C(sp3)–H oxygenation via alkoxypalladium(ii) species: an update for the mechanism

Pd-catalyzed C(sp³)–H oxygenation has emerged as an attractive strategy for organic synthesis. The most commonly proposed mechanism involves C(sp³)–H activation followed by oxidative addition of an oxygen electrophile to give an alkylpalladium(iv) species and further C(sp³)–O reductive elimination. In the present study of γ-C(sp³)–H acyloxylation of amine derivatives, we show a different mechanism when tert-butyl hydroperoxide (TBHP) is used as an oxidant—namely, a bimetallic oxidative addition-oxo-insertion process. This catalytic model results in an alkoxypalladium(ii) intermediate from which acyloxylation and alkoxylation products are formed. Experimental and computational studies, including isolation of the putative post-oxo-insertion alkoxypalladium(ii) intermediates, support this mechanistic model. Density functional theory reveals that the classical alkylpalladium(iv) oxidative addition pathway is higher in energy than the bimetallic oxo-insertion pathway. Further kinetic studies revealed second-order dependence on [Pd] and first-order on [TBHP], which is consistent with DFT analysis. This procedure is compatible with a wide range of acids and alcohols for γ-C(sp³)–H oxygenation. Preliminary functional group transformations of the products underscore the great potential of this protocol for structural manipulation.

Alkoxypalladium(ii) species lead to γ-C(sp³)–H acyloxylation and alkoxylation products using tert-butyl hydroperoxide as the oxidant.     

Between imide,imidyl and nitrene – an imido iron complex in two oxidation states

Imidyl and nitrene metal species play an important role in the N-functionalisation of unreactive C–H bonds as well as the aziridination of olefines. We report on the synthesis of the trigonal imido iron complexes [Fe(NMes)L₂]^0,− (L = –N{Dipp}SiMe₃); Dipp = 2,6-diisopropyl-phenyl; Mes = (2,4,6-trimethylphenyl) via reaction of mesityl azide (MesN₃) with the linear iron precursors [FeL₂]^0,−. UV-vis-, EPR-, ⁵⁷Fe Mössbauer spectroscopy, magnetometry, and computational methods suggest for the reduced form an electronic structure as a ferromagnetically coupled iron(ii) imidyl radical, whereas oxidation leads to mixed iron(iii) imidyl and electrophilic iron(ii) nitrene character. Reactivity studies show that both complexes are capable of H atom abstraction from C–H bonds. Further, the reduced form [Fe(NMes)L₂]⁻ reacts nucleophilically with CS₂ by inserting into the imido iron bond, as well as electrophilically with CO under nitrene transfer. The neutral [Fe(NMes)L₂] complex shows enhanced electrophilic behavior as evidenced by nitrene transfer to a phosphine, yet in combination with an overall reduced reactivity.

A pair of trigonal imido iron complexes ([Fe(NMes)L₂]^0,−) in two oxidation states is reported. The anionic complex K{crypt.222}[Fe(NMes)L₂] is best described as an iron(ii) imide.     

Site-selective coupling of remote C(sp3)–H/meta-C(sp2)–H bonds enabled by Ru/photoredox dual catalysis and mechanistic studies

Construction of C(sp²)–C(sp³) bonds via regioselective coupling of C(sp²)–H/C(sp³)–H bonds is challenging due to the low reactivity and regioselectivity of C–H bonds. Here, a novel photoinduced Ru/photocatalyst-cocatalyzed regioselective cross-dehydrogenative coupling of dual remote C–H bonds, including inert γ-C(sp³)–H bonds in amides and meta-C(sp²)–H bonds in arenes, to construct meta-alkylated arenes has been accomplished. This metallaphotoredox-enabled site-selective coupling between remote inert C(sp³)–H bonds and meta-C(sp²)–H bonds is characterized by its unique site-selectivity, redox-neutral conditions, broad substrate scope and wide use of late-stage functionalization of bioactive molecules. Moreover, this reaction represents a novel case of regioselective cross-dehydrogenative coupling of unactivated alkanes and arenes via a new catalytic process and provides a new strategy for meta-functionalized arenes under mild reaction conditions. Density functional theory (DFT) calculations and control experiments explained the site-selectivity and the detailed mechanism of this reaction.

A novel photoinduced Ru/photocatalyst-cocatalyzed regioselective cross-dehydrogenative coupling of dual remote C–H bonds, including inert γ-C(sp³)–H bonds in amides and meta-C(sp²)–H bonds in arenes, to construct meta-alkylated arenes has been accomplished.     

Exploring benzylic gem-C(sp3)–boron–silicon and boron–tin centers as a synthetic platform

A stepwise build-up of multi-substituted C_sp³ carbon centers is an attractive, conceptually simple, but often synthetically challenging type of disconnection. To this end, this report describes how gem-α,α-dimetalloid-substituted benzylic reagents bearing boron/silicon or boron/tin substituent sets are an excellent stepping stone towards diverse substitution patterns. These gem-dimetalloids were readily accessed, either by known carbenoid insertion into C–B bonds or by the newly developed scalable deprotonation/metallation approach. Highly chemoselective transformations of either the C–Si (or C–Sn) or the C–B bonds in the newly formed gem-C_sp³ centers have been achieved through a set of approaches, with a particular focus on exploiting the synthetically versatile polarity reversal in organometalloids by λ³-aryliodanes. Of particular note is the metal-free arylation of the C–Si (or C–Sn) bonds in such gem-dimetalloids via the iodane-guided C–H coupling approach. DFT calculations show that this transfer of the (α-Bpin)benzyl group proceeds via unusual [5,5]-sigmatropic rearrangement and is driven by the high-energy iodine(iii) center. As a complementary tool, the gem-dimetalloid C–B bond is shown to undergo a potent and chemoselective Suzuki–Miyaura arylation with diverse Ar–Cl, thanks to the development of the reactive gem-α,α-silyl/BF₃K building blocks.

This work explores divergent reactivity of the benzylic gem-boron–silicon and boron–tin double nucleophiles, including the arylation of the C–B bond with Ar–Cl, along with a complementary oxidative λ³-iodane-guided arylation of the C–Si/Sn moiety.     

DFT insight into asymmetric alkyl–alkyl bond formation via nickel-catalysed enantioconvergent reductive coupling of racemic electrophiles with olefins

A DFT study has been conducted to understand the asymmetric alkyl–alkyl bond formation through nickel-catalysed reductive coupling of racemic alkyl bromide with olefin in the presence of hydrosilane and K₃PO₄. The key findings of the study include: (i) under the reductive experimental conditions, the Ni(ii) precursor is easily activated/reduced to Ni(0) species which can serve as an active species to start a Ni(0)/Ni(ii) catalytic cycle. (ii) Alternatively, the reaction may proceed via a Ni(i)/Ni(ii)/Ni(iii) catalytic cycle starting with a Ni(i) species such as Ni(i)–Br. The generation of a Ni(i) active species via comproportionation of Ni(ii) and Ni(0) species is highly unlikely, because the necessary Ni(0) species is strongly stabilized by olefin. Alternatively, a cage effect enabled generation of a Ni(i) active catalyst from the Ni(ii) species involved in the Ni(0)/Ni(ii) cycle was proposed to be a viable mechanism. (iii) In both catalytic cycles, K₃PO₄ greatly facilitates the hydrosilane hydride transfer for reducing olefin to an alkyl coupling partner. The reduction proceeds by converting a Ni–Br bond to a Ni–H bond via hydrosilane hydride transfer to a Ni–alkyl bond via olefin insertion. On the basis of two catalytic cycles, the origins for enantioconvergence and enantioselectivity control were discussed.

The enantioconvergent alkyl–alkyl coupling involves two competitive catalytic cycles with nickel(0) and nickel(i) active catalysts, respectively. K₃PO₄ plays a crucial role to enable the hydride transfer from hydrosilane to nickel–bromine species.     

Temperature-modulated selective C(sp3)–H or C(sp2)–H arylation through palladium catalysis

Transition metal-catalysed C–H bond functionalisations have been extensively developed in organic and medicinal chemistry. Among these catalytic approaches, the selective activation of C(sp³)–H and C(sp²)–H bonds is particularly appealing for its remarkable synthetic versatility, yet it remains highly challenging. Herein, we demonstrate the first example of temperature-dependent selective C–H functionalisation of unactivated C(sp³)–H or C(sp²)–H bonds at remote positions through palladium catalysis using 7-pyridyl-pyrazolo[1,5-a]pyrimidine as a new directing group. At 120 °C, C(sp³)–H arylation was triggered by the chelation of a rare [6,5]-fused palladacycle, whereas at 140 °C, C(sp²)–H arylation proceeded instead through the formation of a 16-membered tetramer containing four 7-pyridyl-pyrazolo[1,5-a]pyrimidine–palladium chelation units. The subsequent mechanistic study revealed that both C–H activations shared a common 6-membered palladacycle intermediate, which was then directly transformed to either the [6,5]-fused palladacycle for C(sp³)–H activation at 120 °C or the tetramer for C(sp²)–H arylation at 140 °C with catalytic amounts of Pd(OAc)₂ and AcOH. Raising the temperature from 120 °C to 140 °C can also convert the [6,5]-fused palladacycle to the tetramer with the above-mentioned catalysts, hence completing the C(sp²)–H arylation ultimately.

Unprecedented 16-membered tetramer or [6,5]-fused palladacycle, mutually shadowboxing-like transformed from the shared common intermediate, accomplishes the Pd-catalysed temperature-dependent selective arylation of C(sp²)–H or C(sp³)–H.     

Copper(ii) ketimides in sp3 C–H amination

Commercially available benzophenone imine (HN CPh₂) reacts with β-diketiminato copper(ii) tert-butoxide complexes [Cu^II]–O^tBu to form isolable copper(ii) ketimides [Cu^II]–N CPh₂. Structural characterization of the three coordinate copper(ii) ketimide [Me₃NN]Cu–N CPh₂ reveals a short Cu-N_ketimide distance (1.700(2) Å) with a nearly linear Cu–N–C linkage (178.9(2)°). Copper(ii) ketimides [Cu^II]–N CPh₂ readily capture alkyl radicals R˙ (PhCH(˙)Me and Cy˙) to form the corresponding R–N CPh₂ products in a process that competes with N–N coupling of copper(ii) ketimides [Cu^II]–N CPh₂ to form the azine Ph₂C N–N CPh₂. Copper(ii) ketimides [Cu^II]–N CAr₂ serve as intermediates in catalytic sp³ C–H amination of substrates R–H with ketimines HN CAr₂ and ^tBuOO^tBu as oxidant to form N-alkyl ketimines R–N CAr₂. This protocol enables the use of unactivated sp³ C–H bonds to give R–N CAr₂ products easily converted to primary amines R–NH₂via simple acidic deprotection.

Commercially available benzophenone imine (HN CPh₂) reacts with β-diketiminato copper(ii) tert-butoxide complexes [Cu^II]–O^tBu to form isolable copper(ii) ketimides [Cu^II]–N CPh₂ that serve as intermediates in catalytic sp³ C−H amination via radical relay.     

Photoinduced C(sp3)–H sulfination empowers the direct and chemoselective introduction of the sulfonyl group

Direct installation of the sulfinate group by the functionalization of unreactive aliphatic C–H bonds can provide access to most classes of organosulfur compounds, because of the central position of sulfinates as sulfonyl group linchpins. Despite the importance of the sulfonyl group in synthesis, medicine, and materials science, a direct C(sp³)–H sulfination reaction that can convert abundant aliphatic C–H bonds to sulfinates has remained elusive, due to the reactivity of sulfinates that are incompatible with typical oxidation-driven C–H functionalization approaches. We report herein a photoinduced C(sp³)–H sulfination reaction that is mediated by sodium metabisulfite and enables access to a variety of sulfinates. The reaction proceeds with high chemoselectivity and moderate to good regioselectivity, affording only monosulfination products and can be used for a solvent-controlled regiodivergent distal C(sp³)–H functionalization.

The photoinduced C–H sulfination of abundant aliphatic C–H bonds provides direct access to all major classes of organosulfur compounds via the intermediacy of synthetically versatile sulfinate salts.     

Ligand-field transition-induced C–S bond formation from nickelacycles

Photoexcitation is one of the acknowledged methods to activate Ni-based cross-coupling reactions, but factors that govern the photoactivity of organonickel complexes have not yet been established. Here we report the excited-state cross-coupling activities of Ni(ii) metallacycle compounds, which display ∼10⁴ times enhancement for the C–S bond-forming reductive elimination reaction upon Ni-centered ligand-field transitions. The effects of excitation energy and ancillary ligands on photoactivity have been investigated with 17 different nickelacycle species in combination with four corresponding acyclic complexes. Spectroscopic and computational electronic structural characterizations reveal that, regardless of coordinated species, d–d transitions can induce Ni–C bond homolysis, and that the reactivity of the resulting Ni(i) species determines the products of the overall reaction. The photoactivity mechanism established in this study provides general insights into the excited-state chemistry of organonickel(ii) complexes.

d–d excitations can accelerate C–S reductive eliminations of nickelacycles via intersystem crossing to a repulsive ³(C-to-Ni charge transfer) state inducing Ni–C bond homolysis. This homolytic photoreactivity is common for organonickel(ii) complexes.     

Controlled monodefluorination and alkylation of C(sp3)–F bonds by lanthanide photocatalysts: importance of metal–ligand cooperativity

The controlled functionalization of a single fluorine in a CF₃ group is difficult and rare. Photochemical C–F bond functionalization of the sp³-C–H bond in trifluorotoluene, PhCF₃, is achieved using catalysts made from earth-abundant lanthanides, (Cp^Me4)₂Ln(2-O-3,5-^tBu₂-C₆H₂)(1-C{N(CH)₂N(ⁱPr)}) (Ln = La, Ce, Nd and Sm, Cp^Me4 = C₅Me₄H). The Ce complex is the most effective at mediating hydrodefluorination and defluoroalkylative coupling of PhCF₃ with alkenes; addition of magnesium dialkyls enables catalytic C–F bond cleavage and C–C bond formation by all the complexes. Mechanistic experiments confirm the essential role of the Lewis acidic metal and support an inner-sphere mechanism of C–F activation. Computational studies agree that coordination of the C–F substrate is essential for C–F bond cleavage. The unexpected catalytic activity for all members is made possible by the light-absorbing ability of the redox non-innocent ligands. The results described herein underscore the importance of metal–ligand cooperativity, specifically the synergy between the metal and ligand in both light absorption and redox reactivity, in organometallic photocatalysis.

The controlled functionalization of a single fluorine in a CF₃ group is difficult and rare. Photochemical C–F bond functionalization is achieved using catalysts made from a range of earth-abundant lanthanides by using a ligand that enables M–L cooperativity.

Photoredox catalysis is a powerful synthetic method for the functionalization of inert molecules using single electron transfer (SET) reactivity^1–3 under irradiation with visible light.⁴ This has enabled challenging transformations under mild conditions including C–H activation,^5–7 radical cross-coupling,^8–11 and the valorization of lignin.^12,13 However, detailed mechanistic studies of photoredox systems are difficult due to their inherent complexity and the short lifetimes of photoexcited intermediates.Many lanthanides are more abundant in the environment than copper and their salts are less toxic than those of iron, so their potential for applications in catalysis merits exploration.^14–17 In 1990, divalent Sm, Eu, and Yb complexes Ln(Cp*)₂ (Cp* = C₅Me₅), were shown to more efficiently cleave vinylic C–F bonds when photolyzed, stoichiometrically forming Ln(iii) halide complexes, and suggesting the value of increasing the reducing power of the Ln^II excited state.¹⁸ Subsequently, analogous reactions to cleave the weaker C–Cl and C–Br bonds could be made catalytic in Ln(ii) halide (Ln = Sm, Eu, Yb), under near UV-photolysis conditions, by the addition of sacrificial reductant such as Zn or Al.^19,20 The addition of simple donor ligands enabled benzylic C–Cl cleavage by Eu^II under blue light irradiation.²¹ The addition of an organic photocatalyst or a photo-absorbing substrate to Lewis acidic LnX₃ salts (X = halide, triflate) has also been used to enhance the catalysis.²² Ln centers (Ln = Nd, Dy, Lu) with light-absorbing ligands such as porphyrins or phthalocyanins have been used to stoichiometrically dechlorinate phenols.²³Few reports of lanthanide photoredox catalysis exist with Ce^III complexes receiving the most attention. Ce possesses both an accessible III/IV redox couple and an allowed excitation from the 4f¹ ground state to the 5d¹ excited state, which can give rise to luminescent behaviour. It is also the cheapest and most readily isolated of the rare earths, offering a promising alternative to current precious metal photocatalysts.Building on the pioneering work on stoichiometric photoluminescent Ce chemistry,^24,25 in 2015 Schelter and co-workers demonstrated the utility of Ce^III in photocatalysis.^26,27 Their Ce^III amido complexes were catalysts for chlorine atom abstraction from benzyl chloride (Fig. 1, top), with both NaN(SiMe₃)₂ and additional Ce⁰ required for turnover.²⁸Open in a separate windowFig. 1Previous examples of photocatalytic C–X (X = halide) bond cleavage, and this work.They proposed an inner-sphere mechanism involving Ce⋯ClCR₃ adduct formation that provides an additional thermodynamic driving force to a bond cleavage that was otherwise out of range of the reducing power of the Ce excited state. A more sterically congested Ce^III tris(guanidinate) operates via an outer-sphere single electron transfer (SET) mechanism to cleave aryl iodides,²⁸ highlighting the mechanistic diversity that is possible in these systems.²⁹To date, ligands that support lanthanide-centered photocatalysts have been limited to halides, pseudohalides, and simple N-donors.^30,31 No organometallic lanthanide photocatalyst has yet been reported that combines the photoexcitable Ce cation with multidentate, tunable ligands. We have developed organometallic lanthanide complexes as sustainable catalysts,^16,17,32,33 and considered that those capable of forming an inner-sphere adduct, and absorbing light, could achieve the unusual and difficult, selective catalytic conversion of strong sp³ C–F bonds.Fluorine forms the strongest single bond to carbon and the C–F bond is ca. 25 kcal mol⁻¹ stronger than the C–Cl bond in monohaloalkanes, and the C–H bond in alkanes.³⁴ The selective activation and functionalization of C–F bonds is important, both due to the high bioaccumulation and toxicity of many perfluorinated compounds,³⁵ and the utility of fluorinated pharmaceuticals.³⁶ However, stoichiometric C(sp³)–F bond activation reactions are rare.^37–40 In particular, it is difficult to facilitate the controlled cleavage of a single C–F bond as the C(sp³)–F bond strength decreases as each F is removed and the remaining C–F bonds lengthen.^41,42This obstacle makes a radical methodology more attractive.^43–49 Jui and co-workers have demonstrated that some common photocatalysts can selectively activate a single C–F bond to form the putative ArCF₂˙ radical, which can either be quenched directly via H atom transfer (HAT), or coupled with an alkene followed by HAT to generate difluoroalkanes (Fig. 1, middle).^50,51 Gschwind and König have shown the photochemical functionalization of electron-poor trifluoromethylarenes.⁵² Nishimoto and Yasuda have described related C–F coupling protocols of perfluoroalkylarenes using tin reagents and an iridium photocatalyst.⁵³Here we show how selective, catalytic C–F bond functionalization can be achieved using a new family of Ln^III compounds supported by a light-absorbing aryloxide-tethered N-heterocyclic carbene, Cp^Me4, and pseudohalide ligands (Fig. 1, lower). We show that visible light-irradiated Ce complexes can selectively abstract a single fluoride from PhCF₃ and catalyze its alkylation by MgR₂ to afford PhCF₂R. The PhCF₂˙ can also be quenched to selectively form PhCF₂H or further alkylated via coupling with an alkene or other metal alkyls. We use combined experiment and density functional theory (DFT) computations to show the importance of coordination of the fluorinated substrate to the Lewis acidic metal in C–F activation, and the utility of the ligand in enabling photoredox catalysis for other lanthanide congeners.     

Asymmetric C–H functionalization of cyclopropanes using an isoleucine-NH2 bidentate directing group

The systematic investigation of substrate-bound α-amino acid auxiliaries has resulted in catalytic asymmetric C–H functionalization of cyclopropanes enabled by amino acid amides as chiral bidentate directing groups. The use of an Ile-NH₂ auxiliary embedded in the substrate provided excellent levels of asymmetric induction (diastereomeric ratio of up to 72 : 1) in the Pd(ii)-catalyzed β-methylene C(sp³)–H bond activation of cyclopropanes and cross-coupling with aryl iodides.     

Cu(i) catalysis for selective condensation/bicycloaromatization of two different arylalkynes: direct and general construction of functionalized C–N axial biaryl compounds

Selective condensation/bicycloaromatization of two different arylalkynes is firstly developed under ligand-free copper(i)-catalysis, which allows the direct synthesis of C–N axial biaryl compounds in high yields with excellent selectivity and functional group tolerance. Due to the critical effects of Cu(i) catalyst and HFIP, many easily occurring undesired reactions are suppressed, and the coupled five–six aromatic rings are constructed via the selective formation of two C(sp²)–N(sp²) bonds and four C(sp²)–C(sp²) bonds. The achievement of moderate enantioselectivity verifies its potential for the simplest asymmetric synthesis of atropoisomeric biaryls. Western blotting demonstrated that the newly developed compounds are promising targets in biology and pharmaceuticals. This unique reaction can construct structurally diverse C–N axial biaryl compounds that have never been reported by other methods, and might be extended to various applications in materials, chemistry, biology, and pharmaceuticals.

Selective condensation/bicycloaromatization of two different arylalkynes is firstly developed under ligand-free copper(i)-catalysis, which allows the direct synthesis of C–N axial biaryl compounds in high yields with excellent selectivity and functional group tolerance.     

The role of hypervalent iodine(iii) reagents in promoting alkoxylation of unactivated C(sp3)–H bonds catalyzed by palladium(ii) complexes

Although Pd(OAc)₂-catalysed alkoxylation of the C(sp³)–H bonds mediated by hypervalent iodine(iii) reagents (ArIX₂) has been developed by several prominent researchers, there is no clear mechanism yet for such crucial transformations. In this study, we shed light on this important issue with the aid of the density functional theory (DFT) calculations for alkoxylation of butyramide derivatives. We found that the previously proposed mechanism in the literature is not consistent with the experimental observations and thus cannot be operating. The calculations allowed us to discover an unprecedented mechanism composed of four main steps as follows: (i) activation of the C(sp³)–H bond, (ii) oxidative addition, (iii) reductive elimination and (iv) regeneration of the active catalyst. After completion of step (i) via the CMD mechanism, the oxidative addition commences with an X ligand transfer from the iodine(iii) reagent (ArIX₂) to Pd(ii) to form a square pyramidal complex in which an iodonium occupies the apical position. Interestingly, a simple isomerization of the resultant five-coordinate complex triggers the Pd(ii) oxidation. Accordingly, the movement of the ligand trans to the Pd–C(sp³) bond to the apical position promotes the electron transfer from Pd(ii) to iodine(iii), resulting in the reduction of iodine(iii) concomitant with the ejection of the second X ligand as a free anion. The ensuing Pd(iv) complex then undergoes the C–O reductive elimination by nucleophilic attack of the solvent (alcohol) on the sp³ carbon via an outer-sphere S_N2 mechanism assisted by the X⁻ anion. Noteworthy, starting from the five coordinate complex, the oxidative addition and reductive elimination processes occur with a very low activation barrier (ΔG^‡ 0–6 kcal mol⁻¹). The strong coordination of the alkoxylated product to the Pd(ii) centre causes the regeneration of the active catalyst, i.e. step (iv), to be considerably endergonic, leading to subsequent catalytic cycles to proceed with a much higher activation barrier than the first cycle. We also found that although, in most cases, the alkoxylation reactions proceed via a Pd(ii)–Pd(iv)–Pd(ii) catalytic cycle, the other alternative in which the oxidation state of the Pd(ii) centre remains unchanged during the catalysis could be operative, depending on the nature of the organic substrate.

This work uses DFT calculations to explore Pd(ii)-catalysed iodine(iii)-mediated alkoxylation of unactivated C(sp³)–H bonds and reveals how important the isomerization is in triggering the oxidative addition of ArIX₂ to Pd(ii).     

Iron-catalysed alkene and heteroarene H/D exchange by reversible protonation of iron-hydride intermediates

C–H functionalisation reactions offer a sustainable method for molecular construction and diversification. These reactions however remain dominated by precious metal catalysis. While significant interest in iron-catalysed C–H activation reactions has emerged, the isolation, characterisation and mechanistic understanding of these processes remain lacking. Herein the iron-catalysed C(sp²)–H bond hydrogen/deuterium exchange reaction using CD₃OD is reported for both heterocycles and, for the first time, alkenes (38 examples). Isolation and characterisation, including by single-crystal X-ray diffraction, of the key iron-aryl and iron-alkenyl C–H metallation intermediates provided evidence for a reversible protonation of the active iron hydride catalyst. Good chemoselectivity was observed for both substrate classes. The developed procedure is orthogonal to previous iron-catalysed H/D exchange methods which used C₆D₆, D₂, or D₂O as the deuterium source, and uses only bench-stable reagents, including the iron(ii) pre-catalyst. Further, a new mechanism of iron-hydride formation is reported in which β-hydride elimination from an alcohol generates the iron hydride. The ability to produce, isolate and characterise the organometallic products arising from C–H activation presents a basis for future discovery and development.

The iron-catalysed C(sp²)–H bond H/D exchange reaction using CD₃OD is reported for both heterocycles and alkenes. Characterisation of the key C–H metallation intermediates provided evidence for reversible protonation of the iron hydride catalyst.     

Ruthenaelectro-catalyzed C–H acyloxylation for late-stage tyrosine and oligopeptide diversification

Ruthenaelectro(ii/iv)-catalyzed intermolecular C–H acyloxylations of phenols have been developed by guidance of experimental, CV and computational insights. The use of electricity bypassed the need for stoichiometric chemical oxidants. The sustainable electrocatalysis strategy was characterized by ample scope, and its unique robustness enabled the late-stage C–H diversification of tyrosine-derived peptides.

Ruthenaelectro(ii/iv)-catalyzed intermolecular C–H acyloxylations of oligopeptides have been developed by the guidance of key experimental, CV and computational insights.     

An iron(ii)-based metalloradical system for intramolecular amination of C(sp2)–H and C(sp3)–H bonds: synthetic applications and mechanistic studies

A catalytic system for intramolecular C(sp²)–H and C(sp³)–H amination of substituted tetrazolopyridines has been successfully developed. The amination reactions are developed using an iron-porphyrin based catalytic system. It has been demonstrated that the same iron-porphyrin based catalytic system efficiently activates both the C(sp²)–H and C(sp³)–H bonds of the tetrazole as well as azide-featuring substrates with a high level of regioselectivity. The method exhibited an excellent functional group tolerance. The method affords three different classes of high-value N-heterocyclic scaffolds. A number of important late-stage C–H aminations have been performed to access important classes of molecules. Detailed studies (experimental and computational) showed that both the C(sp²)–H and C(sp³)–H amination reactions involve a metalloradical activation mechanism, which is different from the previously reported electro-cyclization mechanism. Collectively, this study reports the discovery of a new class of metalloradical activation modes using a base metal catalyst that should find wide application in the context of medicinal chemistry, drug discovery and industrial applications.

A catalytic system for intramolecular C(sp²)–H and C(sp³)–H amination of substituted tetrazolopyridines has been successfully developed.     

Visible light driven deuteration of formyl C–H and hydridic C(sp3)–H bonds in feedstock chemicals and pharmaceutical molecules

Deuterium labelled compounds are of significant importance in chemical mechanism investigations, mass spectrometric studies, diagnoses of drug metabolisms, and pharmaceutical discovery. Herein, we report an efficient hydrogen deuterium exchange reaction using deuterium oxide (D₂O) as the deuterium source, enabled by merging a tetra-n-butylammonium decatungstate (TBADT) hydrogen atom transfer photocatalyst and a thiol catalyst under light irradiation at 390 nm. This deuteration protocol is effective with formyl C–H bonds and a wide range of hydridic C(sp³)–H bonds (e.g. α-oxy, α-thioxy, α-amino, benzylic, and unactivated tertiary C(sp³)–H bonds). It has been successfully applied to the high incorporation of deuterium in 38 feedstock chemicals, 15 pharmaceutical compounds, and 6 drug precursors. Sequential deuteration between formyl C–H bonds of aldehydes and other activated hydridic C(sp³)–H bonds can be achieved in a selective manner.

A selective hydrogen deuterium exchange reaction with formyl C–H bonds and a wide range of hydridic C(sp³)–H bonds has been achieved by merging tetra-n-butylammonium decatungstate photocatalyst and a thiol catalyst under 390 nm light irradiation.     

Recent development in transition metal-catalysed C–H olefination

Transition metal-catalysed functionalizations of inert C–H bonds to construct C–C bonds represent an ideal route in the synthesis of valuable organic molecules. Fine tuning of directing groups, catalysts and ligands has played a crucial role in selective C–H bond (sp² or sp³) activation. Recent developments in these areas have assured a high level of regioselectivity in C–H olefination reactions. In this review, we have summarized the recent progress in the oxidative olefination of sp² and sp³ C–H bonds with special emphasis on distal, atroposelective, non-directed sp² and directed sp³ C–H olefination. The scope, limitation, and mechanism of various transition metal-catalysed olefination reactions have been described briefly.

Transition metal-catalysed functionalizations of inert C–H bonds to construct C–C bonds represent an ideal route in the synthesis of valuable organic molecules.     

Inhibition of (dppf)nickel-catalysed Suzuki–Miyaura cross-coupling reactions by α-halo-N-heterocycles

A nickel/dppf catalyst system was found to successfully achieve the Suzuki–Miyaura cross-coupling reactions of 3- and 4-chloropyridine and of 6-chloroquinoline but not of 2-chloropyridine or of other α-halo-N-heterocycles. Further investigations revealed that chloropyridines undergo rapid oxidative addition to [Ni(COD)(dppf)] but that α-halo-N-heterocycles lead to the formation of stable dimeric nickel species that are catalytically inactive in Suzuki–Miyaura cross-coupling reactions. However, the corresponding Kumada–Tamao–Corriu reactions all proceed readily, which is attributed to more rapid transmetalation of Grignard reagents.

Nickel complexes with a dppf ligand can form inactive dinickel(ii) complexes during Suzuki–Miyaura cross-coupling reactions. However, these complexes can react with Grignard reagents in Kumada–Tamao–Corriu cross-coupling reactions.     

Photocatalytic C(sp3) radical generation via C–H,C–C,and C–X bond cleavage

C(sp³) radicals (R˙) are of broad research interest and synthetic utility. This review collects some of the most recent advancements in photocatalytic R˙ generation and highlights representative examples in this field. Based on the key bond cleavages that generate R˙, these contributions are divided into C–H, C–C, and C–X bond cleavages. A general mechanistic scenario and key R˙-forming steps are presented and discussed in each section.

C(sp³) radicals (R˙) are of broad research interest and synthetic utility.