Enantioselective C-H Bond Functionalization Involving Arene Ruthenium(II) Catalysis.

The p-Cymene ruthenium(II) complex is one of the most widely used catalysts in C-H activation. However, enantioselective C-H activation promoted by arene ruthenium(II) complexes has not been realized until recently. The revealed strategies include intramolecular nitrene C-H insertion, the use of chiral transient directing groups, chiral carboxylic acid, relay catalysis, and chiral arene ligands. In this minireview, these advances are summarized and discussed in the hope of spurring further developments.

Rhodium-Catalyzed C-H Methylation and Alkylation Reactions by Carbene-Transfer Reactions.

In this combined computational and experimental study, the C-H functionalization of 2-phenyl pyridine with diazoalkanes was investigated. Initial evaluation by computational methods allowed the evaluation of different metal catalysts and diazoalkanes and their compatibility in this C-H functionalization reaction. With these findings, suitable reaction conditions for the C-H methylation reactions were quickly identified by using highly reactive TMS diazomethane and C-H alkylation reactions with donor/acceptor diazoalkanes, which is applied to a broad scope on alkylation reactions of 2-aryl pyridines with TMS diazomethane and donor/acceptor diazoalkane (51 examples, up to 98 % yield).

Two Directing Groups Used for Metal Catalysed Meta-C-H Functionalisation Only Effect Ortho Electrophilic C-H Borylation.

Two templates used in meta-directed C-H functionalisation under metal catalysis do not direct meta-C-H borylation under electrophilic borylation conditions. Using BCl3 only Lewis adduct formation with Lewis basic sites in the template is observed. While combining BBr3 and the template containing an amide linker only led to amide directed ortho C-H borylation, with no pyridyl directed meta borylation. The amide directed borylation is selective for the ortho borylation of the aniline derived unit in the template, with no ortho borylation of the phenylacetyl ring - which would also form a six membered boracycle - observed. In the absence of other aromatics amide directed ortho borylation on to phenylacetyl rings can be achieved. The absence of meta-borylation using two templates indicates a higher barrier to pyridyl directed meta borylation relative to amide directed ortho borylation and suggests that bespoke templates for enabling meta-directed electrophilic borylation may be required.

Ligand-Controlled NiH-Catalyzed Regiodivergent Chain-Walking Hydroalkylation of Alkenes.

A NiH-catalyzed migratory hydroalkylation of alkenyl amines with predictable and switchable regioselectivity is reported. By utilizing a ligand-controlled, directing group-assisted strategy, various alkyl units are site-selectively installed at inert sp3 C-H sites far away from the original C=C bonds. A range of structurally diverse α- and ß-branched protected amines are conveniently synthesized via stabilization of 5- and 6-membered nickelacycles respectively. This method exhibits broad scope and high functional group tolerance, and can be applied to late-stage modification of medicinally relevant molecules.

Amine-Catalyzed Copper-Mediated C-H Sulfonylation of Benzaldehydes via a Transient Imine Directing Group.

Transient directing groups (TDGs) can provide a powerful means for C-H functionalization without requiring additional steps for directing group introduction and removal. We report the first use of a TDG in combination with copper to effect C-H functionalization. The regioselective copper mediated ß-C(sp2 )-H sulfonylation of aldehydes with sulfinate salts is accomplished using catalytic ß-alanine to form a transient imine. A broad range of sulfonylated benzaldehydes are prepared using copper fluoride as both copper source and oxidant, involving a [5,6] cupracyclic intermediate. γ-(peri)-Sulfonylation of napthyl and phenanthrenyl carboxaldehydes is achieved through [6,6] cupracyclic intermediates. Further derivatisation of the aldehyde products is demonstrated. Kinetic experiments and Hammett analysis suggest the turnover limiting step to be a concerted asynchronous C-H cleavage via a dearomative Wheland-type transition state.

Palladium-Catalyzed PIDA-Mediated δ-C(sp3 )-H Acetoxylation of Amino Acid Derivatives: Overriding Competitive Intramolecular Amination.

The selective δ-C(sp3 )-H acetoxylation of N-(SO2 Py)-protected amino acid derivatives has been accomplished by using palladium-catalysis and PhI(OAc)2 (PIDA) as both terminal oxidant and acetoxy source. The distinct structural and electronic features of the SO2 Py compared to more traditional carbonyl-based directing groups is essential to override the otherwise more favourable competitive intramolecular C-H amination. The δ-site selectivity predominates over traditionally more favorable 5-membered cyclopalladation at competitive γ-CH2 . Experimental and DFT mechanistic studies provide important insights about the mechanism and the underlying factors controlling the chemo- and regioselectivity.

Metal-Free Phosphorus-Directed Borylation of C(sp2 )-H Bonds.

Spectacular progress has recently been achieved in transition metal-catalyzed C-H borylation of phosphines as well as directed electrophilic C-H borylation. As shown here, P-directed electrophilic borylation provides a new, straightforward, and efficient access to phosphine-boranes. It operates under metal-free conditions and leverages simple, readily available substrates. It is applicable to a broad range of backbones (naphthyl, biphenyl, N-phenylpyrrole, binaphthyl, benzyl, naphthylmethyl) and gives facile access to various substitution patterns at boron (by varying the boron electrophile or post-derivatizing the borane moiety). NMR monitoring supports the involvement of P-stabilized borenium cations as key intermediates. DFT calculations reveal the existence and stabilizing effect of π-arene/boron interactions in the (biphenyl)(i-Pr)2 P→BBr2 + species.

Recent Advances in Late-Stage Construction of Stapled Peptides via C-H Activation.

Stapled peptides have been widely applied in many fields, including pharmaceutical chemistry, diagnostic reagents, and materials science. However, most traditional stapled peptide preparation methods rely on prefunctionalizations, which limit the diversity of stapled peptides. Recently, the emergence of late-stage transition metal-catalyzed C-H activation in amino acids and peptides has attracted wide interest due to its robustness and applicability for peptide stapling. In this review, we summarize the methods for late-stage construction of stapled peptides via transition metal-catalyzed C-H activation.

Decoding Directing Groups and Their Pivotal Role in C-H Activation.

Synthetic organic chemistry has witnessed a plethora of functionalization and defunctionalization strategies. In this regard, C-H functionalization has been at the forefront due to the multifarious applications in the development of simple to complex molecular architectures and holds a brilliant prospect in drug development and discovery. Despite been explored tremendously by chemists, this functionalization strategy still enjoys the employment of novel metal catalysts as well metal-free organic ligands. Moreover, the switch to photo- and electrochemistry has widened our understanding of the alternative pathways via which a reaction can proceed and these strategies have garnered prominence when applied to C-H activation. Synthetic chemists have been foraging for new directing groups and templates for the selective activation of C-H bonds from a myriad of carbon-hydrogen bonds in aromatic as well as aliphatic systems. As a matter of fact, by varying the templates and directing groups, scientists found the answer to the challenge of distal C-H bond activation which remained an obstacle for a very long time. These templates have been frequently harnessed for selectively activating C-H bonds of natural products, drugs, and macromolecules decorated with multiple C-H bonds. This itself was a challenge before the commencement of this field as functionalization of a site other than the targeted site could modify and hamper the biological activity of the pharmacophore. Total synthesis and pharmacophore development often faces the difficulty of superfluous reaction steps towards selective functionalization. This obstacle has been solved by late-stage functionalization simply by harnessing C-H bond activation. Moreover, green chemistry and metal-free reaction conditions have seen light in the past few decades due to the rising concern about environmental issues. Therefore, metal-free catalysts or the usage of non-toxic metals have been recently showcased in a number of elegant works. Also, research groups across the world are developing rational strategies for directing group free or non-directed protocols that are just guided by ligands. This review encapsulates the research works pertinent to C-H bond activation and discusses the science devoted to it at the fundamental level. This review gives the readers a broad understanding of how these strategies work, the execution of various metal catalysts, and directing groups. This not only helps a budding scientist towards the commencement of his/her research but also helps a matured mind searching out for selective functionalization. A detailed picture of this field and its progress with time has been portrayed in lucid scientific language with a motive to inculcate and educate scientific minds about this beautiful strategy with an overview of the most relevant and significant works of this era. The unique trait of this review is the detailed description and classification of various directing groups and their utility over a wide substrate scope. This allows an experimental chemist to understand the applicability of this domain and employ it over any targeted substrate.

Chiral-Directing-Group-Assisted Rhodium(III)-Catalyzed Asymmetric Addition of Inert Arene C-H Bond to Aldimines with Subsequent Intramolecular Cyclization.

By using a chiral directing group, an asymmetric rhodium(III)-catalyzed C-H bond addition to aldimines followed by intramolecular cyclization to form chiral isoindolinones has been achieved (up to 68 % yield, up to 93 % ee). A three-component variant that resembles Mannich reaction was also realized (41 % yield, 83 % ee). Product elaborations and preliminary mechanistic studies were described.

A Guide to Directing Group Removal: 8-Aminoquinoline.

The use of directing groups allows high levels of selectivity to be achieved in transition metal-catalyzed transformations. Efficient removal of these auxiliaries after successful functionalization, however, can be very challenging. This review provides a critical overview of strategies used for removal of Daugulis' 8-aminoquinoline (2005-2020), one of the most widely used N,N-bidentate directing groups. The limitations of these strategies are discussed and alternative approaches are suggested for challenging substrates. Our aim is to provide a comprehensive end-users' guide for chemists in academia and industry who want to harness the synthetic power of directing groups-and be able to remove them from their final products.

Programmed Multiple C-H Bond Functionalization of the Privileged 4-hydroxyquinoline Template.

The introduction of substituents on bare heterocyclic scaffolds can selectively be achieved by directed C-H functionalization. However, such methods have only occasionally been used, in an iterative manner, to decorate various positions of a medicinal scaffold to build chemical libraries. We herein report the multiple, site selective, metal-catalyzed C-H functionalization of a "programmed" 4-hydroxyquinoline. This medicinally privileged template indeed possesses multiple reactive sites for diversity-oriented functionalization, of which four were targeted. The C-2 and C-8 decorations were directed by an N-oxide, before taking benefit of an O-carbamoyl protection at C-4 to perform a Fries rearrangement and install a carboxamide at C-3. This also released the carbonyl group of 4-quinolones, the ultimate directing group to functionalize position 5. Our study highlights the power of multiple C-H functionalization to generate diversity in a biologically relevant library, after showing its strong antimalarial potential.

Transient Directing Groups in Metal-Organic Cooperative Catalysis.

The direct functionalization of C-H bonds is among the most fundamental chemical transformations in organic synthesis. However, when the innate reactivity of the substrate cannot be utilized for the functionalization of a given single C-H bond, this selective C-H bond functionalization mostly relies on the use of directing groups that allow bringing the catalyst in close proximity to the C-H bond to be activated and these directing groups need to be installed before and cleaved after the transformation, which involves two additional undesired synthetic operations. These additional steps dramatically reduce the overall impact and the attractiveness of C-H bond functionalization techniques since classical approaches based on substrate pre-functionalization are sometimes still more straightforward and appealing. During the past decade, a different approach involving both the in situ installation and removal of the directing group, which can then often be used in a catalytic manner, has emerged: the transient directing group strategy. In addition to its innovative character, this strategy has brought C-H bond functionalization to an unprecedented level of usefulness and has enabled the development of remarkably efficient processes for the direct and selective introduction of functional groups onto both aromatic and aliphatic substrates. The processes unlocked by the development of these transient directing groups will be comprehensively overviewed in this review article.

Catalyst Control in Switching the Site Selectivity of C-H Olefinations of 1,2-Dihydroquinolines: An Approach to Positional-Selective Functionalization of Quinolines.

A unique approach to achieve site-selective C-H olefinations exclusively at the C-3- or C-8-positions in the quinoline framework has been developed by catalyst control. Distal C(3)-H functionalization is achieved by using palladium catalysis, whereas proximal C(8)-H functionalization is obtained by employing ruthenium catalysis. Switching the site selectivity within a single substrate directly indicates two diverse pathways, which are operating under the palladium- and ruthenium-catalyzed reaction conditions.

PdII -Catalyzed Enantioselective C(sp3 )-H Arylation of Cyclobutyl Ketones Using a Chiral Transient Directing Group.

The use of chiral transient directing groups (TDGs) is a promising approach for developing PdII -catalyzed enantioselective C(sp3 )-H activation reactions. However, this strategy is challenging because the stereogenic center on the TDG is often far from the C-H bond, and both TDG covalently attached to the substrate and free TDG are capable of coordinating to PdII centers, which can result in a mixture of reactive complexes. We report a PdII -catalyzed enantioselective ß-C(sp3 )-H arylation reaction of aliphatic ketones using a chiral TDG. A chiral trisubstituted cyclobutane was efficiently synthesized from a mono-substituted cyclobutane through sequential C-H arylation reactions, thus demonstrating the utility of this method for accessing structurally complex products from simple starting materials. The use of an electron-deficient pyridone ligand is crucial for the observed enantioselectivity. Interestingly, employing different silver salts can reverse the enantioselectivity.

A Transient-Directing-Group Strategy Enables Enantioselective Reductive Heck Hydroarylation of Alkenes.

Metal-coordinating directing groups have seen extensive use in the field of transition-metal-catalyzed alkene functionalization; however, their waste-generating installation and removal steps limit the efficiency and practicality of reactions that rely on their use. Inspired by developments in asymmetric organocatalysis, where reactions rely on reversible covalent interactions between an organic substrate and a chiral mediator, we have developed a transient-directing-group approach to reductive Heck hydroarylation of alkenyl benzaldehyde substrates that proceeds under mild conditions. Highly stereoselective migratory insertion is facilitated by in situ formation of an imine from catalytic amounts of a commercially available amino acid additive. Computational studies reveal an unusual mode of enantioinduction by the remote chiral center in the transient directing group.

Synthesis of Axially Chiral Styrenes through Pd-Catalyzed Asymmetric C-H Olefination Enabled by an Amino Amide Transient Directing Group.

The atroposelective synthesis of axially chiral styrenes remains a formidable challenge due to their relatively lower rotational barriers compared to the biaryl atropoisomers. Herein, we describe the construction of axially chiral styrenes through PdII -catalyzed atroposelective C-H olefination, using a bulky amino amide as a transient chiral auxiliary. Various axially chiral styrenes were produced with good yields and high enantioselectivity (up to 95 % yield and 99 % ee). Carboxylic acid derivatives of the resulting axially chiral styrenes showed superior enantiocontrol over the biaryl counterparts in CoIII -catalyzed enantioselective C(sp3 )-H amidation of thioamide. Mechanistic studies suggest that C-H cleavage is the enantioselectivity-determining step.

C-H Functionalization-Prediction of Selectivity in Iridium(I)-Catalyzed Hydrogen Isotope Exchange Competition Reactions.

An assessment of the C-H activation catalyst [(COD)Ir(IMes)(PPh3 )]PF6 (COD=1,5-cyclooctadiene, IMes=1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene) in the deuteration of phenyl rings containing different functional directing groups is divulged. Competition experiments have revealed a clear order of the directing groups in the hydrogen isotope exchange (HIE) with an iridium (I) catalyst. Through DFT calculations the iridium-substrate coordination complex has been identified to be the main trigger for reactivity and selectivity in the competition situation with two or more directing groups. We postulate that the competition concept found in this HIE reaction can be used to explain regioselectivities in other transition-metal-catalyzed functionalization reactions of complex drug-type molecules as long as a C-H activation mechanism is involved.

Ligand-Enabled ß-Methylene C(sp3 )-H Arylation of Masked Aliphatic Alcohols.

Despite recent advances, reactivity and site-selectivity remain significant obstacles for the practical application of C(sp3 )-H bond functionalization methods. Here, we describe a system that combines a salicylic-aldehyde-derived L,X-type directing group with an electron-deficient 2-pyridone ligand to enable the ß-methylene C(sp3 )-H arylation of aliphatic alcohols, which has not been possible previously. Notably, this protocol is compatible with heterocycles embedded in both alcohol substrates and aryl coupling partners. A site- and stereo-specific annulation of dihydrocholesterol and the synthesis of a key intermediate of englitazone illustrate the practicality of this method.

Weinreb Amides as Directing Groups for Transition Metal-Catalyzed C-H Functionalizations.

Weinreb amides are a privileged, multi-functional group with well-established utility in classical synthesis. Recently, several studies have demonstrated the use of Weinreb amides as interesting substrates in transition metal-catalyzed C-H functionalization reactions. Herein, we review this part of the literature, including the metal catalysts, transformations explored so far and specific insights from mechanistic studies.