalizations within a hybrid‐ruthenium catalysis manifold. Full characterizations by microscopic and spectroscopic analysis illustrated the outstanding physical and chemical stability of the hybrid‐ruthenium catalysts for position selective C−H functionalization. The modular hybrid‐ruthenium catalyst featured remarkable robustness towards meta‐C−H alkylation in a reusable manner without significant loss of catalytic efficacy. Its versatility was further mirrored by meta‐C−H alkylations under photo‐induced conditions and selective para‐C−H alkylations. Detailed experimental and computational mechanistic studies provided strong support for high position‐selectivity enabled by a reusable hybrid catalyst.

Conflict of interest

The authors declare no conflict of interest.

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Supplementary

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