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
Form(ation) follows function: The first C-H bond activation with pyridotriazoles as a coupling partner is made possible by using a RhIII catalyst. The pyridotriazoles serve as new carbene precursors in C-H activation allowing direct access to fluorescent scaffolds bearing a pyridine-type ligating group. These fluorophores can be applied as dual sensors for colorimetric sensing of Cu2+ ions and fluorescence sensing for Zn2+ ions.
All for one and 1,4-all(yl): 1,3-Enynes containing allylic hydrogens cis to the alkyne act as three-carbon components in rhodium(III)-catalyzed, all-carbon [3+3] oxidative annulations to produce spirodialins. The proposed mechanism of these reactions involves the alkenyl-to-allyl 1,4-rhodium(III) migration.
An efficient synthesis of highly substituted isoxazoles from the reaction of allyl acetates with NaNO2 by using I2 under oxidative conditions is demonstrated. The reactions proceed through an I2-assisted activation of the C-H bond α to the nitro group, nucleophilic addition, and subsequent [3+2] cycloaddition. DMF=N,N-dimethylformamide, DMSO=dimethylsulfoxide.
The Cu(OAc)2-catalyzed para-hydroxy group triggered oxidative coupling of 2,6-disubstituted-4-cresols with fluorinated β-ketone esters or malonates leading to benzylic C(sp3)–C(sp3) bond formation is described with ambient air as the terminal oxidant. Highly functionalized 3-phenylpropanoate derivatives containing fluorinated quaternary carbon-like centers are constructed in an ecofriendly manner.
The title reaction involves Selectfluor–Bu4NI-mediated C–O bond formation in aqueous media under metal-free conditions. A variety of Δ2-isoxazolines are directly synthesized from oximes by remote intramolecular functionalization of C(sp3)–H bonds.
Giving direction: The title reaction leads to the successful functionalization of unreactive Csp3-H bonds in the presence of directing groups (DGs). A rhodacycle having a SbF6− counterion was isolated and is proposed to be a plausible intermediate.
They know their place: Unsymmetrically 2,3-diaryl substituted N-unprotected indoles were synthesized by the rhodium(III)-catalyzed annulation of nitrones with symmetrical diaryl alkynes. Exclusive regioselectivity was observed, as one of the two aryl substituents on the resulting indole ring is derived from the C-aryl ring of the nitrone, and the other from the alkyne.
Directing group and Co: The title reaction proceeds in the presence of an N,O-bidentate directing group. This protocol is characterized by wide substrate scope and cheap cobalt catalysts, and offers a new approach to 3-methyleneisoindolin-1-one, which can be converted into an oxadiazine salt in one step. Moreover, the directing group can be removed in three steps. CAN=ceric ammonium nitrate.
Directly functional! Cyanation and olefination was accomplished in one pot from benzoyl azides through an unprecedented directing group transformation. The method generates benzonitriles and can be used for the synthesis of 2-alkenylated benzonitrile derivatives (see scheme).
In splendid acylation: The major achievements in the acylation of arenes and heteroarenes by C-H activation with aroyl groups are summarized and discussed, based on the aroyl sources employed. In light of these achievements and their mechanistic studies, possible problems for carbonylative diaryl ketone synthesis by C-H activation are also discussed.
The unique reactivity of [Cp*CoIII] versus [Cp*RhIII] is showcased in the direct dehydrative C-H allylation with non-activated allyl alcohols. Cationic [Cp*CoIII] gave C2-allylated indoles, pyrrole, and phenyl-pyrazole in good yields, while the analogous [Cp*RhIII] catalysts were not effective. The high γ-selectivity and C2-selectivity result from directing-group-assisted C-H metalation, insertion of a C-C double bond, and subsequent β-hydroxide elimination. Cp*=C5Me5.
Knock your 'sox' off: A palladium catalyst promotes the cross-coupling of isoxazoles with aryl iodides through the selective C-H bond activation at the 5-position of the heteroaromatic compound. The use of 1,2-bis(diphenylphosphino)benzene as the ligand and silver fluoride as the activator was found to be crucial for this direct arylation. FG=functional group.
Highly efficient palladium-catalyzed fourfold tandem-domino reactions consisting of two carbopalladation and two C-H-activation steps were developed for the synthesis of two types of tetrasubstituted alkenes with intrinsic helical chirality. 20 different substrates were prepared with yields of up to 97 %. Photophysical investigations revealed light-induced switching properties of the products.
4-Substituted tryptophan derivatives and the total synthesis of cis-clavicipitic acid were achieved in reactions in which Ir-catalyzed C-H bond activation was a key step. The starting material for these reactions is asparagine, which is a cheap natural amino acid. The reductive amination step from the 4-substituted tryptophan derivative gave cis-clavicipitic acid with perfect diastereoselectivity (cbz=carbobenzyloxy).
A three-ring circus: A silver-catalyzed coupling of two Csp3-H groups followed by cyclization has been developed. The approach provides a general and efficient access to tetrasubstituted furans, thiophenes, and pyrroles from easily accessible benzyl ketone derivatives in a one-pot reaction process.
An efficient method for the CF3-carbenoid C–H functionalization of benzenes and indoles using readily available methyl 3,3,3-trifluoro-2-diazopropionate under chelation-controlled RhIII catalysis has been developed. The reaction proceeds with high regioselectivity and allows the simultaneous introduction of CF3 and COOMe groups into the 2-position of directing-group-containing benzenes and indoles.
Setting a trap: Described is a strategy for in situ generation of indole-based ortho-quinodimethanes (oQDMs) from the title indoles through either a DDQ- or BQ-mediated dehydrogenative process. These oQDMs are trapped by electron-deficient olefins, thus providing facile access to tetrahydrocarbazoles, carbazoles, and hetereoacenes. BQ=benzoquinone, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
Rounding the cycle: A theoretical investigation shows that the C(sp3)-H bond activation of methylquinoline with Cu(OAc)2 or free acetate occurs by an external base concerted metalation/deprotonation (CMD) mechanism (see scheme: RDS=rate-determining step). The C-H activation is followed by cationic alkyne insertion.
Umpolung of alkynes: The hypervalent iodine reagent EBX (ethynyl benziodoxolone) can be employed for the electrophilic introduction of alkynes. Aside from its unusual reactivity, mild reaction conditions and a high tolerance towards various functional groups are remarkable features of this stable reagent and its reactions.
Relay of chirality: A combined ion-mobility mass spectrometry (IM-MS) and DFT study has been carried out to investigate chiral Pd/monoprotected amino acid (MPAA)-enabled direct asymmetric C-H activation reactions. The enantioselectivity originates from the rigid square-planar Pd coordination in the C-H activation transition state: Bidentate MPAA and substrate coordination (see figure: DG=directing group).
Dyes at the crossroads: By using tBuOK/DMF as base to ionize the phthalonitrile, we have developed a facile method to synthesize asymmetric donor–π-acceptor-type benzo-fused aza-BODIPY complexes. The newly prepared aza-BODIPYs exhibit novel colorimetric properties which could be attributed to the fracturing and restoration of the B-N bond.
Halides not required: Nickel-catalyzed C-O/C-H cross-couplings for the construction of C-C bonds have recently been disclosed. By carefully optimizing the nickel catalyst, new C-C bond-forming reactions were developed, and even quaternary stereogenic centers are now accessible in high yields from readily available phenoxide derivatives and hydrocarbons.
Remote control: Switching the regioselectivity of C-H arylation between remote sites on pyrazolo[1,5-a]pyrimidine can be achieved by tuning the structure of the catalyst. The control appears to be due to a change in mechanistic pathways between electrophilic palladation and base-assisted deprotonation.
Clever cobalt: C-H aminocarbonylation of (hetero)arenes and alkenes was achieved by means of a user-friendly cobalt(III) catalyst. The reaction shows excellent chemo-, site-, and diastereoselectivity, as well as ample substrate scope.
Fluorene structures are commonly encountered in materials science, pharmaceutical chemistry, and organic synthesis. This Minireview summarizes how transition metal catalysis has become the prevalent strategy for the synthesis of fluorenes, as highlighted by examples from throughout the last decade.
Jockeying for position: Reported herein is the palladium-catalyzed synthesis of mono- and divinylbenzenes by meta-C-H olefination of benzyl sulfones. Successful sequential olefinations in a position-selective manner provided a novel route for the synthesis of hetero-dialkenylated products, which are difficult to access using conventional methods. DG=directing group.
Auto-tandem catalysis: A divergent multicomponent approach to imidazothiazinone and imidazothiazole derivatives starting from 2-(prop-2-ynylthio)imidazoles is developed. Imidazothiazinones are obtained from unsubstituted or monosubstituted substrates through an auto-tandem catalysis process that consists of two concatenated catalytic cycles, both catalyzed by PdI2.
C-H arylation of oligopeptides was achieved in aqueous media under exceedingly mild reaction conditions. The chemo- and site-selective nature of the late-stage diversification protocol illustrates the potential of our strategy for peptide ligation and fluorescence labeling (see scheme).
An improved protocol for the direct arylation of N-phenyl-N-benzyl(thiazol-2-yl)amines and regioisomeric 3-benzyl-N-phenylthiazol-2(3H)-imine is described. The two substrates for the arylation were obtained from a common starting material. In the latter case, the regioselectivity of arylation occurs exclusively in the 5-position.
The reaction mechanisms, the role of salts, solvent effects, and substrate scope in the RhIII-catalyzed C–H activation and annulation of N-(pivaloyloxy)benzamide and alkyne MIDA boronates have been investigated by DFT calculations.
The complex cis-[Pd(L)(PPh3)(H2O)2](SO3CF3)2, in which L is an amido-functionalized N-heterocyclic carbene (NHC) ligand, has been prepared. This complex was effective in catalyzing the double C–H functionalization of various nitrogen- and sulfur-containing heteroarenes to form fused polycyclic heteroaromatic compounds with alkynes in the presence of Cu(OAc)2 and tetra-n-butylammonium bromide.
A chemoselective palladium-catalyzed isocyanide insertion reaction of enaminones was developed. Amide derivatives were synthesized by this C–H functionalization and subsequent hydrolysis reactions, and 4-aminoquinoline derivatives were prepared by this C–H functionalization, which includes a 1,3-palladium migration in the process.
The conversion of dihydroartemisinic acid into dihydro-epi-deoxyarteannuin B, a difficult transformation that defied exhaustive efforts in a previous study, can now be readily achieved in excellent yields with Pd(OAc)2/CuCl2/MnO2. This finding makes it easier to access a range of other arteannuins and several potent trioxane-type antimalarial agents.
This review highlights the multifaceted properties of benzoquinone when it is involved in PdII-catalyzed oxidative reactions and presents mechanisms proposed in the literature.
All-in-one! A one-pot, four-component coupling approach was developed for the synthesis of thiophene-based, organic dyes (see scheme). Seven dyes were successfully synthesized in good yields under mild reaction conditions. Evaluation of photovoltaic properties revealed that the dyes containing either a n-hexyloxyphenyl amine donor or the developed, nonplanar donor without a 3,4-ethylenedioxythiophene (EDOT) moiety exerted good cell performance.
Straight to the point! A highly site- selective, heteroatom-guided, palladium-catalyzed direct arylation of 4H-chromenes is reported (see scheme). The C-H functionalization is driven not only by the substituents and structure of the substrate but also by the coupling partner being used. The diastereoselective assembly of the core structure of Myristinin B has been achieved by using a dual C-H functionalization strategy for regioselective direct arylation.
Go natural! A general and scalable access to the aeruginosin family of marine natural products (see graphic), exhibiting potent inhibitory activity against serine proteases, is described. The strategic use of two different Pd-catalyzed C(sp3)-H activation reactions led to the synthesis of aeruginosins 98A–C and 298A.
Bonds aplenty: Diaryliodonium salts were synthesized for the first time from electron-poor arenes by the title reaction. The diaryliodoniums can be readily functionalized by nucleophiles with high chemoselectivity, thus leading to C-C, C-S, C-N, C-P, and C-Br bond formation. Cp*=C5Me5, DG=directing group, Ts=4-toluenesulfonyl.
An efficient synthesis of highly substituted phthalides and 2-furanones from aryl and vinyl carboxylic acids with allenes by using a RhIII catalyst is demonstrated (see scheme). The reactions proceed through a carboxylate-assisted ortho-C-H activation and [4+1] annulation.
A calculated perspective: A mechanistic study of the 1,2,3,4,5-pentamethylcyclopentadienyl (Cp*)RhIII-catalyzed divergent cycloadditions of benzamide and diazo compounds was carried out by using DFT calculations (see scheme; Piv=pivalate; EWG=electron-withdrawing group).
Minor adjustments, major differences: The regiodivergent C-H borylation of 2,5-disubstituted heteroarenes with bis(pinacolato)diboron was achieved by using iridium catalysts formed in situ from [Ir(OMe)(cod)]2/dtbpy (cod=1,5-cyclooctadiene, dtbpy: 4,4'-di-tert-butyl-2,2'-bipyridine) or [Ir(OMe)(cod)]2/2 AsPh3 (see scheme).
Magic methyls: Expedient C-H methylations of (hetero)benzamides, alkenes, anilides, and even alkanes are realized with a broadly applicable and inexpensive iron catalyst by organometallic C(sp2)-H and C(sp3)-H activations (see scheme).
A change in rhythm: The first functional analysis of KL001 derivatives, which are mammalian circadian-clock modulators, was enabled by cutting-edge C-H activation. The sites of the KL001 derivatives that are critical for their rhythm-changing activity were elucidated, which led to the discovery of the first period-shortening molecules that target the cryptochrome.
Direct C(sp2)-H activation of aldehyde C(O)-H bonds with hypervalent alkynyl iodides (G-EBX) provides ynones under metal-free conditions. 1-[(Triisopropylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one (TIPS-EBX) constitutes an efficient alkynylation reagent for the introduction of the triple bond.
A basic diversion: A palladium-catalyzed C-H activation strategy is successfully employed for exclusive synthesis of 27 different 3-substituted indoles from α,β-unsaturated carboxylic acids and diarylamines under basic conditions in yields up to 89 %. Mechanistic studies revealed an ortho-palladation–π-coordination–β-migratory insertion–β-hydride elimination reaction sequence.
Triple N: Photolysis of nickel-azido complex [Ni(N3)(PNP)] (2) in benzene results in a transient NiIV nitrido species that bears significant nitridyl character, as supported by DFT calculations. Subsequent insertion of the nitrogen into a Ni-P bond, followed by Csp2-H activation of solvent yields diamagnetic [Ni(Ph)(PNPNH)] (3) featuring a parent iminophosphorane ligand. Reaction with HCl provides well-defined [Ni(Cl)(PNPNH)] (4).
Pushing the boundaries: The asymmetric 1,2-hydrovinylation of styrene derivatives with terminal alkenes is realised by using a nickel catalyst and specially designed chiral NHC ligands to achieve a new level of complexity for the tail-to-tail cross-coupling of alkenes by C-H activation.
The selective activation of C–H/C–F bonds was realized in the reactions of Fe(PMe3)4 with fluorophenylimines by controlling the substituents of the fluorophenylimines. Iron hydrides were obtained through C–F bond activation with the assistance of silanes. These iron hydrides show excellent catalytic activity in the hydrosilylations of aldehydes, ketones, and α,β-unsaturated aldehydes.
Bis(cyclometallated) IrIII complexes featuring acetylacetonate-type ligands directly conjugated to dyes are prepared by an original synthesis. The introduction of an aromatic pendant promotes fluorescence from the singlet state of the functionalized OO unit.
A variety of 2-acylindoles were readily prepared from N-pyrimidyl-substituted indoles in moderate to good yields by an effective palladium-catalyzed C2-acylation method. The remarkable features of this methodology include good product yields and wide tolerance of various functional groups.
A contemporary method is reported for the Pd(OAc)2/AgOAc catalytic system based bidentate ligand directed, regioselective C–H activation and C–C bond formation of the C-3 position of thiophene- and furan-2-carboxamides. This protocol was used for the direct C-3 arylation and alkylation reactions of both thiophene- and furan-2-carboxamides.
HATs off to photocatalysis! This review covers the recent advancements in the field of photocatalytic hydrogen-atom transfer (HAT) processes for C-H bond functionalization. Applications in organic synthesis, including the formation of C-C, as well as C-halogen, C-O (C=O) and C-N bonds, are presented.
The regioselective cyclometalation reactions of 2-alkenylpyridine/-pyrazine derivatives with Co(CH3)(PMe3)4 provide cobalt complexes by vinylic C(sp2)–H activation. These cobalt complexes smoothly add iodomethane but readily demetalate with carbon monoxide. Conversely, reductive elimination through the release of ethane is the dominant reaction with the same ligands and Fe(CH3)2(PMe3)4.
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.
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.
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.
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.
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.