Exploring Remote C─H Bond Arylation: Transition Metal Catalysis Without “End‐On Template”

Single-electron transfer oxidation-induced C–H bond functionalization via photo-/electrochemistry

A chlorobenzylation of terminal alkynes through Fe(II)-promoted benzylic C(sp(3))-H bond functionalization in the presence of NCS as a chloride source was developed. Compared with previous methods to prepare polysubstituted alkenyl halides, the presented procedure provides an efficient alternative with high atom and step economy under mild conditions. The transformation was established to proceed through a single-electron transfer (SET) process with benzyl cations as key intermediates.

Review: 18 refs.

The transition metal‐catalysed C−H bond functionalization has emerged as a powerful tool for accessing numerous organic compounds in greener manner with step and atom economy. Remarkable progress has been made in the metal‐catalysed C−H bond functionalization during the past decades and the trend is continuing as new reactions are being added. In the transition metal‐catalysed C−H bond functionalization, a growing attention has been paid on ruthenium, particularly, the stable ruthenium(II) as it allows several C−H bond functionalization reactions to perform in water with high selectivity. The ruthenium‐catalysed C−H bond functionalization reactions, such as arylation, alkenylation, annulation, cyanation, amination and silylation just to mention some have been well documented in numerous published papers, book chapters and review articles. However, as ruthenium‐catalysed C−H functionalization has been growing rapidly, a comprehensive review is necessary from time to time to highlight the progress made in this ever expanding field. In view of this, the manuscript presents the ruthenium‐catalysed direct C−O, C−N and C‐halogen bond forming reactions involving aromatic C−H bond covering oxygenation, amination, amidation, imidation, nitration and halogenation reported from 2012 to 2022.

Ammonia (NH3) is an ideal nitrogen source in terms of availability, reactivity, safety, atom economy, environmental compatibility, and ease of isolation. However, its utility for amine synthesis is...

Demonstrated herein is a highly effective 3 starting materials–4 component reaction (3SM‐4CR) strategy for the synthesis of pyrimidine carboxamides from amidines, styrene, and N,N‐dimethylformamide (DMF) by a palladium‐catalyzed oxidative process. This transformation represents the first example of employing DMF as a dual synthon, a one‐carbon‐atom synthon and amide synthon, and was proven by isotope‐labeling experiments. Additionally, the combination of C−H bond functionalization and cross‐dehydrogenative coupling processes affords four chemical bond formations. This sequential 3SM‐4CR strategy features inexpensive, readily available starting materials, green oxidants, as well as atom and step economy. It leads to the preparation of pyrimidine carboxamides and has potential applications in the pharmaceutical industry.

Demonstrated herein is a highly effective 3 starting materials-4 component reaction (3SM-4CR) strategy for the synthesis of pyrimidine carboxamides from amidines, styrene, and N,N-dimethylformamide (DMF) by a palladium-catalyzed oxidative process. This transformation represents the first example of employing DMF as a dual synthon, a one-carbon-atom synthon and amide synthon, and was proven by isotope-labeling experiments. Additionally, the combination of C-H bond functionalization and cross-dehydrogenative coupling processes affords four chemical bond formations. This sequential 3SM-4CR strategy features inexpensive, readily available starting materials, green oxidants, as well as atom and step economy. It leads to the preparation of pyrimidine carboxamides and has potential applications in the pharmaceutical industry.

Direct transformation of unactivated bond such as C-H bond is an important transformation. Because of its high utility from the viewpoints of atom economy and step economy, much effort has been devoted to the development of novel and more efficient strategies. Most of the reported processes have been relied on the use of active, transition metal (TM) catalysts. Unfortunately, this chemistry is hounded by the problem that stoichiometric amounts of oxidants, which become waste after the reaction, are required for the regeneration of the active oxidation state of TM. Needless to say, the use of toxic TM catalysts is also negative point from the economic and practical points of view. We have developed a novel type of C(sp3)-H bond functionalization without external oxidants, and, in some cases, TM catalysts. The key of this reaction is an intramolecular redox process, which is induced by intramolecular hydride shift. This reaction has several useful features: (1) the reaction proceeds via internal redox process, and hence, external oxidants are not required, (2) functionalization of the most tough C-H bond, C(sp3)-H bond, is involved, (3) three dimensional cyclic structures containing chiral centers are produced from non-chiral, linear substrates, (4) functionalization of remote C-H bond (more than five-atoms apart) is achieved. In this article, we want to describe the details of our endeavors to develop the target reactions, and its application to the construction of various useful fused-cycles which are otherwise difficult to achieve by the conventional methods.

Direct C-H functionalization on heteroaromatic rings has emerged as a prominent topic in the field of catalytic organic synthesis. Among these, oxidative coupling methodologies involving C-H bond functionalization have gained significant attention due to their step economy and energy efficiency. This synopsis focuses on recent advances in coupling reactions on various heteroaromatic rings via C-H bond functionalization. We made significant contributions to C-H functionalization on heteroaromatic rings and aim to provide a conceptual summary that will be useful to researchers and inspire further developments in this rapidly growing field.

This is the first comprehensive study that details the synthesis of stable acyclic trisubstituted [3]dendralenes and deciphers their structural requisite for a successful diene transmissive Diels-Alder (DTDA) reaction by employing two different dienophiles and eventually generating a small repository of complex molecules, thus exemplifying how substituted [3]dendralenes could be deployed in diversity-oriented synthesis with high selectivities. A balance of reactivity and stability was struck by prudent selection of the position and nature of functional groups on these [3]dendralenes. Upon tandem Diels-Alder reactions with several symmetrical as well as unsymmetrical dienophiles, these dendralenes afforded diversity-oriented quick access to many polycyclic complex motifs possessing several functional groups and multiple stereogenic centers. Thus, the full potential of the dendralenes could be harnessed. The reactions proceeded under mild conditions with step and atom economy and were highly regio- and stereoselective besides being excellent yielding. The DTDA sequence resulted in the generation of four new carbon-carbon bonds, two new rings, and 3-7 stereogenic centers. The key feature of the method is that we could rapidly generate complexity along with functional and structural diversity from a trivial acyclic substrate with no stereogenic centers.

The choice of appropriate directing groups, catalysts, ligands, bases, and solvents to give different regioisomers from the same precursors can improve the efficiency and atom economy in synthetic organic chemistry, while minimizing costs and expanding know chemical space. Base-controlled regio-divergent C-H bond functionalization is an important control strategy in organic synthesis, with the advantages of being operationally simple, and using cheap and available bases with low-toxicity that are easily separable. This highlight is classified into three sections: base-controlled, base-controlled transition metal-catalysed and base-controlled photocatalytic regio-divergent C-H bond functionalization. By summarizing the C-H bond activation model, the mechanisms underlying the regio-divergence and the influencing factors, this highlight aims to deepen the understanding of selective C-H bond functionalization at a molecular level. We expect that this highlight article will provide valuable information for understanding the mechanism of C-H bond functionalization, whilst providing a reference for developing green, efficient C-H bond transformation strategies.

Environmental concerns have and will continue to have a significant role in determining how chemistry is carried out. Chemists will be challenged to develop new, efficient synthetic processes that have the fewest possible steps leading to a target molecule, the goal being to decrease the amount of waste generated and reduce energy use. Along this path, chemists will need to develop highly selective reactions with atom-economical pathways producing nontoxic byproduct. In this context, C-H bond activation and functionalization is an extremely attractive method. Indeed, for most organic transformations, the presence of a reactive functionality is required. In Total Synthesis, the "protection and deprotection" approach with such reactive groups limits the overall yield of the synthesis, involves the generation of significant chemical waste, costs energy, and in the end is not as green as one would hope. In turn, if a C-H bond functionalization were possible, instead of the use of a prefunctionalized version of the said C-H bond, the number of steps in a synthesis would obviously be reduced. In this case, the C-H bond can be viewed as a dormant functional group that can be activated when necessary during the synthetic strategy. One issue increasing the challenge of such a desired reaction is selectivity. The cleavage of a C-H bond (bond dissociation requires between 85 and 105 kcal/mol) necessitates a high-energy species, which could quickly become a drawback for the control of chemo-, regio-, and stereoselectivity. Transition metal catalysts are useful reagents for surmounting this problem; they can decrease the kinetic barrier of the reaction yet retain control over selectivity. Transition metal complexes also offer important versatility in having distinct pathways that can lead to activation of the C-H bond. An oxidative addition of the metal in the C-H bond, and a base-assisted metal-carbon bond formation in which the base can be coordinated (or not) to the metal complexes are possible. These different C-H bond activation modes provide chemists with several synthetic options. In this Account, we discuss recent discoveries involving the versatile NHC-gold(I) and NHC-copper(I) hydroxide complexes (where NHC is N-heterocyclic carbene) showing interesting Brønsted basic properties for C-H bond activation or C-H bond functionalization purposes. The simple and easy synthesis of these two complexes involves their halide-bearing relatives reacting with simple alkali metal hydroxides. These complexes can react cleanly with organic compounds bearing protons with compatible pK(a) values, producing only water as byproduct. It is a very simple protocol indeed and may be sold as a C-H bond activation, although the less flashy "metalation reaction" also accurately describes the process. The synthesis of these complexes has led us to develop new organometallic chemistry and catalysis involving C-H bond activation (metalation) and subsequent C-H bond functionalization. We further highlight applications with these reactions, in areas such as photoluminescence and biological activities of NHC-gold(I) and NHC-copper(I) complexes.

The development of green and sustainable synthetic methods is of great interest worldwide. Today the direct activation and functionalization of relatively inert C–H bonds is one of the top fields in organic chemistry, and this strategy already represents a sustainable and more environmentally friendly approach due to its atom and step economy compared to alternative C–C and C–Het bond-forming processes. Much progress has been made in developing C–H bond functionalization methods using noble-metal catalysts. Cobalt has recently emerged as an attractive alternative because it is less toxic, cheaper, and more abundant than noble metals. This Account summarizes the cobalt-catalyzed C–H bond-functionalization methods that have been developed during the corresponding author’s research career.1 Introduction and Background2 C–H Bond Functionalization of 8-Aminoquinoline Benzamides3 Mechanistic Investigations of Cobalt-Catalyzed, Aminoquinoline-Directed C–H Bond Functionalization of Benzamides4 C(sp2)–H Bond Functionalization of 8-Aminoquinoline Phosphinamides5 C(sp2)–H Bond Carbonylation of 8-Aminoquinoline Sulfonamides6 C(sp2)–H Bond Functionalization of Benzoic Acids7 C(sp2)–H Bond Functionalization of Phenylglycine Derivatives8 C(sp2)–H Bond Functionalization of Phenylalanine Derivatives9 Conclusion

Transition-metal-catalyzed direct arylations have emerged as a viable alternative to traditional cross coupling chemistry in recent decades, as they constitute an economically attractive strategy for an overall streamlining of sustainable syntheses. Thus, the main focus of the present work was set on the development of generally applicable methodologies for site-selective formations of C−C bonds through direct C−H bond functionalizations. In the first part an efficient and generally applicable protocol for palladium-catalyzed direct C−H bond arylations of electron-deficient heteroarenes with aryl and alkenyl sulfonates was elaborated. The optimized catalytic system provided the direct arylation products with excellent chemo- and site-selectivites in high isolated yields. Various tosylates, as well as more atom-economical aryl mesylates could be successfully used as inexpensive, moisture-stable electrophiles for C−H bond functionalizations. Remarkably, the highly-active catalytic system also allowed the direct arylations of electron-deficient fluoroarenes with deactivated tosylates. In a second project of this thesis, research efforts were directed towards sustainable ruthenium-catalyzed annulations of alkynes by benzhydroxamic acid esters, through C−H/N−O bond functionalizations, under environmentally benign conditions. Intriguingly, ruthenium-catalyzed redox-neutral isoquinolone syntheses with ample scope and excellent regioselectivities were accomplished via carboxylate-assistance in water as a green solvent. The outstanding robustness and chemoselectivity of the ruthenium(II)-carboxylate complex also set the stage for the direct use of free hydroxamic acids for the synthesis of annulated lactames. It was further focused on the development of an efficient strategy for site-selective C−H bond funtionalizations on indoles in the absence of a transition-metal-catalyst. Regioselective C3-arylations on various N-alkyl-substituted, as well as free (NH)-indoles were achieved using diaryliodonium salts as mild arylating reagents. The protocol was not restricted to the functionalization of indoles, but also allowed for direct arylations of pyrroles, hence featuring access to a large number of variously decorated, ubiquitous bioactive heterocycles. In order to benefit from the abundance of carbon dioxide in the earth¡¦s atmosphere, its use as an inexpensive, renewable C1 source for various chemical transformations constitutes a contemporary issue. Thus, in the last project of the presented work, a direct approach towards (hetero)aromatic carboxylic acid derivatives by C−C bond formation through carbon dioxide fixation under mild conditions was investigated. Carboxylic acid esters derived from diverse heteroarenes with moderately acidic C−H bonds were obtained in good isolated yields in the absence of a transition-metal-catalyst, using inexpensive potassium tert-butoxide as the base.

The past decades have witnessed rapid development in organic synthesis via catalysis, particularly the reactions through C–H bond functionalization. Transition metals such as Pd, Rh and Ru constitute a crucial catalyst in these C–H bond functionalization reactions. This process is highly attractive not only because it saves reaction time and reduces waste,but also, more importantly, it allows the reaction to be performed in a highly region specific manner. Indeed, several organic compounds could be readily accessed via C–H bond functionalization with transition metals. In the recent past, tremendous progress has been made on C–H bond functionalization via ruthenium catalysis, including less expensive but more stable ruthenium(II) catalysts. The ruthenium-catalysed C–H bond functionalization, viz. arylation, alkenylation, annulation, oxygenation, and halogenation involving C–C, C–O, C–N, and C–X bond forming reactions, has been described and presented in numerous reviews. This review discusses the recent development of C–H bond functionalization with various ruthenium-based catalysts. The first section of the review presents arylation reactions covering arylation directed by N–Heteroaryl groups, oxidative arylation, dehydrative arylation and arylation involving decarboxylative and sp3-C–H bond functionalization. Subsequently, the ruthenium-catalysed alkenylation, alkylation, allylation including oxidative alkenylation and meta-selective C–H bond alkylation has been presented. Finally, the oxidative annulation of various arenes with alkynes involving C–H/O–H or C–H/N–H bond cleavage reactions has been discussed.