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
Five-atom building unit: N-aryl-substituted nitrones were employed as five-atom coupling partners in the rhodium-catalyzed cyclization with diynes. In this reaction, the nitrone moiety served as a directing group for the catalytic C-H activation of the N-aryl ring. This formal [2+2+5] approach allows rapid access to bridged eight-membered heterocycles with broad substrate scope.
Go with the combo: The title reaction is realized by combining asymmetric counteranion catalysis and palladium-catalyzed allylic C-H activation. This method tolerates a wide scope of α-branched aromatic aldehydes and terminal alkenes, thus affording allylation products in high yields and with good to excellent levels of enantioselectivity.
For your C-H bond only: [Rh(μ-Cl)(H)2(IPr)]2 (IPr=1,3-bis-(2,6-diisopropylphenyl)imidazol-2-ylidene) catalyzes the selective functionalization of 2-(2-thienyl)pyridine efficiently with a range of alkenes and internal alkynes. A catalytic cycle is proposed on the basis of the identification of key reaction intermediates and the study of their reactivity by NMR spectroscopy.
Branching off: The title reaction of unactivated β-methylene C(sp3)-H bonds of α-amino acid substrates with alkyl iodides is described. The C(alkyl)– C(alkyl) bond-forming reaction proceeds in good yields, and by using sequential reactions β-branched amino acids can be obtained.
Carbonylative C-H activation: A procedure for the synthesis of highly substituted 2-quinolinones has been developed. By this newly developed approach, 2-quinolinone derivatives were prepared in moderate to good yields by carbonylative [3+2+1] annulation of N-aryl-pyridine-2-amines and internal alkynes by C-H activation (see scheme).
Electrochemical reactions are shown to be effective for the C-H functionalization of a number of heterocyclic substrates that are recalcitrant to conventional peroxide radical initiation conditions and of interest in medicinal chemistry. Monitoring reaction progress under electrochemical conditions provides mechanistic insight into the C-H functionalization process.
No group help needed: A palladium-catalyzed dehydrogenative coupling between diarylamines and olefins has been discovered for the synthesis of substituted indoles. This intermolecular annulation approach incorporates readily available olefins and obviates the need of any additional directing group. An ortho palladation, olefin coordination, and β-migratory insertion sequence has been proposed for the generation of an olefinated intermediate.
En route: The title redox-neutral reaction provides a convenient route to valuable enantioenriched trifluoromethylated N,O-aminals in good to excellent yields and with excellent regio-, chemo-, and enantioselectivity. The reaction features a CuI/Brønsted acid system and broad substrate scope.
A convenient route to phthalimide: A convergent method for the ruthenium(II)-catalyzed imidation of easily accessible benzamides by C-H functionalization was developed (see scheme). The methodology was successfully applied to the preparation of synthetically challenging unsymmetrical heteroaromatic diamides and proved amenable to a step-economic synthesis of a potent COX-2 enzyme inhibitor.
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.
The synthesis of indole-derived structural analogs of natural antimitotic agent allocolchicine is reported. In a key step, an intramolecular Pd-catalyzed C–H arylation reaction serves to construct the polycyclic ring system, by connecting the two electron-rich arene fragments.
Actin' out: Spiroacetals can be prepared from aldehydes and functionalized dienes through a convergent, telescoped sequence of cycloaddition, oxidative C-H bond cleavage, and acid treatment. The functional-group tolerance and facile accessibility of the components render this protocol suitable for the synthesis of structurally complex natural products such as the actin-binding cytotoxin bistramide A.
Construction of 9-arylacridines was achieved through a new copper-mediated dehydrogenative cyclization of tritylamines involving two C-H and one C-N bond cleavages. Some of obtained acridine derivatives exhibited intense fluorescence in the solid state (see scheme).
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.
Caught in a trap: The title reaction of N,N-disubstituted anilines with diazo compounds and imines is reported for the efficient construction of α,α-diaryl benzylic quaternary stereocenters in good yields with high diastereoselectivities and excellent enantioselectivities. Efficient electrophilic trapping of the metal-carbene-induced zwitterionic intermediate is crucial for the enantiocontrol under RhII/chiral phosphoric acid (PPA) co-catalysis.
Good form: Indolines are important moieties present in various biologically significant molecules. Described is the title sequence for forming indolines with di-tert-butyldiaziridinone. The reaction process likely proceeds via a pallada(II)cycle, which is converted into an indoline by oxidative addition to the diaziridinone and two subsequent C-N bond formations.
Metal-free direct arylations of engineered indole-3-acetamides set the stage for the late-stage diversifications of highly functionalized peptides under mild reaction conditions.
Very neat reactions! A new strategy for the synthesis of benzo[c]chromenes and benzo[b]furans from commercially available starting materials is reported. This two-step, one-pot strategy consists in a gold-catalyzed hydrophenoxylation reaction followed by Pd-catalyzed C-H activation or Mizoroki–Heck reactions.
Modern biocatalysts on the rise: The P450 BM3 monooxygenase mutant A74G/L188Q catalyzes the enantioselective allylic hydroxylation of ω-alkenoic acids and esters under mild conditions using O2 as an oxidant. This reaction offers access to important chiral building blocks for the synthesis of biologically active compounds and demonstrates the highest chemo- and enantioselectivity observed to date for the C-H oxidation of acyclic terminal olefins.
Which C-H bond reacts? N-Ylide complexes of Ir were generated by α-C(sp3--H activation with [Cp*IrCl2]2 and NaOAc. The reaction of an α-imidazolium ester is a rare example of a C-H activation where the site selectivity can be controlled by the choice of metal and ligand; DFT calculations revealed that the N-ylide complex is the kinetic product of an ambiphilic C-H activation, in which the acetate ligand plays the dominant role (see scheme).
Thinking outside the BBOX: γ-Butyrobetaine hydroxylase (BBOX) is a 2-oxoglutarate (2OG)-dependent oxygenase that catalyzes the final hydroxylation step in the biosynthesis of carnitine. BBOX was shown to catalyze the oxidative desymmetrization of achiral N,N-dialkyl piperidine-4-carboxylates to give products with two or three stereogenic centers.
The synthesis of a key intermediate chiral β-hydroxy-γ-butyrolactone (A) by PdII-catalysed stereoselective allylic C–H oxidation is reported. A common synthetic route to transform this intermediate into key building blocks for the synthesis of migrastatin family members has been developed.
The weakest link: Challenging aryl C-H oxygenations with very weakly coordinating aldehydes proceed chemoselectively in the presence of versatile ruthenium(II) catalysts under mild reaction conditions. This transformation features an ample substrate scope and excellent positional selectivity.
Heteroatom-directed C-H borylations of small-ring carbocycles, such as cyclopropanes and cyclobutanes, were achieved with silica-supported monophosphane–Ir catalysts (see scheme). Borylation occurred at the C-H bonds located γ to the directing N or O atoms with exceptional cis stereoselectivity relative to the directing groups.
Proof-of-concept for the use of metal antimonates as bifunctional catalysts for oxidative coupling reactions is described. A well-defined zinc(II) antimonate salt enables the α-functionalization of glycine derivatives through a sequential aerobic oxidation-allylation reaction, in which the antimonate anion is responsible for the aerobic oxidation and the zinc cation acts as a Lewis acid for the allylation reaction. EWG=electron-withdrawing group; PMP=p-methoxyphenyl.
C-H activation: A RhIII-catalyzed intramolecular redox-neutral atom-economic annulation of a tethered alkyne has been developed to efficiently construct 2-amidealkyl indoles with completely reversed regioselectivity by a C-H activation pathway (see scheme). A one-pot synthesis of pyrido[1,2-a]indoles has also been developed and applied to a highly efficient formal total synthesis of (±)-goniomitine.
Square deal: A combination of either ruthenium(II) or rhodium(II) complexes and quinine-derived squaramide enables 3-diazooxindoles, indole, and nitroalkenes to undergo a highly efficient asymmetric three-component reaction. Based on this metal/organo relay catalysis, a total synthesis of (−)-folicanthine was accomplished in seven steps with 14.5 % overall yield.
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.
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.
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.
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.
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.
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.
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 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.
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.
Much milder and environmentally friendly reaction conditions can be used for oxidative Heck reactions through the combined use of rhodium and redox catalysis. This allows the rhodium complex to be catalytically regenerated. A broad range of substrates was tolerated in the reaction and afforded different amides in good to very good yields.
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.
Remote access: The first application of an oxalyl amide to direct C-H functionalizations at remote positions is reported. The results show both C(sp2)-H and C(sp3)-H bonds at δ- and ε-positions are 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.
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.
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.
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.
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 direct transformation of alkyl C-H bonds on polymer surfaces to form small-molecule groups and polymer brushes (see scheme).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.