C–H and C–C activations have proven to bear great potential for the construction of C–C and C–Het bonds, with widespread applications to pharmaceutical, agrochemical chemistry, and material sciences. Ruthenium catalysis offers a powerful tool for site-selective C–H functionalizations. To further promote the catalytic C–H and C–C activation, a mechanistic understanding of the transformations is essential. Within this thesis, several new synthetic strategies were investigated for ruthenium-catalyzed site-selective C–H and C–C functionalization.
First, methods for remote meta-C–H bromination were developed (Scheme 97).[95] Both of homogeneous RuCl3·nH2O (30) and heterogeneous ruthenium catalyst 152 showed comparable catalytic efficacy, furnishing the meta-brominated products 133 with excellent levels of positional selectivity. In addition to pyridine and pyrimidine, biorelevant purines 123 was for the first time employed as a directing group in remote C–H functionalization.
Scheme 97: Remote meta-C–H bromination of purine 123 by homogeneous or heterogenous ruthenium catalyst.
The second project focused on remote meta-C–H alkylations of arenes bearing with removable and transformable ketimines 135 (Scheme 98).[96] The alkylation reaction required PhCMe3 as the solvent to prevent a side reaction at the benzylic position. Sequential one-pot remote alkylation followed by acid hydrolysis highlighted a broad substrate scope of different arylketimines 135 and a variety of secondary and tertiary alkyl bromides 136. Moreover, the method was tolerant of various functional groups, valuable heterocycles, and structurally complex cholesterol. TMP-NH2
could be recovered by an acid-base extraction. Mechanistic experiments gave strong support for a radical-type mechanism of meta-C–H alkylations. The power of this remote transformation set the stage for operationally simple one-pot protocols for the synthesis of meta-alkylated benzyl amines and the sequential twofold meta-/ortho-C–H activation. Furthermore, the transformation of the obtained alkylated phenones 154 provided a general platform to synthetically useful meta-substituted arenes, including anilines, phenols, acids, and indoles.
4 Summary and Outlook
Scheme 98: Sequential one-pot ruthenium-catalyzed remote meta-alkylation.
In continuation of ruthenium-catalyzed remote transformations, the cooperation of carboxylate and phosphine ligands in ruthenium catalysis offered a general method for highly selective meta-C–H alkylations of α-bromo carbonyl compounds 140, such as ketones, esters, and amides (Scheme 99a).[101] In contrast to the previous projects, the synergistic ruthenium catalysis was performed at lower reaction temperature. Moreover, the remote protocol was applicable to broad heterocyclic directing groups, such as pyridines, pyrimidines, removable pyrazoles, transformable oxazolines, and biologically relevant purines. In particular, remote alkylation of ketimine led to concise synthesis of an anti-inflammatory drug, Ketoprofen derivatives.
Furthermore, the synergistic transformation was highlighted by sequential meta-alkylation/ortho-arylation in a user-friendly one-pot fashion, allowing for late-stage fluorescence labelling on purine bases. In addition to site-selectivity, the excellent chemo-selectivity of ruthenium-catalyzed twofold C–H activations was obtained by controlling reaction temperature. Detailed experimental mechanistic studies, including unprecedented EPR studies, were strongly supportive of a reversible C–H ruthenation and a single-electron transfer process, suggesting the formation of an arene-ligand-free cyclometalated ruthenium(III) complex. In contrast, the catalytic alkylation of N-pyrimidyl aniline 125a took place on the arene at the position para to directing group, delivering the para-alkylated product 180a (Scheme 99b). Detailed mechanistic investigations for para-selective transformation should be provided in the future.
4 Summary and Outlook
Scheme 99: Carboxylate-phosphine ruthenium catalysis for remote meta- or para-C–H alkylation.
In addition to meta-alkylation, the synergistic ruthenium catalysis proved to be a general tool for remote meta-benzylation (Scheme 100a).[104] The addition of phosphine ligand exerted an influence on positional selectivity of a ruthenium-catalyzed C–H benzylation. In addition to a broad substrate scope, the cooperative ruthenium catalysis set a stage for broadly effective late-stage C–H diversification of biologically relevant molecules and structurally complex drugs, including monosaccharides, nucleotides, triglycerides, amino acids, and peptides, as well as fluorescence label BODIPY (Scheme 100b). Particularly, fully unprotected OH-free monosaccharides proved to be tolerant. Mechanistic insights were suggestive of a reversible, carboxylate-assisted C–H ruthenation and a radical-involving mechanism. Moreover, the well-defined ruthenacycle trans-192a showed a reversible redox event and proved to be a key intermediate of the remote functionalization.
4 Summary and Outlook
Scheme 100: Remote meta-benzylation and late-stage diversification.
The next project focused on a ruthenium-catalyzed decarboxylative C–C activation enabled site-selective new C–C bond formation (Scheme 101).[106] Catalytic reaction of primary alkyl bromides provided the ortho-alkylated products 145, whereas secondary and tertiary alkyl bromides mostly led to meta-selective alkylation. Surprisingly, the decarboxylative transformations of bromocyclohexane (136j) and exo-2-bromonorbornane (136u) afforded the alkylation at the ortho position, which were unusual for secondary alkyl halides. In case of α-bromo carbonyl compounds and secondary benzyl chlorides, the addition of phosphine ligand was essential for the decarboxylative alkylation. Mechanistic insights including experiments with radical scavengers and the observed benzylation as a side-reaction were supportive of the homolytic C–X bond cleavage of alkyl halide. Additionally, p-cymene-free cyclometalated ruthenium complex was proposed as a catalytically active species. To understand the working mode of C–C activation, more detailed mechanistic insights by experiment and computation should be investigated in the future.
4 Summary and Outlook
Scheme 101: Ruthenium-catalyzed decarboxylative alkylation of acid 144.
In spite of major breakthrough in C–C activation chemistry, the nucleophilic substitution of carboxylate to alkyl halide forming alkyl ester became the limitation of the decarboxylative transformation.
Owing to decarboxylative ortho-selective alkylation of bromocyclohexane and exo-2-bromonorbornane, positional selectivity in ruthenium-catalyzed C–H alkylation of pyrazoles was examined (Scheme 102).[106] Steric hindrance of alkyl halides and directing group of arenes had significant impacts on positional selectivity of the catalytic alkylation. Detailed mechanistic experiments were suggestive of two distinct mechanisms, a concerted oxidative addition/reductive elimination event for the ortho-C–H alkylation, while a SET pathway is proposed for the meta-functionalization. In addition, an arene-ligand-free ruthenacycle was identified as the catalytically active species in the catalysis.
Scheme 102: Site-selective ortho- or meta-alkylation of pyrazoles 147 under ruthenium catalysis.
The last project focused on integrating the chemistry of C–H activation and photoredox for direct arylation under exceedingly mild conditions (Scheme 103). Visible-light-induced ruthenium-catalyzed direct C–H arylation at room temperature was evolved without exogenous photocatalysts.[114] The catalytic method was tolerant of various functional groups and valuable heteroaromatic compounds, especially NH-free indole. In addition, twofold and threefold C–H activations of di- and triiodoarenes were highly effective. Notably, the power of this photoredox transformation set a stage for late-stage C–H arylation of sensitive nucleosides and nucleotides.
4 Summary and Outlook
Detailed mechanistic investigations by experiments and computations were indicative of the in situ generated cyclometalated ruthenium complex 219 being a photocatalytically active species, which underwent light-induced metal-to-ligand charge-transfer and intersystem crossing to form long-lived triplet species. In addition, calculations were suggestive of an inner-sphere electron transfer process to be a preferable pathway.
Scheme 103: Visible-light-induced ruthenium-catalyzed direct arylation at room temperature.