The possibility of direct introduction of a new functionality (or a new C–C bond) via direct C–H bond transformation is a highly attractive strategy in covalent synthesis. The range of substrates is virtually unlimited, including hydrocarbons, complex organic compounds of small molecular weight, and synthetic and biological polymers. Below is a list of recent articles on this topic. For a review, see
MC Flex: A flexidentate PN(C) scaffold amenable to acting as either a bi- or tridentate ligand to a RhI center is described. Tridentate coordination involves facile aromatic C-H activation to generate a rare low-valent RhI metallacycle. The formation of a C-H agostic complex, dual-mode ligand reactivity, and the synthesis of the corresponding RhIII–diiodide complex is discussed.
Making one into two: Palladium-catalyzed direct C(sp3)-H activation of an N-allyl imine led to the generation of an all-carbon π-allyl complex which presumably remains in equilibrium with a rare 2-aza π-allyl species. Nucleophilic attack on the π-allyl intermediates gave either a 1-aza-1,3-diene or 2-aza-1,3-diene in a completely regioselective manner.
N-Alkynylated sulfonimidamides have been synthesised through the CuII-catalysed N–H/C–H activation reaction of N-deprotected sulfonimidamides and terminal alkynes. The resulting N-alkynylated sulfonimidamides react with SiO2 or BH3·SMe2 to give the corresponding carbonyl or alkyl derivative, respectively.
I(003) is a double agent: A tandem C-N and C-C bond-forming reaction has been achieved through RhII/Pd0 catalysis. The sequence first involves an iodine(III) oxidant, then the in situ generated iodine(I) by-product is used as a coupling partner. The overall process affords complex building blocks with high yields, and demonstrates the synthetic value of iodoarenes produced in trivalent iodine reagent mediated oxidations.
On the double: An efficient, regiospecific, and general oxidative dimerization of simple aryl acids to generate diaryl acids was developed. The reaction involves two direct aryl C-H activations catalyzed by rhodium, uses water as the solvent, and can be easily scaled up. The natural product ellagic acid was obtained in only two steps by using this method.
Switch it on: η6-arene–transition-metal complexes are significant intermediates in organic chemistry; however, their use in C-H functionalization remain largely unexplored. Recently, new methodologies for the Pd-catalyzed C-H activation of unreactive sp2 and sp3 bonds that rely on the efficient activation of arenes by π-complexation have been developed. These reactions significantly expand the toolbox of modern C-H activation methods.
Double crossed! Reported is the rhodium(III)-catalyzed double C-H cross-coupling of benzyl thioethers and carboxylic acids. Two directing groups (DGs) are used to enhance the selectivity of the double C-H activation. One DG becomes part of the product and the other is removed in situ.
Do the twist again! A twisted π-extended double helicene was synthesized through a palladium-catalyzed coupling reaction. X-ray crystallography revealed grossly twisted structures that were soluble in various conventional organic solvents. Electrochemical properties were also studied by measurements of cyclic voltammetry, which revealed its HOMO and LUMO energies (see scheme).
One catalyst fits all: One single catalyst, [RuCl2(p-cymene)]2, was used for oxidative dehydrogenation followed by cross-coupling/annulation reactions to access diversely decorated N-fused polycyclic heteroarenes from dihydroquinazolinones and alkynes. DCE=1,2-dichloroethane.
Air and water: Ruthenium(II) biscarboxylates allow for the annulation of alkynes and alkenes by oxidative C-H functionalizations with molecular oxygen as the sole oxidant. The C-H/O-H functionalization process occurs with excellent selectivities under mild reaction conditions, with water produced as the only by-product.
Bridging oxygen: A combination of mass spectrometry and quantum chemical calculations shows that [Ga2Mg2O5].+, bearing an unpaired electron at a bridging oxygen atom, is capable of activating the C-H bond of methane. The roles of spin density and charge distributions in hydrogen-atom transfer processes provide important guidance for the rational design of catalysts.
Palladium-catalyzed dehydrogenative coupling reactions between acetanilides and benzylic alcohols under aqueous conditions are reported. A wide range of benzophenone derivatives could be obtained in good to excellent yields up to 98 %. Mechanism studies showed that a bimetallic palladium cyclopalladated complex might be involved in the catalysis.
Family ties: An efficient access to the aeruginosin family of marine natural products, which exhibit potent inhibitory activity against serine proteases, was achieved. The strategic use of two different C(sp3)-H activation reactions led to the synthesis of aeruginosins 98B and 298 A, with the latter being obtained on an unprecedentedly large scale.
TIPS and tricks for alkynylation: The first direct alkynylation of 2-vinylphenols was developed. The rationally optimized hypervalent iodine reagent TIPS-EBX* (see scheme)in combination with [(Cp*RhCl2)2] as a C-H-activating transition metal catalyst enables the construction of a variety of highly substituted 1,3-enynes in high yield under mild conditions and with excellent chemo- and stereoselectivity.
Co-catalyzed! The first highly efficient and scalable cobalt-catalyzed directed C-H functionalization with carbene precursors is presented. This methodology provides a modular route towards a new class of conjugated polycyclic hydrocarbons with tunable emission wavelengths.
Along came “Poly”: C(sp2)-C(sp3) bond formation through direct C-H functionalization proceeds through a copper(I)-catalyzed alkylation of electron-poor polyfluoroarenes with N-tosylhydrazones or diazo compounds. The transformation represents a highly efficient practical method for the direct alkylation of polyfluoroarenes. phen=1,10-phenanthroline, Ts=4-toluenesulfonyl.
Scratching the surface: Easy control of the intermolecular coupling of 5,11-dibromotetracene on a Cu(110) surface by temperature has been achieved. Organometallic oligomers characterized by copper atoms that bridge the tetracene molecule in the 5,11 positions are formed at mild temperature (room temperature to 523 K), whereas the higher intrinsic stability of the radical sites at the 3,2 and 8,9 positions determines the formation of linear chains produced by C-C coupling between the ends of the molecules at higher temperature (see picture).
Broadly applicable cobalt-catalyzed C-H arylations with weakly-coordinating amides or tetrazoles provided step-economical access to biaryl tetrazoles as key structural motifs of angiotensin-II-receptor blockers (ARBs), such as the blockbuster drug Losartan (see scheme).
Getting the skeleton right: Biaryl skeletons were directly constructed via palladium-catalyzed ortho-arylation of N,N-dimethyl benzylamine with aryl boronic acids under open-flask conditions. The N,N-dimethylaminomethyl group was first applied as a directing group in such an oxidative coupling. Various substrates proved to be efficient coupling partners, furnishing the corresponding ortho-monoarylated or -diarylated arenes in moderate to good yields under mild conditions.
Piece of pi: Transition-metal-catalyzed directing-group-assisted C-H activation reactions play an indispensable role in organic synthesis. Most directing groups interact with metals through the σ coordination of their lone pairs, yet π-bond directing groups also exist (see figure). The π-coordination-assisted C-H bond functionalization reactions are summarized.
Killing two birds with one stone: A bis(η5,η1-pentafulvene)titanium complex reacts with secondary N-methylamines resulting in simultaneous N-H and C-H activation and formation of titanaaziridines. These reactions can even be performed below room temperature und generate three-membered titanacycles. The first molecular structure of a titanium methyleneaniline complex is determined.
High tolerance: An oxidative, Ru-catalysed, and highly selective C-H arylation of indoles and pyrroles is accomplished by using boronic acids (see picture; pym=2-pyrimidyl). The reaction tolerates a wide range of functional groups, including aryl iodides and tryptophan derivatives. New indole-based ruthenacycles are described and their role in the mechanism is investigated.
Platinum level: The efficient and versatile title reaction is based on the radical reactivity of perfluoroalkyl halides. The ready availability of the starting materials, the excellent substrate tolerance, and the reusability of catalyst make this protocol attractive for the economic synthesis of perfluoroalkyl-group-substituted aromatic compounds.
Direct and mild: A variety of alkyltrifluoromethylthioethers were efficiently synthesized by direct trifluoromethylthiolation of unactivated C(sp3)-H bonds under mild reaction conditions. The reagent system comprises AgSCF3 and K2S2O8, the latter of which both activates the C(sp3)-H bond and oxidizes AgSCF3. The reaction has a broad substrate scope with good functional-group tolerance and good selectivity.
Functionalized azoles: Pd-catalyzed direct C-H bond functionalization of heteroarenes via an isocyanide insertion strategy (see scheme) for the synthesis of di-(hetero)aryl ketones and di-(hetero)aryl alkylamines is described.
An operationally simple manganese-catalyzed C-H functionalization of ketimines provides access to β-amino acid esters. The mechanism of this transformation was studied, and its utility proven by further modifications of the synthetically useful β-amino acid esters into attractive compounds.
The silver-mediated trifluoromethylthiolation of unactivated aliphatic C-H bonds is reported. The reaction is operationally simple, amenable to gram-scale synthesis, and can be employed for the late-stage trifluoromethylthiolation of complex small molecules.
Who was in control? A rhodium(III)-catalyzed carboxylic acid directed decarboxylative C-H/C-H cross-coupling of benzoic acids with thiophenes has been developed. This method provides straightforward access to biaryl scaffolds with diverse substitution patterns, many of which previously required lengthy synthetic sequences.
The oxidation states of IV and V are achievable for electron-poor iron tetraamido macrocyclic ligand (TAML) activators. The corresponding oxidoiron(V) species demonstrates the highest reactivity reported so far for any TAML activator in the oxidation of thioanisole and C–H bond activations of ethylbenzene and cyclohexane.
Directed activation: Cationic Cp*CoIII (Cp*=1,2,3,4,5-pentamethylcyclopentadienyl) complexes, either well-defined or in situ-generated, promote catalytic functionalization of arene C-H bonds with a variety of electrophilic reaction partners by directed C-H activation. These complexes not only emulate known reaction patterns of Cp*RhIII analogues, but also exhibit remarkable catalytic activity or unique reactivity. DG=Directing group.
Quinazoline acted as efficient directing group for the rhodium-catalyzed C–H amidation of 2,4-diarylquinazoline by using sulfonyl azides as the amine source. Satisfactory yields and excellent monoamidation selectivities were achieved with the assistance of meta substitutents.
A facile, efficient, and practical method for the copper-catalyzed direct C–H amination of 2-aryl-1,2,3-triazole N-oxides with various amines, including primary and secondary aliphatic and aromatic amines, has been developed. Furthermore, the targeted N+–O– bond cleavage is observed during the reaction and, thus, an additional deoxygenation step is obviated.
Trimethoxylpyridine is an efficient ligand for promoting Pd-catalyzed ortho-C-H amination of both benzamides and triflyl-protected benzylamines. This finding provides guidance for the development of ligands that can improve or enable PdII-catalyzed Csp2-H activation reactions directed by weakly coordinating functional groups.
Benzo[e]indazole derivatives are obtained by a sequential triple C-H activation directed by a pyrazole and an amide group. This cascade reaction demonstrates that the often problematic competing C-H activation pathways in the presence of multiple directing groups can be utilized to improve step economy in synthesis. Pyrazole as a relatively weak coordinating group is shown to direct Csp3-H activation.
An improved procedure for the stereoselective synthesis of anti-β-hydroxy-α-amino acids (anti-βhAAs) by palladium-catalyzed sequential C(sp3)-H functionalization directed by 8-aminoquinoline auxiliary is described (see scheme; Phth=phthaloyl). The synthetic potential of this protocol is further demonstrated by the synthesis of various β-branched α-AAs and β-mercapto-α-AAs.
Skeleton crew: The synthesis of 2H-chromene skeletons was achieved by means of a rhodium(III)-catalyzed oxidative annulation of 2-alkenylphenols and allenes. This unconventional (5+1) process involves the cleavage of the terminal C-H bond of the alkenyl moiety and the participation of the allene as a one-carbon cycloaddition component.
A strict director: The title reaction produced a wide range of salicylic acid derivatives with high efficiency and selectivity. The scope of this method was demonstrated by the carboxylation of estrone (see scheme; TBAF=tetrabutylammonium fluoride) and by the unsymmetrical bisfunctionalization of a phenolic compound through sequential C-H functionalization reactions.
A pre-ferryl cat: Through in situ resonance-enhanced Raman spectroscopy, we identify an active, binuclear Fe-O(H)-Fe core and an FeIII-OOH intermediate in Fe-containing ZSM-5 following activation with H2O2. The pre-ferryl nature of this biomimetic intermediate may account for the unique ability of this solid catalyst to selectively oxidise methane to methanol under mild conditions.
A photogenic pair: Photoredox catalysis with visible light and molecular oxygen as oxidant in combination with palladium catalysis enables highly efficient activation of C-H bonds. Mild photochemical reaction conditions generally facilitate the combination of different catalytic reactions.
Chlorination revisited: A radical chlorine species, generated by ligand exchange in hypervalent iodine(III) compounds, is demonstrated to promote Pd-catalyzed directed C-H chlorination. In this protocol, ammonium salts are used as chlorine sources.
A new silver(I)-mediated Cα(sp3)–H bond functionalization of primary amines followed by an oxidative C–N cross-coupling reaction to form highly diverse 1,2,4,5-tetrasubstituted imidazoles has been demonstrated. This protocol provides a simple, highly efficient, and straightforward approach, which is promoted by a silver species, to give the products in good to excellent yields.
Activation complete: The direct synthesis of isoquinolones from benzamides and alkynes through C-H activation is developed by using Pd/C as a heterogeneous catalyst. The Pd/C catalyst can be recycled three times without a significant decrease in the activity.
Soul acyl-um: Palladium-catalyzed oxidative C-C cleavage of α-hydroxyketones and 2-aryl acetophenones in the presence of tert-butyl hydrogen peroxide (TBHP) and subsequent C-H acylation of azoarenes with the generated acyl moiety provides easy access to acyl azoarenes.
The all around influence of 4,5-diazafluorenone as a ligand enables the dehydrogenative Heck reaction of furans and thiophenes with hindered alkenes. Very high stereoselectivity can be achieved. The ligand has an influence on C–H bond activation, insertion of the alkene, the stereodetermining step, and the aerobic regeneration of the catalyst.
By no means π in the sky! The activation of aromatic C-H bonds by a transition metal catalyst has received significant attention in the synthetic chemistry community. In recent years, rapid and site-selective extension of π-electron systems by C–H activation has emerged as an ideal methodology for preparing conjugated organic materials. This Review focuses on recent developments in this area directed toward new optoelectronic materials.
Versatile C-H bonds: We discuss Manna and Antonchick's metal-free isoquinolone synthesis through the dehydrogenative condensation of benzamides with alkynes and what it means for the fields of C-H functionalization and organic synthesis. DG=Directing group, E=electrophile.
Intramolecular HAT scope: The investigation of the less commonly encountered 1,n-hydrogen-atom transfer (HAT) reactions in which n≠5 has led to high yielding original synthetic applications. The aim of this Review is to make a critical updated inventory, highlighting the most elegant cascade reactions based on a 1,n-HAT elementary step (from A to B) in which n=4, 6, 7, 8, 9, and so forth.
Things go better without coke! The selective activation of methane and its direct conversion into light olefins and aromatic compounds remains a formidable challenge. Recent work shows that a catalyst material consisting of lattice-confined single iron atoms is very active and selective in the direct, nonoxidative conversion of methane into ethylene, benzene, and naphthalene without the formation of coke deposits.
The coordination of alkanes to metal centers is a complex matter! Advances in synthetic strategies to produce alkane σ-complexes, and ever more detailed analyses of such complexes, is leading to an understanding of how alkanes bind to specific metal centers. Such analysis is vital in understanding selectivity in C-H activation reactions.
Novel tool set: New methodologies for the functionalization of remote C-H bonds have been developed recently. In diverse approaches high selectivities are achieved for the functionalization of less reactive C(sp2)-H as well as C(sp3)-H bonds distal to any substituents.
This review outlines some selected examples and present challenges relating to palladium-catalyzed direct allylic functionalization. This old reaction, ignored for many years, is enjoying a new age.
When palladium meets a support: The functionalization of the C-H bond is the most straightforward approach to create new bonds. Although most studies involve homogeneous transition-metal catalysts, in this Minireview we aim to give a picture of recent advances of direct C-H arylations enabled by heterogeneous Pd catalysts.
The latest developments in the field of imidazo[1,2-a]pyridine functionalization by means of cross-coupling reactions such as the Sonogashira, Heck, Negishi, Suzuki–Miyaura, and Stille reactions, as well as by C-arylation, C-alkenylation, carbonylation, and double functionalization, are reviewed and discussed.
Ligands at the wheel: The pivotal role of ligands for the palladium-catalyzed functionalization of remote C sp3-H bonds has been demonstrated. The presence of the ligand enhances the reactivity of the inert C sp3-H bond and controls the selectivity of the process. DG=Directing group, FG=functional group.
PhenAll: Recent breakthroughs in site-selective and direct functionalization of free phenols by transition-metal-catalyzed C-O or C-H bond activation are highlighted here as role models for the complete and switchable positional control of transformations of important core structures.
We summarize a powerful methodology for the alkynylation of C(sp3), C(sp2), and C(sp) carbon atoms, as well as some heteroatoms, with alkynylsulfones. It is based on the fact that β-substituted sulfonylacetylenes undergo unexpected anti-Michael addition of organolithiums and radical species, giving intermediates that evolve into alkynyl derivatives in situ by elimination of the anion or radical TolSO2.
To wit: The title reaction resembles a photoinduced electron-transfer process, and allows the direct formation of medium-sized lactams by C-H activation of the indole nucleus. Therefore it is a versatile tool for the construction of polycyclic indole alkaloid scaffolds.
Chemical power tools: The Fujiwara–Moritani reaction is the palladium-catalyzed coupling reaction of a simple aryl C-H bond with an alkenyl C-H bond to form a new C-C bond (see scheme). This Minireview focuses on the advances in the past five years related to the activation of various aryl C-H bonds in this coupling reaction.
Waste not, want not: The title CDC reactions have emerged as versatile tools for selective and waste-minimized C-C bond formations. They rely on the direct coupling of two different C-H bonds under oxidative conditions. This Review focuses on the recent progress in cross-dehydrogenative Csp3-C formation and provides a comprehensive overview on existing procedures and employed methodologies.
Caught in the cross-fire: This Review highlights the recent developments in catalytic cross-dehydrogenative coupling (CDC) reactions, which join together two aromatic C-H fragments through a palladium-catalyzed dehydrogenative pathway.
Large Iodine: The site-selective oxidation of unactivated secondary sp3 C-H bonds was accomplished by using a newly defined reactive hypervalent iodine(III) radical in the presence of tert-butyl hydroperoxide (see scheme). Recent studies on hypervalent iodine radicals have significantly contributed to the further development and design of organic molecules in radical oxidation chemistry.