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
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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 to the synthesis of pyridines that involves four-component reactions is presented.
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.
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).
Remote control: The orthopalladation, through C-H bond activation, of substituted amino esters and amino phosphonates derived from phenylglycine has been studied (see scheme). Determination of the reaction rates indicated a clear acceleration of the C-H activation rate when the n-amine and/or the C-α atom are substituted. Substitutions at the aryl ring do not promote changes. The use of hydrochloride salts of the amino esters also has a strong accelerating effect on the process.
Simplify! Substituted 2,2':6',2''-terpyridines were efficiently prepared by coupling of 2,2'-bipyridine N-oxides with 2-halopyridines by using a palladium catalyst (see scheme). The bipyridine N-oxide starting materials were prepared from pyridine N-oxides by the same method. This method significantly reduces the number of steps for the preparation of substituted terpyridines and therefore allows convenient and scalable access to this important class of chelating ligands.
Waste not, want not: The title CDC reactions have emerged to 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.
Carbene reactivity: Pyridine reacts with benzyne by a nucleophilic addition/intramolecular proton shift sequence to generate N-phenyl pyrid-2-ylidenes (see scheme). These unusual carbenes react with isatin derivatives in an original three-component bis-arylation reaction involving a formal pyridine C-H bond functionalisation. The mechanism of the reaction has been investigated experimentally and theoretically.
The amide decides: Three different rhodium(III)-catalyzed reaction pathways of a wide variety of tethered alkenes can be accessed through changing the amide directing group. This provides an efficient route to a myriad of complex polycyclic products, many containing newly formed all-carbon quaternary centers. Amidoarylations can diastereoselectively deliver products with up to three contiguous stereocenters.
All the hype: The title reaction has been developed for the facile synthesis of a variety of complex alkyl ethers. Cyclic hypervalent iodine (I3+) reagents serve as oxidants for this unique C-H alkoxylation reaction. The reaction demonstrates excellent reactivity, good functional-group tolerance, and high yields. Q=8-aminoquinoline-derived auxiliary.
C-3Pd: A direct C3 acylation of benzofurans and benzothiophenes by sp2 C-H activation catalyzed by palladium acetate is reported. tert-Butyl hydroperoxide (TBHP) is used as the oxidant and aldehydes are used as aroyl sources to give the desired products in excellent yields. This cross-dehydrogenative coupling reaction provides practical access to 3-acylbenzofurans and 3-acylbenzothiophenes.
Palladium and CO.: The title reaction proceeds in the presence of CO, thus providing a synthesis for 1,3-oxazin-6-ones (see scheme; DABCO=1,4-diazabicyclo[2.2.2]octane, DMF=N,N-dimethylformamide). The reaction tolerates a variety of functional groups on both the aryl ring and the amide of the substrate. Initial mechanistic studies suggest the activation of the alkenyl C-H bond to be a key step.
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.
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.
Give Me an Ar, give Me an N! Arylation of the methyl group in a simple derivative of readily available alanine under palladium catalysis was followed by intramolecular amidation at the same position to give chiral α-amino-β-lactams with a wide range of aryl substituents (see scheme; Phth=phthaloyl). The α-amino-β-lactams were obtained in moderate to high yields with good functional-group tolerance and high diastereoselectivity.
The direct γ-hydroxylation of enones using oxygen from the air and potassium tert-butoxide in the presence of a copper–aluminium mixed oxide as catalyst is reported. This catalyst is inexpensive and easy to prepare. The reactions were optimized using design of experiments techniques.
Lights on! Aided by morpholine, bromination of sp3 C-H bonds can be achieved under visible light irradiation by using a low loading of Eosin Y as a photoredox catalyst, a low-power household lamp as a light source, and CBr4 as the source of bromine. The potential to use this reaction for mild and regioselective bromination of sp3 C-H bonds in complex molecules is exemplified by the bromination of (+)-sclareolide and acetate-protected estrone.
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.
Only water: Phenols have been shown to undergo a ruthenium-catalyzed ortho-alkylation reaction (see scheme; Cy=cyclohexyl). Unactivated alcohols are used as the alkylating agents and water is the only by-product that is generated, making this transformation more atom-economical and greener than traditional methods.
Give a direction: A rationally designed, removable meta-directing group enables the selective, remote functionalization of aromatic substrates (see scheme). The generality of the concept was shown with alkenylation reactions of hydrocinnamic acid derivatives, the selectivities of which were similar to the ones described for benzyl derivatives.
Complement for Fischer: An efficient palladium-catalyzed indole synthesis proceeds by the intramolecular cross-dehydrogenative coupling of N-aryl imines under mild conditions using molecular oxygen as the sole oxidant. This practical method relies on anilines and ketones as starting materials (and thus the same retrosynthetic disconnection as the Fischer indole synthesis) and will likely become a popular route.
On the bumpy road to direct success: With a growing number of convenient synthetic methodologies at hand, the direct α-functionalization of cyclic amines has become more straightforward than ever before. This Review covers the recent methodological advances in this challenging field (from the end of 2006) and classifies them according to their associated in situ formed reactive intermediates.
The total synthesis of natural products has been carried out showcasing the creative and ingenious application of C-H activation in the construction of complex molecular architectures that are compared with their “non-C-H activation” counterparts. These accomplishments stood as true testaments of the growing potential of C-H activation, and further cementing the power of this emerging synthetic technology (see figure).
Best director: C-H activation reactions have received widespread interest over the past decade. This Focus Review addresses the recent developments in the amide-directed tandem process of C-C/C-N bond formation through C-H activation.
Access to chiral isoindolinones: The Mg-catalyzed enantioselective benzylic C-H bond functionalization of isoindolinones is described. A Bu2Mg/Schiff base catalyst (1:1) promoted the enantioselective addition of N-Boc-isoindolinones to aryl, heteroaryl, alkenyl, and alkyl imines, giving 3-substituted isoindolinones in 84–99 % ee and 50:50–91:9 d.r. (see scheme).
The selective redistribution of hydrocarbon chains C(n) on a polyhydrido triruthenium cyclopentadienyl complex (see scheme; Ru red spheres) involves a repeated sequence of face-to-face C-H group transfers (A to C) through the open cluster B, followed by individual concerted skeletal rearrangements on the two faces (C to A'). This process is just one of several spectacular examples illustrating the power of a molecular polymetallic system.
The need for spin: Owing to its importance for numerous chemical processes, the nature of hydrogen-atom transfer (HAT) has become a major area of research. This Minireview shows the intrinsic requirements that enable gaseous oxo clusters to bring about HAT reactivity from saturated hydrocarbons at room temperature, thus revealing the crucial role of unpaired spin density at the abstracting atom.
A tri-ing transformation: The increasingly high demand for trifluoromethylated arenes and heteroarenes is a major challenge that has been addressed through the development of trifluoromethylation reactions. Several effective approaches for late-stage trifluoromethylation, as well as the use of practical and cheap trifluoromethylation reagents, are highlighted.
Two at once: Xanthones with different functional groups were obtained with CO (balloon) in the presence of a simple catalytic system that consists of Pd(OAc)2, K2S2O8, and trifluoroacetic acid (see scheme). Preliminary mechanism studies reveal that the second C-H functionalization might be the rate-determining step.
Taking direction well: Substituted phenylalanine derivatives were prepared by C-H bond functionalization (see scheme). The syntheses are highly convergent and employ an N-phthaloylalanine with a 2-thiomethylaniline directing group. The use of an 8-aminoquinoline directing group allows for the diarylation of methyl and the diastereoselective arylation of methylene groups.
Activate and reiterate: The activation of C(sp3)-H bonds is a highly desirable transformation because molecular complexity can be increased at the expense of the most simple and readily available organic linkage. In recent contributions this approach was used for coupling reactions with small all-carbon rings, as exemplified by the sequential C-H activation steps in an elegant total synthesis of the piperarborenines (see scheme; DG=directing group).
Director's cut: Not only conventional alcohols but also silanols can act as directing groups in oxidative palladium(Ii)-catalyzed C-H alkenylations. The silicon-tethered hydroxy groups are “traceless”, thereby facilitating the regioselective C-H activation of toluene derivitives as well as phenols (see scheme).
Tomorrow always dyes! Organic dyes (e.g., Rose Bengal, Eosin Y) have been recently used as versatile photoredox organocatalysts in place of metal complexes (e.g., Ru2+ salts). Accordingly, photoinduced electron transfer reactions induced by excited dyes were exploited in various synthetic processes. The reactions were performed under metal-free conditions and visible light irradiation.
Aliphatic PNP pincer ligands, HN(CH2CH2PR2)2, and ligands derived from them by backbone functionalization, are versatile chelating ligands for metal–ligand cooperative small molecule activation and catalysis. This microreview covers the recent work with these ligands and provides a comprehensive comparison with related pincer systems.