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 straightforward one-pot synthetic method including cyclotrimerization, C–H activation, and ring formation to novel hexaferrocenylbenzene is discussed. The electrochemical and spectro-electrochemical behavior as well as a mechanism for the formation of the title compound is reported.
A chance meeting: A rhodium(III)-catalyzed redox-neutral coupling of quinoline N-oxides with alkynes has been realized, thus leading to the synthesis of α-substituted acetophenones. This system integrates C-H activation with O-atom transfer.
Atomic bean counters succeed! An efficient and atom-economical method for the synthesis of substituted indenamines from N-tosylarylimines and alkynes via ruthenium(II)-catalyzed C-H bond activation and annulation is described.
Novel urchin-like FeF2 nanoarchitectures have been fabricated by an unconventional nonhomogeneous ionic liquid/diphenyl ether solvothermal method and converted into 3D urchin-like mesoporous α-Fe2O3 nanoarchitectures by solid-state thermal annealing. The α-Fe2O3 nanoarchitectures exhibit good catalytic properties in methane activation reactions.
Gas up: Direct partial oxidation of methane, ethane, and propane to their respective trifluoroacetate (TFA) esters is achieved by a homogeneous hypervalent iodine(III) complex in non-superacidic solvent (HTFA). The reaction is highly selective, and for ethane, greater than 0.5 M Et-TFA can be achieved. Preliminary kinetic analysis and density functional calculations support a nonradical electrophilic CH activation and iodine alkyl functionalization mechanism.
Leukemia ablator: The naturally occurring and highly potent and selective antileukemic agent Δ12-prostaglandin J3 (Δ12-PGJ3) has been assembled through a catalytic, asymmetric, and convergent strategy. The total synthesis renders this precious but rare substance readily available for thorough biological investigations and opens the way for analogue design, synthesis, and biological evaluation.
CF3 installation: The direct ortho-trifluoromethylation of arenes including heteroarenes with TMSCF3 has been accomplished by a copper(II)-promoted C-H activation reaction. Mechanistic investigations are consistent with the involvement of C-H activation rather than a simple electrophilic aromatic substitution as the key step. DG=directing group, TMS=trimethylsilyl.
An efficient one-pot synthesis of N-aryl heterocycles by a Cu-catalysed double C–N bond formation is reported. This strategy involves a CuI-catalysed C–N bond-forming reaction between azoles and electron-deficient bromopyridines followed by an intramolecular sp2 C–H amination.
G'day, (carba)mate! A new removable directing group for sp2 C-H activation, the aniline carbamate, is examined in detail. Its utility as a directing group is demonstrated by the ortho-arylation of aniline derivatives under PdII catalysis, with iodonium salts as aryl donors and oxidants. Excellent regio- and chemoselectivity were observed. The directing group can also be easily removed to yield 2-aminobiaryl products (see scheme).
The direct ortho alkylation of 8-aminoquinoline-based aryl amides was achieved with primary alkyl bromides in high yields in the presence of an iron catalyst, 1,2-bis(diphenylphosphino)ethane (dppe), and PhMgBr in 2-MeTHF.
d or s regime? That is the question! A catalyst’s orbital electronic regime (see illustration) and bite-angle flexibility are proposed as unifying concepts that serve a more rational design of catalysts. They emerge from quantum-chemical activation strain analyses of 72 different d10-M(L)n model catalyst-mediated C-H bond-activation reactions.
Capturing: Carbon dioxide in the presence of H2 is shown to be an efficient methylating reagent for carbon nucleophiles such as 2-substituted indoles, pyrroles, and electron-rich arenes. Experimental data support the formal capture of formaldehyde. acac=acetylacetonate, triphos=1,1,1-tris(diphenylphosphinomethyl)ethane.
The palladium-catalyzed selective C-H bond trifluoroethylation of aryl iodides allows for an efficient synthesis of a variety of ortho-trifluoroethyl-substituted styrenes. Preliminary mechanistic studies indicate that the reaction might proceed through rate-determining oxidative addition of CF3CH2I to a palladacycle.
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.
An efficient and general method for the regiospecific synthesis of substituted 2-nitrobenzaldehydes from related benzaldehydes has been developed. The approach involves palladium-catalyzed chelation-assisted C–H nitration as the key step, and enables regiospecific nitration of C–H bonds free from the effect of orientation rules.
A catalyst for ether direction: Cleavage of the alkyl C-O bond of aryl ethers is catalyzed by pincer Ir catalysts, without the need for additional reagents, including H2. The corresponding phenols are generated in up to 99 % conversion, with reaction times as short as 1 hour.
In the air: Excellent functional-group tolerance is observed in the title reaction, and both internal and terminal alkynes are competent substrates for the coupling. The reaction employs Co(OAc)2·4 H2O as the catalyst, Mn(OAc)2 as the co-catalyst, and oxygen (from air) as the terminal oxidant. Piv=pivalate.
Getting promoted: The site-selective acyloxylation of aliphatic amides was achieved via a copper-promoted C(sp3)-H bond functionalization process directed by a bidentate ligand. The reaction showed a great preference for activating C-H bonds of β-methyl groups over those of γ-methyl and unactivated methylene groups.
Recycling itself! A bio-inspired artificial recycling reaction system has been constructed based on the strategic design of a photoinduced Ce3+–Ce4+ recycling redox reaction, leading to efficient photorecovery of reactants to achieve a reactant-loss-free sustainable chemical-modification strategy for the direct transformation of alkyl C-H bonds on polymer surfaces to form small-molecule groups and polymer brushes (see scheme).
Remote access: The first application of an oxalyl amide to direct C-H functionalizations at remote positions was reported. The results showed both C(sp2)-H and C(sp3)-H bonds at δ- and ε-positions were effectively activated, thus giving tetrahydroquinolines, benzomorpholines, pyrrolidines, and indolines in moderate to excellent yields by palladium-catalyzed intramolecular C-H amination.
Activated and annulated: A rhodium-catalyzed one-pot synthesis of highly substituted polyheteroaromatic compounds from N-hydroxybenzamidines and alkynes is described. This reaction likely proceeds through multiple C-H bond activation and annulation.
Nitrate makes it possible: A novel and facile method for C-H bond fluorination entails remarkably mild reaction conditions (close to room temperature in most cases). Both aromatic and olefinic C(sp2)-H bonds were selectively fluorinated in the presence of a catalytic amount of inexpensive and nontoxic nitrate as the promoter.
Uses beyond asymmetric catalysis: Iridium complexes with a wide variety of N,P-ligands were explored in hydrogen isotope exchange reactions (see scheme; pyr.=pyridine). Complexes with electron-rich ligands were found to be highly reactive, leading to efficient deuterium incorporation even in compounds bearing only weakly coordinating directing groups.
A bit hyper: A practical approach for the oxidation of unactivated Csp3-H bonds by o-nitro(diacetoxyiodo)benzene is presented. The nitro group coordinates to the adjacent iodine center through dipolar interaction, which leads to a single substitution of the acetate ligand by tert-butyl hydroperoxide (TBHP). As a result, a strong iodanyl radical is formed, which can activate the inert Csp3-H bonds in a highly efficient manner.
Di-verse: The use of the C-H activation/1,3-diyne general strategy allowed the challenges of selectivity (chemo-, regio-, and mono-/diannulation) to be overcome. This allowed direct construction of diverse polysubstituted bisheterocycles, which are highly important but difficult to access, through the formation of four strategic bonds with high efficiency and high selectivity.
N-(Naphthyl)-4-R-salicylaldimines (R = OCH3, H, Cl; H2L1–H2L3) and 2-hydroxy-N-(naphthyl)naphthaldimine (H2L4) react with [Ru(PPh3)2(CO)2Cl2], undergoing C–H bond activation at the peri position, to afford complexes of the type [Ru(PPh3)2(L)(CO)] (L = L1–L4), which can efficiently catalyze the transfer hydrogenation of carbonyl compounds.
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.
Active ingredient: A new efficient method for the direct alkenylation of 4H-pyrido[1,2-a]pyrimidin-4-ones via palladium-catalyzed C-H bond activation has been developed. This transformation presents a useful approach to functionalize 4H-pyrido[1,2-a]pyrimidin-4-ones, which are privileged structures in many bioactive molecules and versatile synthetic blocks.
Sorry for being so direct: The heterogeneously catalyzed direct amination of benzoxazole with a wide range of primary and secondary amines, using molecular oxygen as a green oxidant under mild reaction conditions, is reported. The catalyst can easily be separated by filtration and reused. The 2-aminobenzoxazole products are important skeletons in several biologically active compounds.
Ring expansion: The alkaloids assoanine (1), pratosine (2), hippadine (3), and dehydroanhydrolycorine (4), which belong to the pyrrolophenanthridine family of alkaloids, have been successfully synthesized by using C-H activation chemistry. The tetracyclic skeletons are constructed in a stepwise manner by C(sp3)-H functionalization and a Catellani reaction involving C(sp2)-H functionalization.
Methane activation: Methane can be catalytically converted into ethyl propionate upon reaction with ethyl diazoacetate in the presence of highly fluorinated silver complexes as catalysts and by using supercritical carbon dioxide; (scCO2) as the reaction medium (see scheme; TOF=time of flight).
SCF3 building blocks: A unique reaction route allows access to SCF3-functionalized arenes, which are borylated at the ortho-position. The functionalization proceeds by C-H borylation with [Rh(Bpin)(PEt3)3] (pin=pinacolato), and the SCF3 group likely serves as directing group. The generated borylated SCF3 compounds are versatile building blocks for further transformations.
Overcoming strain: A range of valuable 1-indanols and 1-indanamines containing a tertiary C1 atom were synthesized by intramolecular palladium(0)-catalyzed C(sp3)-H arylation (see scheme; PivOK=potassium pivalate). Reactivity and diastereoselectivity differences among the different substrates can be rationalized by conformational analysis.
Strain away: Chiral β-lactams are obtained from readily accessible chloroacetamides by an asymmetric palladium(II)-catalyzed C-H functionalization in high yields and excellent enantioselectivities. Important aspects of this transformation are the challenging strain-building C(sp3)-C(sp3) reductive elimination to form the four-membered ring. Ad=adamanyl.
Well placed: An efficient protocol for the Pd-catalyzed regiospecific ortho-nitration of (E)-azoarenes has been achieved by using tBuONO as a nitrating agent under atmospheric oxygen. A series of both symmetrical and unsymmetrical azoarenes were nitrated efficiently by this procedure, providing excellent chemo- and regioselectivity and compatibility with a broad array of functional groups.
C-H activation: The ruthenium catalyst 1 promoted coupling between acrylic esters and amides with internal alkynes to form 1,3-diene products at room temperature. A proposed catalytic cycle involves C-C bond formation by oxidative cyclization, β-hydride elimination, and C-H bond reductive elimination.
A series of terarylenes incorporating a benzothiophene or a benzofuran as the central ethene unit was synthesized by means of sequential Pd-catalysed C-H activation reactions (see figure). This new methodology allows easy modification of the nature of the pendant heteroarene groups. A study on their photochromic properties revealed that the natures of the heteroarene nature and the central unit drastically modify their photochromic behavior.
Mild and selective: In the presence of [CuNO3(PPh3)2], aromatic and heteroaromatic 8-aminoquinolinyl amides undergo selective ortho-C-H nitration under exceptionally mild conditions. A microwave-assisted cleavage of the amide directing group allows regeneration of the carboxylate group within minutes. The carboxylate may be tracelessly removed in situ, or substituted by aryl or alkoxy groups in decarboxylative processes (see scheme; NH2Q=8-aminoquinoline, X=CO2H, H, Ar, OR).
A 'SiN'ch: In the title reaction of benzylamines or anilines, (hydrido)silyl amines are generated in situ which undergo selective silylation at the C-H bond γ to the amino group. The silylation products can be further functionalized through oxidation, halogenation, and cross-coupling reactions. cod=1,5-cyclooctadiene, nbe=norbornene.
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.
Transition-metal- and halogen-free synthesis of N-aryl-substituted 1H-indazole and derivatives is accomplished on the basis of the iodobenzene-catalyzed intramolecular C–H amination of hydrazones in the presence of Oxone in trifluoroacetic acid at –10 °C. The 1H-indazole derivatives are obtained in moderate to good yields (up to 90 %).
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.
Assisting activation: Ruthenium(II)-catalyzed C-H arylations of (hetero)arenes and alkenes have been achieved with aryl halides through removable bidentate auxiliaries derived from modular 1,2,3-triazoles (see scheme; TAM=triazolyldimethylmethyl).
Three C-C bond formation reactions are successively coupled in a convergent synthesis of phenanthro[9,10-c]thiophenes A. The key reaction is an unprecedented photocyclization of precursors B, which proceeds cleanly at λ=254 nm (60–82 % yield). Diarylthiophenes B are conveniently assembled employing a sequence of oxidative and regular Suzuki cross-coupling reactions.
Heterocycle synthesis: Chiral isoindolones are obtained by rhodium(III)-catalyzed enantioselective reactions of aryl hydroxamates with alkyl-substituted diazo esters through C-H functionalization under mild conditions. Chiral cyclopentadienyl ligands with a biaryl backbone lead to excellent enantioselectivities.
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.
Linear progress: A new Ti complex with 2,6-bis(phenylamino)pyridinato ligands catalyzes highly regioselective hydroaminoalkylation reactions of styrenes. The process that directly gives access to the corresponding linear hydroaminoalkylation products offers a new and flexible synthetic approach towards pharmaceutically important 3-arylpropylamines. It is also possible to convert (E)-1-phenyl-1,3-butadienes into the corresponding linear products.
Divinyl-substituted double-decker silsesquioxanes (DDSQ-2SiVi) have been functionalized by a highly effective silylative coupling and/or metathesis with olefins. Both reactions proceed highly stereoselectively and lead to nearly quantitative formation of E isomers. Preliminary studies on the silylative coupling of DDSQ-2SiVi with 1,4-divinylbenzene resulted in a stereoregular cooligomer containing double-decker (silsesquioxyl-silylene)-vinylene-phenylene units.
Vinylidene complex: An efficient RhI-catalyzed cycloisomerization of benzylallene-alkynes produced the tricyclo[9.4.0.03,8]pentadecapentaene skeleton through Csp2-H bond activation. Based on deuteration and competition experiments, a reaction mechanism was proposed, which proceeds via a vinylidenecarbene–RhI intermediate.
Inspiroing dearomatization: The dearomatizing oxidative annulation of 2-alkenylphenols with alkynes and enynes proceeds with high yields and regioselectivities under RhIII catalysis (see scheme). These reactions are successful using Cu(OAc)2 or air as the stoichiometric oxidant, and provide spirocyclic enones. Application of this process to the preparation of a highly functionalized tetracycle is also demonstrated (Ac=acetyl).
PEG400 was found to be a suitable solvent for condensation of various 2-amino pyridines with α-bromo ketones. 2-Arylimidazo[1,2-a]pyridines were obtained in a short time through microwave irradiation. A combination of the previous condensation with a C–H arylation reaction was developed to access various 2,3-diarylimidazo[1,2-a]pyridines with a reduced amount of palladium catalyst and no ligand.
Functionalization at the C–H bond of α-arylcarboxylic acids with a Grignard reagent results in metalation. Treatment of the metalated intermediates with aryl halides in the presence of a Pd catalyst leads to diarylcarboxylic acids in good to excellent yields through the formation of a C(sp3)–C(sp2) bond. The use of the Grignard reagent is the key to a successful coupling reaction.
I challenge you to a dual! An intramolecular oxidative coupling reaction that uses carboxyl-group-directed dual C-H bond activation catalyzed by palladium has been developed. In this reaction, the use of diphenylacetic acid and their derivatives as substrates gives substituted fluorenones in high yields. This method offers a highly favorable synthetic pathway to efficiently build a variety of substituted fluorenones.
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.
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.
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.