Thioether-enabled palladium-catalyzed atroposelective C–H olefination for N–C and C–C axial chirality

Thioethers allowed for highly atroposelective C–H olefinations by a palladium/chiral phosphoric acid catalytic system under ambient air. Both N–C and C–C axial chiral (hetero)biaryls were successfully constructed, leading to a broad range of axially chiral N-aryl indoles and biaryls with excellent enantioselectivities up to 99% ee. Experimental and computational studies were conducted to unravel the walking mode for the atroposelective C–H olefination. A plausible chiral induction model for the enantioselectivity-determining step was established by detailed DFT calculations.

Thioethers allowed for highly atroposelective C–H olefinations by a palladium/chiral phosphoric acid catalytic system under ambient air.     

Atropoenantioselective palladaelectro-catalyzed anilide C–H olefinations viable with natural sunlight as sustainable power source

Enantioselective electrocatalyzed transformations represent a major challenge. We herein achieved atropoenantioselective pallada-electrocatalyzed C–H olefinations and C–H allylations with high efficacy and enantioselectivity under exceedingly mild reaction conditions. With (S)-5-oxoproline as the chiral ligand, activated and non-activated olefins were suitable substrates for the electro-C–H activations. Dual catalysis was devised in terms of electro-C–H olefination, along with catalytic hydrogenation. Challenging enantiomerically-enriched chiral anilide scaffolds were thereby obtained with high levels of enantio-control in the absence of toxic and cost-intensive silver salts. The resource-economy of the transformation was even improved by directly employing renewable solar energy.

Asymmetric pallada-electrocatalyzed C–H activation of achiral anilides were accomplished by catalyst control with high levels of enantioselectivity. Dual catalysis was devised, while photovoltaic cells could be used to empower the electrocatalysis.     

Nickel-catalyzed C–O/N–H,C–S/N–H,and C–CN/N–H annulation of aromatic amides with alkynes: C–O,C–S,and C–CN activation

The Ni-catalyzed reaction of ortho-phenoxy-substituted aromatic amides with alkynes in the presence of LiO^tBu as a base results in C–O/N–H annulation with the formation of 1(2H)-isoquinolinones. The use of a base is essential for the reaction to proceed. The reaction proceeds, even in the absence of a ligand, and under mild reaction conditions (40 °C). An electron-donating group on the aromatic ring facilitates the reaction. The reaction was also applicable to carbamate (C–O bond activation), methylthio (C–S bond activation), and cyano (C–CN bond activation) groups as leaving groups.

The Ni-catalyzed reaction of ortho-phenoxy-substituted aromatic amides with alkynes in the presence of LiO^tBu as a base results in C–O/N–H annulation with the formation of 1(2H)-isoquinolinones.     

Metal-free tandem carbene N–H insertions and C–C bond cleavages

A metal-free C–H [5 + 1] annulation reaction of 2-arylanilines with diazo compounds has been achieved, giving rise to two types of prevalent phenanthridines via highly selective C–C cleavage. Compared to the simple N–H insertion manipulation of diazo, this method elegantly accomplishes a tandem N–H insertion/S_EAr/C–C cleavage/aromatization reaction, and the synthetic utility of this new transformation is exemplified by the succinct syntheses of trisphaeridine and bicolorine alkaloids.

A metal-free C–H [5 + 1] annulation reaction of 2-arylanilines with diazo compounds has been achieved, giving rise to two types of prevalent phenanthridines via highly selective C–C cleavage.     

Photocatalytic C(sp3) radical generation via C–H,C–C,and C–X bond cleavage

C(sp³) radicals (R˙) are of broad research interest and synthetic utility. This review collects some of the most recent advancements in photocatalytic R˙ generation and highlights representative examples in this field. Based on the key bond cleavages that generate R˙, these contributions are divided into C–H, C–C, and C–X bond cleavages. A general mechanistic scenario and key R˙-forming steps are presented and discussed in each section.

C(sp³) radicals (R˙) are of broad research interest and synthetic utility.     

Functionalisation of ethereal-based saturated heterocycles with concomitant aerobic C–H activation and C–C bond formation

With an ever-growing emphasis on sustainable synthesis, aerobic C–H activation (the use of oxygen in air to activate C–H bonds) represents a highly attractive conduit for the development of novel synthetic methodologies. Herein, we report the air mediated functionalisation of various saturated heterocycles and ethers via aerobically generated radical intermediates to form new C–C bonds using acetylenic and vinyl triflones as radical acceptors. This enables access to a variety of acetylenic and vinyl substituted saturated heterocycles that are rich in synthetic value. Mechanistic studies and control reactions support an aerobic radical-based C–H activation mechanism.

Herein we disclose a novel method for the aerobic C–H activation of ethereal-based heterocycles to generate various α-functionalised building blocks.     

Site-selective functionalization of remote aliphatic C–H bonds via C–H metallation

Directing group assistance provided a paradigm for controlling site-selectivity in transition metal-catalyzed C–H functionalization reactions. However, the kinetically and thermodynamically favored formation of 5-membered metallacycles has greatly hampered the selective activation of remote C(sp³)–H bonds via larger-membered metallacycles. Recent development to achieve remote C(sp³)–H functionalization via the C–H metallation process largely relies on employing specific substrates without accessible proximal C–H bonds. Encouragingly, recent advances in this field have enabled the selective functionalization of remote aliphatic C–H bonds in the presence of equally accessible proximal ones by taking advantage of the switch of the regiodetermining step, ring strain of metallacycles, multiple non-covalent interactions, and favourable reductive elimination from larger-membered metallacycles. In this review, we summarize these advancements according to the strategies used, hoping to facilitate further efforts to achieve site- and even enantioselective functionalization of remote C(sp³)–H bonds.

Recent advances in site-selective functionalization of remote aliphatic C–H bonds in organometallic pathways are summarized.     

Cyanoisocyanoacetylene,N≡C−C≡C−N≡C

Vacuum pyrolysis of the precursor complex [(CO)₅Cr(CN−CCl=CF−CN)] resulted in the isolation and structure elucidation by molecular spectroscopy of isomer 1 . According to ab initio calculations 1 is 109 kJ mol⁻¹ less stable than NC−C≡C−CN, which has been known for some time. An accurate equilibrium structure for 1 has been determined with mixed experimental and theoretical methods.     

Renewable resources for sustainable metallaelectro-catalysed C–H activation

The necessity for more sustainable industrial chemical processes has internationally been agreed upon. During the last decade, the scientific community has responded to this urgent need by developing novel sustainable methodologies targeted at molecular transformations that not only produce reduced amounts of byproducts, but also by the use of cleaner and renewable energy sources. A prime example is the electrochemical functionalization of organic molecules, by which toxic and costly chemicals can be replaced by renewable electricity. Unrivalled levels of resource economy can thereby be achieved via the merger of metal-catalyzed C–H activation with electrosynthesis. This perspective aims at highlighting the most relevant advances in metallaelectro-catalysed C–H activations, with a particular focus on the use of green solvents and sustainable wind power and solar energy until June 2020.

The merger of C–H activation with electrosynthesis, powered by renewable energies and resources, will guide towards a sustainable future.     

Selective cleavage of unactivated arene ring C–C bonds by iridium: key roles of benzylic C–H activation and metal–metal cooperativity

The cleavage of aromatic C–C bonds is central for conversion of fossil fuels into industrial chemicals and designing novel arene functionalisations through ring opening, expansion and contraction. However, the current progress is hampered by both the lack of experimental examples of selective oxidative addition of aromatic C–C bonds and limited understanding of the factors that favour insertion into the C–C rather than the C–H bonds. Here, we describe the comprehensive mechanism of the only reported chemo- and regioselective insertion of a transition metal into a range of substituted arene rings in simple iridium(i) complexes. The experimental and computational data reveal that this ring cleavage requires both reversible scission of a benzylic C–H bond and cooperativity of two Ir centres sandwiching the arene in the product-determining intermediate. The mechanism explains the chemoselectivity and scope of this unique C–C activation in industrially important methylarenes and provides a general insight into the role of metal–metal cooperativity in the cleavage of unsaturated C–C bonds.

The detailed mechanism of iridium-mediated C–C cleavage in unactivated arenes reveals the key factors enabling the process and helps predict the scope of the cleavage reaction.     

Enantioselective Synthesis of C−N Axially Chiral N‐Aryloxindoles by Asymmetric Rhodium‐Catalyzed Dual C−H Activation

The first enantioselective Satoh–Miura‐type reaction is reported. A variety of C?N axially chiral N‐aryloxindoles have been enantioselectively synthesized by an asymmetric rhodium‐catalyzed dual C?H activation reaction of N‐aryloxindoles and alkynes. High yields and enantioselectivities were obtained (up to 99 % yield and up to 99 % ee). To date, it is also the first example of the asymmetric synthesis of C?N axially chiral compounds by such a C?H activation strategy.     

Ruthenaelectro-catalyzed C–H acyloxylation for late-stage tyrosine and oligopeptide diversification

Ruthenaelectro(ii/iv)-catalyzed intermolecular C–H acyloxylations of phenols have been developed by guidance of experimental, CV and computational insights. The use of electricity bypassed the need for stoichiometric chemical oxidants. The sustainable electrocatalysis strategy was characterized by ample scope, and its unique robustness enabled the late-stage C–H diversification of tyrosine-derived peptides.

Ruthenaelectro(ii/iv)-catalyzed intermolecular C–H acyloxylations of oligopeptides have been developed by the guidance of key experimental, CV and computational insights.     

Ortho C–H arylation of arenes at room temperature using visible light ruthenium C–H activation

A ruthenium-catalyzed ortho C–H arylation process is described using visible light. Using the readily available catalyst [RuCl₂(p-cymene)]₂, visible light irradiation was found to enable arylation of 2-aryl-pyridines at room temperature for a range of aryl bromides and iodides.

A ruthenium-catalyzed ortho C–H arylation process is described using visible light.     

A Bulky Chiral N‐Heterocyclic Carbene Nickel Catalyst Enables Enantioselective C−H Functionalizations of Indoles and Pyrroles

An enantioselective nickel(0)‐catalyzed C?H functionalization of indoles and pyrroles that does not require the typical Lewis basic directing groups is disclosed. The reaction provides access to valuable tetrahydropyridoindoles and tetrahydroindolizines in high yields and enantioselectivity under mild reaction conditions. The process is characterized by a clear endo‐cyclization preference to yield the sought‐after six‐membered‐ring products. Key for the success of the activation and selectivity in the cyclization was the development of a novel chiral SIPr carbene ligand analogue with very bulky flanking groups.     

Heteroarylation of unactivated C–H bonds suitable for late-stage functionalization

The late-stage introduction of diverse heterocycles onto complex small molecules enables efficient access to new medicinally relevant compounds. An attractive approach to such a transformation would utilize the ubiquitous aliphatic C–H bonds of a complex substrate. Herein, we report a system that enables direct C–H heteroarylation using a stable, commercially available O-alkenylhydroxamate with heterocyclic sulfone partners. The C–H heteroarylation proceeds efficiently with a range of aliphatic substrates and common heterocycles, and is a rare example of heteroarylation of strong C–H bonds. Importantly, the present approach is amenable to late-stage functionalization as the substrate is the limiting reagent in all cases.

The late-stage introduction of diverse heterocycles onto complex small molecules enables efficient access to new medicinally relevant compounds.     

Hexafluoroisopropanol: the magical solvent for Pd-catalyzed C–H activation

Among numerous solvents available for chemical transformations, 1,1,1,3,3,3-hexafluoro-2-propanol (popularly known as HFIP) has attracted enough attention of the scientific community in recent years. Several unique features of HFIP compared to its non-fluoro analogue isopropanol have helped this solvent to make a difference in various subdomains of organic chemistry. One such area is transition metal-catalyzed C–H bond functionalization reactions. While, on one side, HFIP is emerging as a green and sustainable deep eutectic solvent (DES), on the other side, a major proportion of Pd-catalyzed C–H functionalization is heavily relying on this solvent. In particular, for distal aromatic C–H functionalizations, the exceptional impact of HFIP to elevate the yield and selectivity has made this solvent irreplaceable. Recent research studies have also highlighted the H-bond-donating ability of HFIP to enhance the chiral induction in Pd-catalyzed atroposelective C–H activation. This perspective aims to portray different shades of HFIP as a magical solvent in Pd-catalyzed C–H functionalization reactions.

Among numerous solvents available for chemical transformations, 1,1,1,3,3,3-hexafluoro-2-propanol (popularly known as HFIP) has attracted enough attention of the scientific community in recent years.     

Pd-catalysed C–H functionalisation of free carboxylic acids

Pd-catalysed C–H functionalisation of free carboxylic acids has drawn significant attention over the last few years due to the predominance of carboxylic acid moieties in pharmaceuticals and agrochemicals. But their coordinating ability was overlooked and masked by exogenous directing groups for a long time. Even other crucial roles of carboxylic acids as additives and steric inducers that directly influence the mode of a reaction have been widely neglected. This review aims to embrace all of the diverse aspects of carboxylic acids except additive and steric effects by concisely and systematically describing their versatile role in Pd-catalysed proximal and distal C–H activation reactions that could be implemented in the pharmaceutical and agrochemical industries. In addition, the mechanistic perspectives along with several recent strategies developed in the last few years discussed here will serve as educational resources for future research.

Pd-catalysed C–H functionalisation of free carboxylic acids has drawn significant attention over the last few years due to the predominance of carboxylic acid moieties in pharmaceuticals and agrochemicals.