Electrostatically-directed Pd-catalysis in combination with C–H activation: site-selective coupling of remote chlorides with fluoroarenes and fluoroheteroarenes

Systems incorporating catalyst–substrate non-covalent interactions are emerging as a versatile approach to address site-selectivity challenges in remote functionalization reactions. Given the achievements that have been made in this regard using metals such as iridium, manganese and rhodium, it is surprising that non-covalent catalyst direction has not been utilized in reactions incorporating palladium-catalyzed C–H activation steps, despite palladium being arguably the most versatile metal for C–H activation. Herein, we demonstrate that electrostatically directed, site-selective C–Cl oxidative addition is compatible with a subsequent C–H activation step, proceeding via a concerted metalation deprotonation-type mechanism. This results in site-selective cross-coupling of dichloroarenes with fluoroarenes and fluoroheteroarenes, with selectivity controlled by catalyst structure. This study demonstrates that Pd-catalyzed C–H activation can be used productively in combination with a non-covalently-directed mode of catalysis, with important implications in both fields.

Electrostatically-directed oxidative addition is compatible with a subsequent C–H activation step, enabling site-selective coupling of remote chlorides with fluoroarenes and fluoroheteroarenes.     

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.     

Palladium-catalyzed direct asymmetric C–H bond functionalization enabled by the directing group strategy

In the past decade, selective C–C and C-heteroatom bond construction through palladium-catalyzed direct C–H bond functionalization has been extensively studied by employing a variety of directing groups. Within this category, direct asymmetric C(sp²)–H and C(sp³)–H activation for the construction of highly enantiomerically enriched skeletons still progressed at a slow pace. This minireview briefly introduces the major advances in the field for palladium-catalyzed direct asymmetric C–H bond functionalization via the directing group strategy.

This minireview introduces Pd-catalyzed direct asymmetric C–H functionalization reactions using a directing group strategy.     

Iron-catalyzed α-C–H functionalization of π-bonds: cross-dehydrogenative coupling and mechanistic insights

The deprotonation of propargylic C–H bonds for subsequent functionalization typically requires stoichiometric metal alkyl or amide reagents. In addition to the undesirable generation of stoichiometric metallic waste, these conditions limit the functional group compatibility and versatility of this functionalization strategy and often result in regioisomeric mixtures. In this article, we report the use of dicarbonyl cyclopentadienyliron(ii) complexes for the generation of propargylic anion equivalents toward the direct electrophilic functionalization of propargylic C–H bonds under mild, catalytic conditions. This technology was applied to the direct conversion of C–H bonds to C–C bonds for the synthesis of several functionalized scaffolds through a one-pot cross dehydrogenative coupling reaction with tetrahydroisoquinoline and related privileged heterocyclic scaffolds. A series of NMR studies and deuterium-labelling experiments indicated that the deprotonation of the propargylic C–H bond was the rate-determining step when a Cp*Fe(CO)₂-based catalyst system was employed.

[Cp*Fe(CO)₂]⁺ facilitates the α-deprotonation of unsaturated C–C bond for propargylic and allylic C–H functionalization. Mechanistic studies reveal insights into the superior performance of the electron-rich and hindered ligand on iron.     

Magnesium-mediated sp3 C–H activation in cascade cyclization of 1-arylethynyl-2-alkyl-o-carboranes: efficient synthesis of carborane-fused cyclopentanes

This work reports an unprecedented cascade cyclization of 1-arylethynyl-2-alkyl-o-carboranes promoted by magnesium-mediated sp³ C–H activation. Treatment of 1-arylethynyl-2-alkyl-o-carboranes with MeMgBr gives a series of carborane-fused cyclopentanes in very good yields. Deuterium labelling and control experiments suggest that HMgBr, resulting in situ from the nucleophilic substitution of cage B–H bonds with Grignard reagent, initiates the reaction, in which magnesium-promoted intramolecular sp³ C–H activation serves as a key step. This work not only offers a new route for the synthesis of carborane-fused cyclopentanes, but also sheds some light on Mg-mediated C–H activation and functionalization.

An unprecedented cascade cyclization of 1-arylethynyl-2-alkyl-o-carboranes with Grignard reagent for synthesizing carborane-fused cyclopentanes has been disclosed, in which magnesium-mediated intramolecular sp³ C–H activation serves as a key step.     

The site-selectivity and mechanism of Pd-catalyzed C(sp2)–H arylation of simple arenes

Control over site-selectivity is a critical challenge for practical application of catalytic C–H functionalization reactions in organic synthesis. Despite the seminal breakthrough of the Pd-catalyzed C(sp²)–H arylation of simple arenes via a concerted metalation–deprotonation (CMD) pathway in 2006, understanding the site-selectivity of the reaction still remains elusive. Here, we have comprehensively investigated the scope, site-selectivity, and mechanism of the Pd-catalyzed direct C–H arylation reaction of simple arenes. Counterintuitively, electron-rich arenes preferably undergo meta-arylation without the need for a specifically designed directing group, whereas electron-deficient arenes bearing fluoro or cyano groups exhibit high ortho-selectivity and electron-deficient arenes bearing bulky electron-withdrawing groups favor the meta-product. Comprehensive mechanistic investigations through a combination of kinetic measurements and stoichiometric experiments using arylpalladium complexes have revealed that the Pd-based catalytic system works via a cooperative bimetallic mechanism, not the originally proposed monometallic CMD mechanism, regardless of the presence of a strongly coordinating L-type ligand. Notably, the transmetalation step, which is influenced by a potassium cation, is suggested as the selectivity-determining step.

The transmetalation step, not the C–H activation step, is suggested as the selectivity-determining step in Pd-catalyzed C–H arylation of simple arenes.     

C–H functionalization reactions enabled by hydrogen atom transfer to carbon-centered radicals

Selective functionalization of ubiquitous unactivated C–H bonds is a continuous quest for synthetic organic chemists. In addition to transition metal catalysis, which typically operates under a two-electron manifold, a recent renaissance in the radical approach relying on the hydrogen atom transfer (HAT) process has led to tremendous growth in the area. Despite several challenges, protocols proceeding via HAT are highly sought after as they allow for relatively easy activation of inert C–H bonds under mild conditions leading to a broader scope and higher functional group tolerance and sometimes complementary reactivity over methods relying on traditional transition metal catalysis. A number of methods operating via heteroatom-based HAT have been extensively reported over the past few years, while methods employing more challenging carbon analogues have been less explored. Recent developments of mild methodologies for generation of various carbon-centered radical species enabled their utilization in the HAT process, which, in turn, led to the development of remote C(sp³)–H functionalization reactions of alcohols, amines, amides and related compounds. This review covers mostly recent advances in C–H functionalization reactions involving the HAT step to carbon-centered radicals.

Intramolecular and intermolecular HAT to C-centered radicals enables selective C–H functionalization of organic molecules.     

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.     

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.     

Photoinduced C(sp3)–H sulfination empowers the direct and chemoselective introduction of the sulfonyl group

Direct installation of the sulfinate group by the functionalization of unreactive aliphatic C–H bonds can provide access to most classes of organosulfur compounds, because of the central position of sulfinates as sulfonyl group linchpins. Despite the importance of the sulfonyl group in synthesis, medicine, and materials science, a direct C(sp³)–H sulfination reaction that can convert abundant aliphatic C–H bonds to sulfinates has remained elusive, due to the reactivity of sulfinates that are incompatible with typical oxidation-driven C–H functionalization approaches. We report herein a photoinduced C(sp³)–H sulfination reaction that is mediated by sodium metabisulfite and enables access to a variety of sulfinates. The reaction proceeds with high chemoselectivity and moderate to good regioselectivity, affording only monosulfination products and can be used for a solvent-controlled regiodivergent distal C(sp³)–H functionalization.

The photoinduced C–H sulfination of abundant aliphatic C–H bonds provides direct access to all major classes of organosulfur compounds via the intermediacy of synthetically versatile sulfinate salts.     

Sulfur stereogenic centers in transition-metal-catalyzed asymmetric C–H functionalization: generation and utilization

Transition-metal-catalyzed enantioselective C–H functionalization has emerged as a powerful tool for the synthesis of enantioenriched compounds in chemical and pharmaceutical industries. Sulfur-based functionalities are ubiquitous in many of the biologically active compounds, medicinal agents, functional materials, chiral auxiliaries and ligands. This perspective highlights recent advances in sulfur functional group enabled transition-metal-catalyzed enantioselective C–H functionalization for the construction of sulfur stereogenic centers, as well as the utilization of chiral sulfoxides to realize stereoselective C–H functionalization.

This perspective highlights sulfur functional groups enabled enantioselective C–H functionalization for the construction of sulfur stereogenic centers, and the utilization of chiral sulfoxide to realize stereoselective C–H functionalization.     

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.     

Facile synthesis of axially chiral styrene-type carboxylic acids via palladium-catalyzed asymmetric C–H activation

A novel method by a one-step introduction of axial chirality and sterically hindered group has been developed for facile synthesis of axially chiral styrene-type carboxylic acids. With the palladium-catalyzed C–H arylation and olefination of readily available cinnamic acid established, this transformation demonstrated excellent yield, excellent stereocontrol (up to 99% yield and 99% ee), and broad substrate scope under mild conditions. The axially chiral styrene-type carboxylic acids produced have been successfully applied to Cp*Co^III-catalyzed asymmetric C–H activation reactions, indicating their potential as chiral ligands or catalysts in asymmetric synthesis.

Palladium-catalyzed asymmetric C–H functionalization to yield axially chiral styrene-type carboxylic acids is described, in which axial chirality and sterically hindered group were incorporated in one-step.     

Understanding the unique reactivity patterns of nickel/JoSPOphos manifold in the nickel-catalyzed enantioselective C–H cyclization of imidazoles

The 3d transition metal-catalyzed enantioselective C–H functionalization provides a sustainable strategy for the construction of chiral molecules. A better understanding of the catalytic nature of the reactions and the factors controlling the enantioselectivity is important for rational design of more efficient systems. Herein, the mechanisms of Ni-catalyzed enantioselective C–H cyclization of imidazoles are investigated by density functional theory (DFT) calculations. Both the π-allyl nickel(ii)-promoted σ-complex-assisted metathesis (σ-CAM) and the nickel(0)-catalyzed oxidative addition (OA) mechanisms are disfavored. In addition to the typically proposed ligand-to-ligand hydrogen transfer (LLHT) mechanism, the reaction can also proceed via an unconventional σ-CAM mechanism that involves hydrogen transfer from the JoSPOphos ligand to the alkene through P–H oxidative addition/migratory insertion, C(sp²)–H activation via σ-CAM, and C–C reductive elimination. Importantly, computational results based on this new mechanism can indeed reproduce the experimentally observed enantioselectivities. Further, the catalytic activity of the π-allyl nickel(ii) complex can be rationalized by the regeneration of the active nickel(0) catalyst via a stepwise hydrogen transfer, which was confirmed by experimental studies. The calculations reveal several significant roles of the secondary phosphine oxide (SPO) unit in JoSPOphos during the reaction. The improved mechanistic understanding will enable design of novel enantioselective C–H transformations.

Several unique reactivity patterns of the Ni/JoSPOphos manifold, including facile hydrogen transfer via the two-step oxidative addition/migratory insertion and C(sp²)–H activation via an unconventional σ-CAM mechanism, were disclosed in this work.     

Pd-catalyzed cross-electrophile Coupling/C–H alkylation reaction enabled by a mediator generated via C(sp3)–H activation

Transition-metal-catalyzed cross-electrophile C(sp²)–(sp³) coupling and C–H alkylation reactions represent two efficient methods for the incorporation of an alkyl group into aromatic rings. Herein, we report a Pd-catalyzed cascade cross-electrophile coupling and C–H alkylation reaction of 2-iodo-alkoxylarenes with alkyl chlorides. Methoxy and benzyloxy groups, which are ubiquitous functional groups and common protecting groups, were utilized as crucial mediators via primary or secondary C(sp³)–H activation. The reaction provides an innovative and convenient access for the synthesis of alkylated phenol derivatives, which are widely found in bioactive compounds and organic functional materials.

A cascade Pd-catalyzed cross-electrophile coupling and C–H alkylation reaction of 2-iodo-alkoxylarenes with alkyl chlorides has been developed by using an ortho-methoxy or benzyloxy group as a mediator via C(sp³)–H activation.     

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.     

Palladium-catalyzed synthesis of β-hydroxy compounds via a strained 6,4-palladacycle from directed C–H activation of anilines and C–O insertion of epoxides

A palladium-catalyzed C–H activation of acetylated anilines (acetanilides, 1,1-dimethyl-3-phenylurea, 1-phenylpyrrolidin-2-one, and 1-(indolin-1-yl)ethan-1-one) with epoxides using O-coordinating directing groups was accomplished. This C–H alkylation reaction proceeds via formation of a previously unknown 6,4-palladacycle intermediate and provides rapid access to regioselectively functionalized β-hydroxy products. Notably, this catalytic system is applicable for the gram scale mono-functionalization of acetanilide in good yields. The palladium-catalyzed coupling reaction of the ortho-C(sp²) atom of O-coordinating directing groups with a C(sp³) carbon of chiral epoxides offers diverse substrate scope in good to excellent yields. In addition, further transformations of the synthesized compound led to biologically important heterocycles. Density functional theory reveals that the 6,4-palladacycle leveraged in this work is significantly more strained (>10 kcal mol⁻¹) than the literature known 5,4 palladacycles.

The combined experimental and computational study on palladium-catalyzed regioselective C–H functionalization of O-coordinating directing groups with epoxides is described.     

Iron porphyrin catalysed light driven C–H bond amination and alkene aziridination with organic azides

Visible light driven nitrene transfer and insertion reactions of organic azides are an attractive strategy for the design of C–N bond formation reactions under mild reaction conditions, the challenge being lack of selectivity as a free nitrene reactive intermediate is usually involved. Herein is described an iron(iii) porphyrin catalysed sp³ C–H amination and alkene aziridination with selectivity by using organic azides as the nitrogen source under blue LED light (469 nm) irradiation. The photochemical reactions display chemo- and regio-selectivity and are effective for the late-stage functionalization of natural and bioactive compounds with complexity. Mechanistic studies revealed that iron porphyrin plays a dual role as a photosensitizer and as a catalyst giving rise to a reactive iron–nitrene intermediate for subsequent C–N bond formation.

An iron(iii) porphyrin catalysed sp³ C–H amination and alkene aziridination with broad substrate scope under mild conditions is conducted, with selectivity through the use of organic azides as the nitrogen source under blue LED light irradiation.