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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 (AAs) by palladium-catalyzed sequential C(sp3)-H functionalization directed by 8-aminoquinoline auxiliary is described. 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.
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.
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.
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.
Silver hammer: The silver-catalyzed decarboxylative arylation of electron-deficient (hetero)arenes has been successfully developed using aromatic carboxylic acids as arylating reagents. For most of aromatic carboxylic acids evaluated, 5 mol % of the silver(I) salt was enough for the oxidative decarboxylation. An ortho substituent was not necessary for this decarboxylative cross-coupling protocol.
Two at once: A novel palladium-catalyzed C-H double carbonylation introduces two adjacent carbonyl groups for the synthesis of isatins from readily available anilines. The reaction proceeds under atmospheric pressure of CO with high regioselectivity and without any additives. Density functional theory investigations indicate that the palladium-catalyzed double carbonylation catalytic cycle is plausible.
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.
As directed: The title reactions were accomplished with in situ generated cobalt(III) carboxylate complexes for highly efficient C-H activations. The direct cyanation proved viable with removable directing groups and displayed a broad substrate scope and mild reaction conditions.
Selective vinylation: The rhodium-catalysed oxidative coupling of alkenes and 3-aryl-5-R-pyrazoles gives vinylated products, some of which can cyclise through intramolecular Michael reactions (see scheme). DFT calculations show a clear preference for 2,1-insertion with β-H elimination, calculated to favour the trans vinyl products in all cases, as found experimentally.
Aminopyridinate (Ap) complexes of composition [Ir(Ap)(η5-C5Me5)]+ exist in the form of two isomers (shown here) that equilibrate in the presence of H2 by means of a reversible prototropic rearrangement within the Ap ligand. The isomerisation reaction is catalysed by dihydrogen and implies reversible formation and cleavage of H-H, C-H and N-H bonds.
Proximity matters: Electrophilic terminal phosphinidene complexes (left, with Ar-Ar being biaryl or an analogue thereof) undergo a spontaneous insertion of the P atom into the vicinal C-H bond to give annelated phospholes. The latter compounds are valuable precursors for the preparation of a variety of optoelectronic devices.
Trio con brio: Several unorthodox complexes of high relevance for the understanding of iron-catalyzed C–H activation and C–C bond formation have been obtained. These include a surrogate of an intermediate in [2+2+2] cycloaddition reactions, a 14 e [L2Fe(X)R] species that is (meta)stable despite its potential for β-H elimination, and an iron allyl hydride complex formed by two consecutive C–H activation events mediated by a single iron center.
Kill the director: The rhodium-catalyzed amidation of substituted benzoic acids with isocyanates via directed C-H functionalization followed by decarboxylation to afford the corresponding N-aryl benzamides is demonstrated. The carboxylate serves as a unique, removable directing group. Notably, less common meta-substituted N-aryl benzamides are formed readily from more accessible para- or ortho-substituted groups by employing this strategy.
Scoped out: An efficient synthesis of the title compounds by a palladium-catalyzed C-H difluoroalkylation is described. This method features a broad substrate scope, operational simplicity, and utilizes readily available starting materials. BrettPhos was found to facilitate this transformation with unique efficiency. CPME=cyclopentyl methyl ether, dba=dibenzylidene acetone.
Ruthenium(II)-catalyzed oxygenations of phenols with removable pyridyl (py) auxiliaries were accomplished with high catalytic efficacy and broad substrate scope (see scheme). Notably, the robust and versatile catalyst was tolerant of synthetically valuable electrophilic functional groups and Lewis basic heterocycles.
Dyes from laughing gas: Azoimidazolium dyes can be obtained by a simple coupling reaction of N-heterocyclic carbenes with nitrous oxide and arenes. This shows that N2O can be used as an efficient N2 donor in synthetic organic chemistry.
The devil is in the detail: Linear correlation between Gibbs free energies of activation ΔG≠ and C-H bond dissociation energies DC−H for hydrocarbon oxidation by a FeVO–TAML complex (TAML=tetra-amidato macrocyclic ligand) falsely dictates a common mechanism for all substrates. Dissecting ΔG≠ into ΔH≠ and ΔS≠, and plotting ΔH≠ vs. DC−H reveals an alternate oxidation mechanism for the hydrocarbon with lowest DC−H.
Metal-free α-arylation of ketones: A regioselective synthesis of symmetrical and unsymmetrical benzopinacolones through a metal-free aerobic dehydrogenative α-arylation at the tertiary sp3 C-H bond of substituted 1,1-diphenylketones with aromatic and heteroaromatic compounds, in the presence of K2S2O8 in CF3COOH at room temperature, is described. In addition, benzopinacolones were converted into sterically hindered, tetrasubstituted alkenes and polycyclic aromatic compounds (see scheme; DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone).
It's T time: The title reaction has been achieved using a commercially available nitrile-containing template. The identification of N-formyl-protected glycine as the ligand (Formyl-Gly-OH) was crucial for the development of this reaction. Versatility of the template approach in accommodating macrocyclopalladation processes with different ring sizes is demonstrated.
Activating methane: Free-energy activation and functionalization barriers were calculated for a series of rhodium(III) bis(quinolinyl)benzene (bisqx) complexes for partial oxidation of methane. An η2-benzene coordination mode encourages methyl group functionalization by serving as an effective leaving group (LG) for SN2 and SR2 attack.
Superoxoman: The title reaction was investigated and the calculations reveal that Mn–O2.− and Fe–O2.− are stronger oxidants compared to either Cr–O2.− or Cu–O2.−, and the oxidative abilities are found to be correlated to the magnetic exchange parameter J. These findings have direct relevance to the functions of several metalloenzymes.
Nickeled and dimed: Nickel(0)-catalyzed C-H functionalization of 2-pyridones and subsequent ligand-controlled regioselective cyclization affords 1,6-annulated 2-pyridones. Cyclooctadiene (L1) selectively leads to exo cyclization, whereas the addition of a bulky N-heterocyclic carbene ligand (L2) switches to the endo mode. The method was applied in the synthesis of the lupin alkaloid (±)-cytisine. LA=Lewis acid.
A copper/silver-mediated oxidative ortho-ethynylation of unactivated aryl C-H bonds with terminal alkyne has been developed using a removable bidentate directing group (PIP; see scheme) derived from 2-(pyridine-2-yl)isopropylamine. The reaction provides an efficient synthesis of aryl alkynes with broad substrate scope, high functional-group tolerance, and compatibility with a wide range of heterocycles.
Alcohols in action: A wide range of alcohols and benzamide substrates functionalized with electron-rich or electron-poor substituents are tolerated in the title reaction. This practical reaction occurs under mild conditions.
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.
CAN can activate: Inexpensive ceric ammonium nitrate (CAN) is an efficient oxidant for the Pd-catalyzed substrate-directed o-benzoxylation and decarboxylative o-aroylation processes. In the presence of CAN, the reaction of directing arenes with carboxylic acids resulted in o-benzoxylated products, and that with α-keto acids led to the formation of o-aroylation products.
So nitro: We report Pd- and Ni-catalyzed, guided, and regioselective C-H arylations of a series of fused 3-nitropyridines. The method described here is a facile tool for the chemical functionalization of drug-like fused pyridines. The scope and limitations of the reaction, the chemical potential of the nitro group, and a putative reaction mechanism are discussed.
A highly effective protocol for the synthesis of C-3-substituted prolines has been developed. Pd-catalyzed C(sp3)–H activation is used for the straightforward functionalization of prolines. The use of an 8-aminoquinolinecarboxamide directing group allows direct arylation, alkenylation, and alkylation at the C-3 position of prolines in moderate to high yields with diverse iodo- or bromo precursors.
An IrIII-catalyzed C-7 selective C–H amidation of indolines with organic azides has been achieved. This method offers an environmentally benign, readily scalable synthesis for 7-aminoindolines. More importantly, acyl, sulfonyl, and aryl azides can be employed in this C–H amidation reaction under very mild reaction conditions (DCE = 1,2-dichloroethane).
A selective catalyst system for the hydrosilylation of alkyl alkynes under mild, solvent-free conditions has been developed with the ruthenium pincer complex [Ru(tBuPNP)(H2)(H)2] [tBuPNP = 2,6-bis(di-tert-butylphosphinomethyl)pyridine].
Playing the ac-yl: A practical palladium-catalyzed strategy to synthesize azoxybenzene derivatives in a chemo- and regioselective manner by direct C-H acylation has been developed. Easily available aldehydes were used as a cheap aroyl source. The protocol proceeds smoothly and can tolerate a variety of functional groups to give moderate to high yields. DCE=1,2-dichloroethane; TBHP=tert-butyl hydroperoxide.
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.
Platinum plays favorites: PtII complexes containing unsymmetrical (pyridyl)pyrrolide ligands are shown to catalyze the hydroarylation of unactivated alkenes with selectivity for the anti-Markovnikov product (see scheme). Substitution on the pyrrolide portion of the ligand allows effective tuning of the selectivity to anti-Markovnikov alkylarene products, whereas substitution on the pyridyl portion can promote competitive alkenylarene production.
What a pair: A RhIII/CuII-promoted process is reported to provide tetrasubstituted enol esters in a trans-selective fashion. This three-component reaction uses a rhodium(III) catalyst for the C2-selective activation of electron-rich heteroarenes and the addition across the alkyne. Copper(II) then takes over to forge the vinyl ester bond. The method was also used for the functionalization of bioactive furocoumarin natural products.
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.
An efficient iron-catalyzed C–H bond functionalization that proceeded through an intramolecular C–H amination reaction under nitrogen was employed for the synthesis of pyrido[1,2-a]indoles from 2-benzhydrylpyridines. Under oxygen, the same 2-benzhydrylpyridines were used for the synthesis of the corresponding tertiary alcohols. Overall, a change of atmosphere altered the course of the reaction.
The direct arylation of benzo-fused heterocycles is reported. A common strategy could be applied to benzofuran, benzothiophene, and indole with good selectivity for arylation at the 2-position. In addition, the same method could be applied to the arylation at C3 in a second C–H activation step.
A new efficient method for the direct alkenylation of 3-arylsydnones by palladium-catalyzed C–H functionalization is developed. The reaction proceeds smoothly at room temperature and delivers the products in yields up to 83 %.
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.