Experimental research for elastic modulus of cement paste at ultra-early age based on indentation technique

Article Cite This: J. Am. Chem. Soc. 2019, 141, 13914−13922

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Three-Component Ruthenium-Catalyzed Direct Meta-Selective C−H Activation of Arenes: A New Approach to the Alkylarylation of Alkenes Xin-Gang Wang,†,§ Yuke Li,‡,§ Hong-Chao Liu,† Bo-Sheng Zhang,† Xue-Ya Gou,† Qiang Wang,† Jun-Wei Ma,† and Yong-Min Liang*,† †

State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P.R. China Department of Chemistry and Centre for Scientific Modeling and Computation, Chinese University of Hong Kong, Shatin, Hong Kong, China

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‡

S Supporting Information *

ABSTRACT: Multicomponent reactions are fundamentally different from two-component reactions, as multicomponent reactions can enable the efficient and step-economical construction of complex molecular scaffolds from simple precursors. Here, an unprecedented threecomponent direct C−H addition was achieved in the challenging meta-selective fashion. Fluoroalkyl halides and a wide range of alkenes, including vinylarenes, unactivated alkenes, and internal alkenes, were employed as the coupling partners of arenes in this strategy. The detailed mechanism presented is supported by kinetic isotope studies, radical clock experiments, and density functional theory calculations. Moreover, this strategy provided access to various fluoride-containing bioactive 1,1diarylalkanes and other challenging synthetically potential products.

1. INTRODUCTION Multicomponent reactions involving three or more coupling partners provide strategically efficient and synthetically useful methods for constructing complex carbon frameworks from relatively simple precursors, thus meeting the elementary demands of an “ideal synthesis”.1 As exemplified by the prototypical three-component Passerini reaction and fourcomponent Ugi reaction, multicomponent reactions are well suited for diversity-oriented synthesis in drug discovery and total synthesis of natural products.1,2 The difficulty of a multicomponent reaction is the precise control of the order of each subreaction, which often depends on the use of specific functional groups. As a result, many synthetically useful multicomponent methods are limited. Employing the ubiquitous and unbiased C−H bond with high positional selectivity as the coupling site of a multicomponent reaction fundamentally expands the applicability of these reactions but remains a great challenge. Herein, we describe the first example of a three-component direct meta-selective aryl C−H functionalization as well as the unprecedented ruthenium-catalyzed (fluoro)alkyl arylation of alkenes (Figure 1). While the promising three-component C−H addition reactions have recently been accomplished in an ortho-selective fashion by means of chelation assistance, as first reported by Ellman3 (Figure 2A), the meta-CAr−H involved threecomponent addition reaction has thus far proven elusive. In this context, challenging two-component direct CAr−H © 2019 American Chemical Society

Figure 1. Direct three-component meta-C−H functionalization.

functionalizations that provide access to meta-decorated arenes are considerably available.4 Strategies to functionalize meta-CAr−H are generally divided into four categories at present (Figure 2B): (a) auxiliarycoordinated strategies employing template-directing groups5 or hydrogen-bonding ligands6 as elegantly devised by Yu and others, (b) steric control pattern typically realized by Hartwig,7 (c) transient norbornene mediators developed by Yu and others,2f,8 and (d) remarkable ruthenium-catalyzed σ-activation representatively disclosed by Ackermann, Frost, and others.9 Noticeably, the inexpensive ruthenium catalyst has recently been further highlighted for its dual function, as it can also act Received: June 25, 2019 Published: August 8, 2019 13914

DOI: 10.1021/jacs.9b06608 J. Am. Chem. Soc. 2019, 141, 13914−13922

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Journal of the American Chemical Society

Table 1. Optimization of Ruthenium-Catalyzed ThreeComponent C−H Functionalizationa

entry

[Ru]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

[RuCl2(p-cymene)]2 [RuCl2(p-cymene)]2 [RuCl2(p-cymene)]2 [RuCl2(p-cymene)]2 [Ru(O2CMes)2(p-cymene)] [Ru(O2CMes)2(p-cymene)] [Ru(O2CMes)2(p-cymene)] [Ru(O2CMes)2(p-cymene)] [Ru(O2CMes)2(p-cymene)] [Ru(O2CMes)2(p-cymene)] [Ru(O2CMes)2(p-cymene)] [Ru(O2CMes)2(p-cymene)] [Ru(O2CMes)2(PPh3)2] Ru3(CO)12

Figure 2. Prior art and strategies.

ligand/additive MesCO2H PPh3 MesCO2H+PPh3 PPh3 PCy3 Xantphos P(4-MeOC6H4)3 P(3-MeC6H4)3 P(4-C6H4CF3)3 P(4-C6H4CF3)3 P(4-C6H4CF3)3 P(4-C6H4CF3)3 P(4-C6H4CF3)3

yield (%) 0 0 26 32 50 0 0 33 45 65 42b 46c 40 0 0

a

Reaction conditions: 1a (0.4 mmol), 2a (1.2 mmol), 3a (1.2 mmol), [Ru] (10 mol %), ligand (10 mol %), additive (20 mol %), Na2CO3 (0.8 mmol), solvent (2.5 mL), 60 °C, 12 h, and under argon atmosphere, yields of isolated products. b40 °C. cK2CO3 was employed instead of Na2CO3.

as a photosensitizer.10 Despite the indisputable progress, metaselective C−H transformations remain at the two-component level and fall short in reaching the demands of step-economical synthesis. Transition-metal-catalyzed difunctionalization of olefins is an unarguably effective three-component strategy to rapidly increase the complexity of a molecule. Among the numerous efforts that have been made,11 typical and remarkable advances are constituted by the transition-metal-catalyzed direct alkylarylation of alkenes, as reported by Baran and others.12 These advancements can concisely construct 1,1-diarylalkanes,13 which show strong bioactivity against cancers and other diseases,14 by employing premanufactured organometallic nucleophilic reagents or heterocyclic compounds as the aryl source. Therefore, expanding the scope of the aryl source has great significance for the direct alkylarylation of alkenes. Moreover, fluorinated compounds are embedded in a wide array of agrochemicals, pharmaceuticals, and materials science products because of their unique and fascinating properties.15 Hence, developing a method to install fluorinated functional groups into organic molecules is a long-standing goal in methodology studies. To address these reactivity challenges, we envisioned a directing group-assisted three-component strategy with a readily available (fluoro)alkyl halide as a coupling partner, which would enable the three-component direct meta-CAr−H functionalization and introduce a pharmacokinetically valuable fluoride moiety into potentially bioactive compounds to provide an efficient protocol for drug discovery.

remote-C−H functionalization process (entries 3−9). The best results were realized with the ruthenium(II) biscarboxylate catalysis manifold as the catalyst and electron-deficient P(4C6H4CF3)3 as the ligand (entry 10). The optimized catalytic system was shown to be efficient; lowering the temperature from 60 to 40 °C resulted in a moderate drop in yield (entry 11). Variation in other simple ruthenium complexes, Ru3(CO)12 or Ru(O2CMes)2(PPh3)2, fell short in the threecomponent meta-functionalization under otherwise identical reaction conditions (entries 13 and 14). Control experiments verified the crucial role of the ruthenium (entry 15). Investigation of Substrate Scope. Under the optimized conditions, the three-component meta-C−H functionalization of a variety of arenes with methyl acrylate 2a and 3a can be accomplished (Scheme 1a). A range of synthetically useful electron-withdrawing groups, such as fluoro, chloro, and bromo substituents, were well tolerated, resulting in products 4b−4e in good to excellent yield. Different directing groups were investigated (Scheme 1b). We observed that substituted pyridyl-, pyrimidine-, and pyrazole-containing substrates delivered the desired products. Indeed, by employing a bioactive purine derivative as the directing group, to our great delight, the desired meta-functionalization product 4k was successfully obtained, which is of considerable importance for the synthesis of bioactive compounds as well as the modification of biologically relevant molecules. In addition, ketoxime 1l and ketamine 1m were completely unreactive under these conditions. The current meta-functionalization reaction can be conducted with a wide range of acrylates and vinylarenes (Scheme 1c). Several substituted acrylates containing different alkyl groups on the ester moieties or substituents at the internal vinyl carbon positions were effective, as evidenced by the generation of products 4n−4t. Vinyl acetate, another type of

2. RESULTS AND DISCUSSION Optimization. We commenced our study by utilizing 2phenylpyridine 1a, methyl acrylate 2a, and BrCF2CO2Et as model substrates for optimization of the reaction (Table 1). When triphenylphosphine was added as a ligand, to our delight, the desired three-component meta-functionalized product 4a was obtained in 26% yield (entry 3). Further optimization revealed that carboxylate assistance/synergistic phosphine was the key to success for the three-component 13915

DOI: 10.1021/jacs.9b06608 J. Am. Chem. Soc. 2019, 141, 13914−13922

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Journal of the American Chemical Society Scheme 1. Meta-C−H Functionalization with Alkenes and (Fluoro)alkyl Halidesa

a

Reactions were performed on a 0.4 mmol scale, see the SI for experimental details. bGram-scale reaction, [Ru] (5 mol %) and P(4-C6H4CF3)3 (5 mol %). 13916

DOI: 10.1021/jacs.9b06608 J. Am. Chem. Soc. 2019, 141, 13914−13922

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Journal of the American Chemical Society activated alkene, could also be used to generate the desired product (4u). A wide range of vinylarenes could also be used as coupling partners. The reaction can be performed with vinylarenes containing various functional groups, such as F, Cl, Br, OMe, esters, and nitro (4v−4ag). Both vinylnaphthalene and vinylferrocene provided products (4af, 4ag) in good yield. We expanded the reaction scope by enabling the use of aliphatic and internal alkenes as substrates (Scheme 1d). This representative type of substrate proved more challenging than the vinylarenes and acrylates because radical additions are significantly slower.16 Unfunctionalized α-olefins and allylbenzene were reactive (4ah−4aj), providing the products regioselectively in moderate yields. The representative natural 1,1-disubstituted alkene β-pinene was also a viable component, enabling the formation of a highly hindered quaternary carbon center (4ak). Employing more hindered internal alkenes, compared with terminal alkenes, as the coupling partner in the reaction readily provides highly substituted products (4al, 4am, 4an). Internal diene and cyclic internal alkenes could also afford the products (4ao−4ar) with diverse carbon frameworks in good yields. Moreover, the synthetic utility of this approach was further illustrated by employing the corresponding amides (3as, 3at), difluoromethanephosphonate 3au, monofluoroacetate 3av, and perfluoroalkane 3aw as the coupling partners (Scheme 1e). It is noteworthy that bromoacetates including BrCH2CO2Et were identified as viable substrates and delivered desired products 4ax−4ba. The limitation is that employing common alkyl halides as the coupling partners was extremely difficult to achieve (4bb, 4bc). Last, an attractive practical feature of the present approach is that it can be performed on a gram scale using reduced loading (5 mol %) of the Ru salt to drive the process. The structures of products 4 were explicitly established by single-crystal X-ray diffraction analyses of representative 4bd (Scheme 1f). Historically, such a meta-substituted carbon framework requires many synthetic operations for assembly. This protocol not only provides access to a customizable meta-additionpattern carbon skeleton in a single step from readily obtainable inexpensive materials but also increases functional group complexity, which may have potential synthetic utility. Mechanistic Studies. Various control experiments were conducted to elucidate a mechanism for this three-component transformation. The presynthesized chloro ruthenacycle 517 was found to possess acceptable catalytic activity, solely in the presence of MesCO2H as the additive (Scheme 2a). Likewise, carboxylate ruthenacycle 6 was completely ineffective in the three-component reaction unless the ligand P(4-C6H4CF3)3 was present. The synergy of this phosphine assistance was further proven by attempting the transformation with the carboxylate-free ruthenium(II) phosphine complex 7,18 which still provided the desired product (Scheme 2b). On the other hand, these results revealed that the carboxylate assistance occurs by co-acceleration and does not have a decisive role in the reaction. The unique meta-selectivity of the transformation likely involved ortho-C−H cyclometalation of the aromatic ring. To explore this aspect, the isotopically labeled derivative [D5]-1a was subjected to the standard conditions (Scheme 3a), and the results showed that there was obvious H/D scrambling in the unreacted starting material and the product. Meanwhile, negligible H/D scrambling was found in the meta-position of the product, which accounted for the sole meta-C−H

Scheme 2. Control Experiments

Scheme 3. Mechanistic Studies by Isotopic Labeling

functionalization. A reaction with the deuterated cosolvent D2O was also conducted, leading to significant H/D scrambling in the ortho-position (Scheme 3b). Distinctly different degrees of H/D scrambling in each ortho-position provided strong evidence for the remote C−H activation para to the C−Ru bond. Intermolecular kinetic experiments with substrates 1a and [D5]-1a suggested that C−H cleavage is not kinetically relevant. 13917

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Journal of the American Chemical Society In line with the radical nature of the transformation, the formation of a meta-functionalization product was completely inhibited when TEMPO (1.0 equiv) was added as the radical scavenger (Scheme 4a). We then conducted a radical clock

Scheme 5. Calculated Relative Radical Fukui Indices at the B3LYP/def2-SVP Level of Theorya

Scheme 4. Radical Process Experiments

experiment to probe the fate of the radical intermediate. A cyclopropyl moiety adjacent to olefin 8, which is known to participate in radical rearrangements,19 was found to open under the reaction conditions, providing the corresponding ring closure product 9 (Scheme 4b, eq 1). When allyl ether 10 was subjected to the reaction conditions, 5-exo-trig cyclization was observed, affording the expected corresponding product in 21% isolated yield and 4:1 dr (Scheme 4b, eq 2). These radical-trap experiments demonstrate that the free-radical pathway is involved in this three-component meta-selective functionalization reaction. The Fukui indices calculated by density functional theory at the B3LYP/def2-SVP level are used to rationalize the positional selectivity of the meta-C−C bond formation. The relative Fukui indices between C-5 and C-4 increased significantly for the ruthenium(III) complexes (Scheme 5). These findings agree with previous experimental and theoretical studies that support a single electron transfer (SET) in this process.9q,20 Subsequently, a mechanistic study was conducted (Scheme 6). Initially, the phosphine ligand leaves intermediate G raising 32.7 kcal/mol energy. Then the 1a molecule attacks the Ru atom of intermediate H to form intermediate I lowering by 18.8 kcal/mol. The C−H activation process occurs with a barrier of 5 kcal/mol (TS1). Active intermediate K was formed by discarding MesCO2H, which led to SET. On the basis of the experimental results and DFT calculations, the phosphine electrically influenced the center ruthenium in intermediate K and further decided the SET process. Because Na2CO3 was the optimized base compared to K2CO3 for this reaction, we hypothesized that the cation interacted with the F(Br) atom in BrCF2CO2Et and stabilized the •CF2CO2Et radical. Therefore, Na+ and K+ were taken into account in this SET process. Compared with the reaction energy of −31.7 kcal/mol in the presence of Na+, the reaction energy with K+ (−28.40 kcal/mol) was much larger. This result supported the condition optimization results that

a

L = 1,4-dioxane. P = PPh3.

Na2CO3 was beneficial to the yields. After the SET step, the triplet-state intermediate was generated. The •CF2NaCO2Et+ radical cation attacks the carbon atom through the minimum energy cross point mecp1, generating the singlet state M with a barrier of 5.7 kcal/mol, while the radical could also react 2a with the barrier of 20.2 kcal/mol and release 14.7 kcal/mol. Although the energy TS2 is 7.3 kcal/mol, which is larger than that of mecp1, the energy of intermediate N (−31.9 kcal/mol) is much smaller than that of M. Above all, •CF2NaCO2Et+ prefers to react with 2a. The addition of intermediate P was ultimately generated through mecp2 with a barrier of 21.2 kcal/mol. On the basis of the results of mechanistic investigations, a plausible catalytic cycle has been proposed that commences by reversible carboxylate-assisted C−H ruthenation (Scheme 7). Subsequently, SET occurs from the active ruthenium(II) complex 13 to the fluoroalkyl halide 2. The radical is generated after halide transfer to the cyclometalated ruthenium(III) complex 14, followed by the immediate addition to the alkene. The newly formed radical undergoes CAr−H bond addition at the para-position to the C−Ru bond, leading to species 15, and the subsequent rearomatization furnishes ruthenacycle 16. Finally, the desired meta-functionalization product 4 is delivered by demetalation, which simultaneously regenerates the catalytically active ruthenium(II) complex 12. 13918

DOI: 10.1021/jacs.9b06608 J. Am. Chem. Soc. 2019, 141, 13914−13922

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Journal of the American Chemical Society Scheme 6. Computed Free Energy Surface

well with acrylates, vinylarenes, aliphatic and internal alkenes, and a variety of functional groups and directing groups, generating diverse carbon frameworks including 1,1-diarylalkanes in one step. Detailed mechanistic studies, including control experiments and computational analyses, provided an unambiguous understanding of the efficient and facile threecomponent reaction under mild conditions.

Scheme 7. Plausible Catalytic Cycle

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.9b06608. Experimental procedures, compound characterization, and NMR spectra (PDF) X-ray data for compound 4bd (CIF)

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Yong-Min Liang: 0000-0001-8280-8211 Author Contributions §

X.-G.W. and Y.L. contributed equally.

3. CONCLUSIONS In summary, we have developed a three-component Rucatalyzed meta-functionalization of arenes. The reaction works

Notes

The authors declare no competing financial interest. 13919

DOI: 10.1021/jacs.9b06608 J. Am. Chem. Soc. 2019, 141, 13914−13922

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (NSF 21472073, 21772075 and 21532001) for support. Computations reported in this paper were performed on the computer clusters at the Centre for Scientific Modeling and Computation, CUHK. We thank ACS ChemWorx Authoring Services for providing linguistic assistance during the preparation of this manuscript.

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DOI: 10.1021/jacs.9b06608 J. Am. Chem. Soc. 2019, 141, 13914−13922

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DOI: 10.1021/jacs.9b06608 J. Am. Chem. Soc. 2019, 141, 13914−13922