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
Hypervalent iodine: An efficient IIII-mediated selective oxidative functionalization of alkanes with chromones and (thio)chromones has been developed. The developed methodology provides a direct access to the 2-alkyl chromones under metal-free and ambient conditions. Both cyclic and acyclic alkanes can be selectively functionalized (see scheme).
With a little help: A versatile iron catalyst allows the arylation of C(sp2)-H and C(sp3)-H bonds in the presence of a modular and removable triazolyldimethylmethyl (TAM) auxiliary, whose structure can be varied through 1,3-dipolar azide–alkyne cycloadditions.
Copper brings us together: The title reaction involves copper-catalyzed N-O bond cleavage, activation of a vinyl sp2 C-H bond and C-S bond formation; it uses simple oxime acetates and sodium sulfinates to synthesize sulfonylvinylamine products without the need for additional oxidants or additives. Upon hydrolysis, useful β-ketosulfones are obtained.
Highly regioselective intermolecular hydroaminoalkylation reactions of styrenes are achieved in the presence of the commercially available homoleptic catalyst [Ta(NMe2)5]. The process activates the α-C–H bonds of N-methylanilines and 1,2,3,4-tetrahydroquinoline and gives access to the corresponding branched hydroaminoalkylation products in good-to-excellent yields.
Lettin' the cat outta the bag: An efficient IrIII-catalyzed oxidative coupling of N-substituted indolines with various alkenes at the C7-position in air assisted by a carbonyl or carbamoyl group as a directing group is reported. The catalyst was prepared from [Cp*IrCl2]2 and AgOTf. A variety of 7-alkenylindolines were obtained in moderated to high yields. The reaction is potentially applicable to the synthesis of 7-alkylindoles and 7-alkenylindoles.
Two birds with one stone: Two new centers of chirality are created by the cytochrome P450 catalyzed regio-, diastereo-, and enantioselective oxidative hydroxylation of appropriate achiral compounds. When using either wild type cytochrome P450 BM3 or mutants generated by directed evolution, a high preference for one of the four stereotopic H atoms is observed depending on the nature of the X moiety in the substrate.
Taking NO for an answer: C2-Arylation of substituted pyridine N-oxides with heteroaryl carboxylic acids through a palladium-catalyzed decarboxylative coupling is described. Pyridine N-oxides connected to other heteroaryl rings can be obtained in a single step. The regioselectivity with respect to both components is excellent. Further, pyridine N-oxides were used to study the efficiency of decarboxylative coupling compared with aryl halide coupling.
Getting ahead on tams: The intramolecular dehydrogenative amidation of aliphatic amides, directed by a bidentate ligand, was developed using a copper-catalyzed sp3 C-H bond functionalization process to deliver β-lactams. The reaction favors the C-H bonds of β-methyl groups over the unactivated methylene C-H bonds, as well as aromatic sp2 C-H bonds and unactivated secondary sp3 C-H bonds of rings.
A new approach to the synthesis of indoloisoquinoline derivatives is described. The activation of the indole C2–H bond is accomplished here by using a Pd(OAc)2 and Cu(OTf)2 bi-catalytic system. In this reaction aldoximes are converted into the corresponding isoquinolines in open atmosphere under mild reaction condition.
C-H bond activation: A highly regioselective ortho-benzoxylation of benzamides with substituted benzoic acids in the presence of ruthenium catalyst is described. Further, Ru-catalyzed alkenylation is carried out at the ortho C-H bond of benzoxylated N-alkyl benzamides with alkenes in water solvent. Subsequently, the benzoxyl moiety of N-alkyl benzamides was converted into the hydroxyl group in the presence of base or acid (see scheme).
Synthetic methods: A ruthenium-catalyzed direct C7 amidation of indoline C-H bonds with sulfonyl azides was developed (see scheme). This procedure allows the synthesis of a variety of 7-amino-substituted indolines in good yields. The good functional-group tolerance as well as the mild conditions are prominent features of this method.
How big is too big? The consequences of extremely high steric loading have been probed in late transition metal complexes featuring the expanded ring NHC 6-Dipp. In the presence of [(6-Dipp)Au]+, the first example of backbone C-H activation of a saturated N-heterocyclic carbene is revealed, proceeding via a mechanism which involves free carbene in addition to the AuI centre (see illustration).
Silver ox: By using a Cu(OAc)2 catalyst and an Ag2CO3 oxidant in dichloroethane solvent, C(sp3)-H amidation proceeded at a terminal methyl group as well as at the internal benzylic position of an alkyl chain. This reaction has a broad substrate scope, and various β-lactams were obtained in excellent yield, even on gram scale. Use of CuCl2 and Ag2CO3 under an O2 atmosphere led to 2-indolinone selectively synthesized by C(sp2)-H amidation. DMSO=dimethylsulfoxide.
Three out of five steps in the Rh-catalyzed stereoselective transformation of aryl-substituted tert-cyclobutanols into indanols were shown by DFT calculations to make important contributions to determining the stereoselectivity, while the rate-determining step is the 1,4-Rh transfer. The present study corroborated the previous proposal that the reaction occurs by metalation, β-C elimination, 1,4-Rh transfer, C=O insertion, and a final catalyst-regeneration step (see figure).
Get a handle on it: Highly regio- and enantioselective subterminal hydroxylation of n-octane and propylbenzene was observed with P450 enzymes obtained by the directed evolution of terminal-selective P450pyr hydroxylase (see scheme). The engineered enzymes with their fully altered selectivities are useful for the functionalization of alkanes and the preparation of enantiomerically pure alcohols.
No–No–No: Amination of a non-acidic C-H bond, no pre-activation of the coupling partners, no chelate-assisting directing group. Dehydrogenative C–N cross-coupling through the ortho-N-carbazolation of unprotected, secondary anilines has been achieved using a Ru catalyst with O2 as the terminal oxidant. The reactions proceed in an intermolecular fashion, selectively in the ortho position.
CuII-catalyzed trifluoromethylation of internal olefins has been achieved by using Cu(OH)2 as a catalyst and TMSCF3 as a trifluoromethylating reagent (see scheme). The push–pull effect from the olefin substrates facilitates the internal olefinic C-H bond trifluoromethylation. A mechanism involving radicals is proposed, and derivatization of the resultant CF3 olefins led to multifunctionalized CF3 olefins and trifluoromethylated N-heterocycles.
Testing a new tactic: In a concise synthesis of podophyllotoxin with a crucial palladium-catalyzed arylation step, subtle conformational effects govern reductive elimination pathways from the high-valent palladium center. This route to aryltetralin lignan derivatives may be of interest in drug discovery.
The solid-state structures of tetrahedral and octahedral titanium amide complexes with bulky dicyclohexylamido ligands reveal a characteristic close contact between the titanium atom and a carbon atom in the β-position. The exchange of a chlorine atom by a bulky pentafulvene ligand increases this effect. The introduction of other sterically demanding amines to complexes initiates a spontaneous C–H activation.
An efficient Cu-catalyzed direct CH-functionalization of indoles with methyl 3,3,3-trifluoro-2-diazopropionate has been developed. The reactions proceed within a few minutes under low catalyst loading to give the corresponding C3 or C2 substitution products with high regioselectivity. This method has been successfully applied for the synthesis of trifluoromethyl-containing paullone.
Hot rhod: A rhodium-catalyzed, electronically reversed Sonogashira reaction between unbiased arenes and the hypervalent iodine reagent 1 proceeds through C-H activation. This reaction displays excellent functional-group tolerance and high efficiency, and thus opens a new synthetic pathway to access functionalized alkynes. Cp*=C5Me5, DCE=1,2-dichloroethane, Piv=pivaloyl, TIPS=triisopropylsilyl.
Down to one: A C-H alkenylation of simple arenes without the need for an excess amount of the arene was possible with a bimetallic RhII catalyst (see scheme). A phosphine ligand as well as a combination of the oxidants Cu(TFA)2 and V2O5 proved essential for the efficient synthesis of monoalkenylated products with good selectivity, especially for di- and trisubstituted arene substrates.
Who needs alkynes? α-Halo and pseudohalo ketones (as C(sp3)-based electrophiles) are utilized as oxidized alkyne equivalents in RhIII-catalyzed redox-neutral annulations to efficiently generate diverse N-heterocycles. Owing to the mild reaction conditions, a variety of functional groups are tolerated.
Unprecedented examples of double aromatic ring C-H bond activation associated with C-O bond formation reactions to phenazine architecture in RuIII complexes are presented. The chemical transformations have led to formation of new RuIV complexes with angular pentacyclo heterocyclic ligands (see scheme).
Pyrazoles with an aldehyde function at C-4 underwent a palladium-catalyzed direct arylation reaction to provide a regioselective approach to 5-aryl-substituted pyrazoles. The formyl substituent can be easily removed by using a Pd catalyst and, therefore, is considered a temporary protecting group.
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.
COs with a local branch: A hydroacylation of vinylphenols with aryl, alkenyl, and alkyl aldehydes gave the branched products: α-aryl ketone precursors to benzofurans. This cross-coupling enabled access to eupomatenoid natural products in four steps or less from eugenol (see scheme; cod=1,5-cyclooctadiene). Aldehyde decarbonylation was avoided by use of an anionic directing group on the alkene and a small-bite-angle diphosphine ligand.
Reoxidation by dioxygen: The combination of C-H activation by a homogeneous catalytic palladium complex with a vanadiumoxo co-catalyst allows the selective aerobic oxidation of propane with dioxygen (see scheme).
In an absence of activation: A robust nickel(II) catalyst enabled secondary alkylations of unactivated aryl C-H bonds with secondary alkyl bromides and chlorides with ample substrate scope. Based on this system the first C-H trifluoroethylations of arenes with unactivated C-H bonds could be carried out (see scheme; Q=8-quinolinyl).
Two gold centers combined for cyclization: Diynes containing a 3,4-thiophene backbone cyclize under gold catalysis, via gold–vinylidenes and C-H activation, generating pentaleno[c]thiophenes. Switching the diyne backbone changes the cyclization pathway. A DFT study analyzed the influence of the diyne backbone and gave an explanation for the 5-endo versus 6-endo selectivity (see figure).
Hydrazones were employed as auto-formed and auto-cleavable directing groups (DGauto) for RhIII-catalyzed C-H activation. This strategy, which was inspired by the venerable Fischer indole synthesis, was successfully applied for efficient and external-oxidant-free synthesis of unprotected indoles from readily available aryl hydrazines and alkynes.
Three is better than two: CrIII silicates, in contrast to the CrII analogues, were found to be efficient ethylene-polymerization catalysts that initiate the reaction without a cocatalyst through the heterolytic splitting of an ethylene C-H bond across a Cr-O bond (see picture). This study provides clues about the active sites and initiation mechanism of the industrial Phillips catalyst.
Asleep or awake? Unsaturated N nucleophiles react through two competing pathways under PdII catalysis: C-H allylic activation and aminopalladation. New data are in accord with the initial generation of a high-energy cyclic aminopalladated intermediate (API) that can either evolve along different pathways such as β-H elimination, oxidation, or carbopalladation, or lay dormant, the latter leading to alternative types of reactivity, such as allylic C-H activation or [3,3]-sigmatropic rearrangement, gaining the upper hand (see scheme; Ts=p-toluenesulfonyl).
Carbon coupling cascade: Arylacetophenones react with Michael acceptors under ruthenium catalysis to set up triple and quadruple C-H functionalization pathways. Through choice of reaction conditions, novel indanone carbacycles, indeno indene carbacycles, and indeno furanone heterocycles can each be accessed in a single step.
The 5-exo-trig cyclization of 1,6-dienes with alkyl chlorides through a visible-light-facilitated radical strategy is presented. This is achieved by selectively splitting the C(sp3)–H bond adjacent to the chloride atom to form an alkyl radical. bpy = 2,2'-bipyridyl.
A tBu3P-coordinated 2-phenylaniline-based palladacycle complex was found to be an efficient precatalyst for Pd-catalyzed coupling reactions of aryl halides with polyfluoroarenes that operates through a C–H activation strategy, with good to excellent product yields being observed.
We present a regioselective ortho-halogenation of [2.2]paracyclophanes by palladium-catalyzed C–H activation with O-methylaldoxime as a directing group. As exemplarily shown, this new protocol in combination with the subsequent deprotection provides practical access to various ortho-disubstituted [2.2]paracyclophanes.
Mono-P-ly: Site-selective C-H borylation of quinoline derivatives at the C8 position was achieved by using a heterogeneous Ir catalyst system based on the silica-supported cage-type monophosphane ligand Silica-SMAP. The efficient synthesis of a corticotropin-releasing factor1 (CRF1) receptor antagonist based on a late-stage C-H borylation strategy demonstrates the utility of the C8 borylation reaction.
It's all in the design: Seoul-Fluors with predictable photophysical properties, including a fluorescent reactive-oxygen-species sensor that was not previously accessible, were synthesized efficiently by coinage-metal-catalyzed intramolecular 1,3-dipolar cycloaddition and subsequent palladium-mediated C-H activation (see scheme). The quantum yield of the products could be controlled systematically by altering the electronic nature of the substituents.
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.
The coupling reaction of N-phenoxyacetamides with N-tosylhydrazones or diazoesters proceeds through RhIII-catalyzed C-H bond activation. ortho-Alkenyl phenols are obtained in good yields and with excellent regio- and stereoselectivity.
Size does matter: Size-dependent reactivity of (Sc2O3)NO− (N=1–18) clusters in hydrogen atom abstraction from n-butane was found by mass spectrometry and DFT calculations. Larger (Sc2O3)NO− clusters generally have a higher reactivity than smaller ones (see figure). Atomic oxygen radical anions are responsible for the high reactivity of (Sc2O3)NO− in the C-H bond activation.
A rare gathering: Two new trinuclear μ3-bridged rare-earth metal phosphinidene complexes were synthesized by treatment of the corresponding carbene precursors with phenylphosphine; some new transformation patterns of phosphinidenes are revealed. A possible pathway for reaction of these phosphinidene complexes with CS2 was determined by DFT calculations.
Weaker is better! Phenylacetic acids and benzoic acids are suitable substrates for a palladium-catalyzed ortho-selective C-H deuteration of arenes with deuterated acetic acid (see scheme; R=H, alkyl, CF3, OMe, NO2, Cl, F). This reaction demonstrates the superior reactivity of weakly coordinated palladacycle intermediates in C-H functionalization reactions.
Activation on N-heterocycles: Scorpionate-ligand-supported yttrium alkyl complexes react with imidazole substrates either through a three-component reaction involving ring-opening of the imidazole substrate or a transformation leading to the formation of a C=C bond through multiple C-H activations (see scheme; TpMe2=tri(3,5-dimethylpyrazolyl)borate).
Unsymmetric triarylmethanes have been synthesized starting from methyl phenyl sulfone as an inexpensive and readily available template. The three aryl groups were installed through two sequential palladium-catalyzed C-H arylation reactions, followed by an arylative desulfonation.
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.
Mono- or dithiolation: The first rhodium-catalyzed intermolecular direct C-H thiolation of arenes with aryl and alkyl disulfides is developed to provide a convenient route to aryl thioethers. This strategy is compatible with different directing groups and exhibits excellent functional group tolerance. Significantly, mono- or dithiolation can be selectively achieved, thus providing a straightforward way for selective preparation of aryl thioethers and dithioethers (see scheme).
C-H activation: Double C-H bond activation took place efficiently upon treatment of 3-phenylthiophenes with alkynes in the presence of a rhodium catalyst and a copper salt oxidant to form the corresponding naphthothiophene derivatives. Dehydrogenative coupling with alkenes was also found to occur on the phenyl moiety rather than the thiophene ring (see scheme).
Dihydrofurans that bear methyl-substituted quaternary stereocenters were obtained by rhodium(III)-catalyzed enantioselective hydroarylation and C-H functionalization at mild conditions. The use of chiral cyclopentadienyl ligands with a biaryl backbone led to excellent enantioselectivities.
The mild synthesis of imines paves the way to aminonitriles and amino acids. Aerobic oxidation of primary and secondary amines in a continuous photoreactor with singlet oxygen generated in situ led to the rapid formation of imines, which were quantitatively trapped as α-aminonitriles (see scheme; TMS=trimethylsilyl). Benzylic and primary α-aminonitriles, precursors for amino acids, could be efficiently produced in three minutes.
Ring road: One-pot N-annulation reactions of aryl and α,β-unsaturated ketones with alkynes in the presence of NH4OAc under microwave (MW) irradiation conditions have been developed (see scheme). These processes lead to the rapid formation of the respective isoquinoline and pyridine derivatives. In addition, an approach for the synthesis of pyridines that involves four-component reactions is presented.
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.
Don't just slap a label on it! A regioselective and stereospecific method for the deuteration of nitrogen-containing compounds has been developed on the basis of a C-H activation process triggered by Ru nanoparticles (RuNps). This general and efficient approach to deuterium labeling was applied to 22 compounds, including 8 biologically active substances (see scheme; PVP=polyvinylpyrrolidone).
Direct action: C-H bond direct chalcogenation of aromatic compounds by using elemental sulfur and selenium as chalcogen sources under oxidative conditions has been developed. The reaction proceeds with suitable copper salts under aerobic oxidation conditions by formal oxidation of elemental chalcogens (see scheme). A variety of nucleophilic aromatic compounds were chalcogenated and an oxidative coupling reaction of diselenides and aromatic compounds also took place.
Out of metal! A metal- and oxidant-free method for direct sp3 C-H arylation of pyrrolidine has been developed. As an alternative to metal-mediated reactions, the method relies on a highly atom economic three-component reaction, which is selective for single regioisomers of aryl pyrrolidines that are important in chemistry as well as in biology. The method, operating under simple and mild reaction conditions, is very efficient, even on a multigram scale.
Benzyltriazoles have been catalytically oxidized by using CuI and tert-butyl hydroperoxide to yield phenyl(1H-1,2,3-triazol-4-yl)methanone derivatives in good yields at room temperature.
Direct carbon–carbon bond formation between nonfunctionalized carbon atoms (C–H) in the presence of KOtBu for the synthesis of cinnoline derivatives was achieved.
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.
Ar we having fun yet? Selective monoarylation of aryl 2-pyridyl ketones by arene sp2 C-H bond activation/functionalization is achieved, via an unprecedented 6-membered ruthenacycle, and is highly selective as only one non-protected ortho arene C-H bond is activated and arylated. The reaction takes place with a variety of aryl bromides, and is promoted by a RuII-carboxylate catalyst arising from a catalytic amount of p-trifluoromethyl-benzoic acid.
Do it in tandem: An efficient regioselective aryl C-H activation and tandem o-hydroxylation/alkoxylation method for 2-aryl benzimidazoles has been developed using a Pd(OAc)2/oxone/Cs2CO3 catalytic system. Some of the compounds have significant IC50 values ranging from 1–10 μM in selected human cancer cell lines. The DNA-binding potential of the compounds was also investigated by UV/vis, fluorescence, and circular dichroism spectroscopy.
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.
A practical and simple synthesis of benzoxazoles from easily available substrates is developed. The protocol is triggered by an iron-catalyzed tandem oxidative process from simple ether derivatives.
Chelation-assisted arylation of the ortho C-H bonds in 2-arylpyridine derivatives was achieved by using [Ru(OAc)2(p-cymene)] as the catalyst and diaryliodonium salts as the arylation reagent.