Sulfur stereogenic centers in transition-metal-catalyzed asymmetric C–H functionalization: generation and utilization

Transition-metal-catalyzed enantioselective C–H functionalization has emerged as a powerful tool for the synthesis of enantioenriched compounds in chemical and pharmaceutical industries. Sulfur-based functionalities are ubiquitous in many of the biologically active compounds, medicinal agents, functional materials, chiral auxiliaries and ligands. This perspective highlights recent advances in sulfur functional group enabled transition-metal-catalyzed enantioselective C–H functionalization for the construction of sulfur stereogenic centers, as well as the utilization of chiral sulfoxides to realize stereoselective C–H functionalization.

This perspective highlights sulfur functional groups enabled enantioselective C–H functionalization for the construction of sulfur stereogenic centers, and the utilization of chiral sulfoxide to realize stereoselective C–H functionalization.     

EDOT-based conjugated polymers accessed via C–H direct arylation for efficient photocatalytic hydrogen production

3,4-Ethylene dioxythiophene (EDOT), as a monomer of commercial conductive poly(3,4-ethylene dioxythiophene) (PEDOT), has been facilely incorporated into a series of new π-conjugated polymer-based photocatalysts, i.e., BSO₂–EDOT, DBT–EDOT, Py–EDOT and DFB–EDOT, through atom-economic C–H direct arylation polymerization (DArP). The photocatalytic hydrogen production (PHP) test shows that donor–acceptor (D–A)-type BSO₂–EDOT renders the highest hydrogen evolution rate (HER) among the linear conjugated polymers (CPs) ever reported. A HER up to 0.95 mmol h⁻¹/6 mg under visible light irradiation and an unprecedented apparent quantum yield of 13.6% at 550 nm are successfully achieved. Note that the photocatalytic activities of the C–H/C–Br coupling-derived EDOT-based CPs are superior to those of their counterparts derived from the classical C–Sn/C–Br Stille coupling, demonstrating that EDOT is a promising electron-rich building block which can be facilely integrated into CP-based photocatalysts. Systematic studies reveal that the enhanced water wettability by the integration of polar BSO₂ with hydrophilic EDOT, the increased electron-donating ability by O–C p–π conjugation, the improved electron transfer by D–A architecture, broad light harvesting, and the nano-sized colloidal character in a H₂O/NMP mixed solvent rendered BSO₂–EDOT as one of the best CP photocatalysts toward PHP.

The excellent reactivity toward C–H direct arylation, water wettability and O–C p–π conjugation endow EDOT to be an attractive electron donor unit for CP photocatalysts, yielding an unprecedented hydrogen evolution rate up to 0.95 mmol h⁻¹/6 mg catalyst.     

Flow electrochemistry: a safe tool for fluorine chemistry

The heightened activity of compounds containing fluorine, especially in the field of pharmaceuticals, provides major impetus for the development of new fluorination procedures. A scalable, versatile, and safe electrochemical fluorination protocol is conferred. The strategy proceeds through a transient (difluoroiodo)arene, generated by anodic oxidation of an iodoarene mediator. Even the isolation of iodine(iii) difluorides was facile since electrolysis was performed in the absence of other reagents. A broad range of hypervalent iodine mediated reactions were achieved in high yields by coupling the electrolysis step with downstream reactions in flow, surpassing limitations of batch chemistry. (Difluoroiodo)arenes are toxic and suffer from chemical instability, so the uninterrupted generation and immediate use in flow is highly advantageous. High flow rates facilitated productivities of up to 834 mg h⁻¹ with vastly reduced reaction times. Integration into a fully automated machine and in-line quenching was key in reducing the hazards surrounding the use of hydrofluoric acid.

A scalable, efficient and safe electrochemical fluorination protocol is conferred. A broad range of iodine(iii) mediated transformations were performed in high yields without exposure to toxic HF.     

Benzylic C–H isocyanation/amine coupling sequence enabling high-throughput synthesis of pharmaceutically relevant ureas

C(sp³)–H functionalization methods provide an ideal synthetic platform for medicinal chemistry; however, such methods are often constrained by practical limitations. The present study outlines a C(sp³)–H isocyanation protocol that enables the synthesis of diverse, pharmaceutically relevant benzylic ureas in high-throughput format. The operationally simple C–H isocyanation method shows high site selectivity and good functional group tolerance, and uses commercially available catalyst components and reagents [CuOAc, 2,2′-bis(oxazoline) ligand, (trimethylsilyl)isocyanate, and N-fluorobenzenesulfonimide]. The isocyanate products may be used without isolation or purification in a subsequent coupling step with primary and secondary amines to afford hundreds of diverse ureas. These results provide a template for implementation of C–H functionalization/cross-coupling in drug discovery.

A copper-based catalyst system composed of commercially available reagents enables C–H isocyanation with exquisite (hetero)benzylic site selectivity, enabling high-throughput access to pharmaceutically relevant ureas via coupling with amines.     

Polyoxometalates as chemically and structurally versatile components in self-assembled materials

Polyoxometalates (POMs) are anionic molecular metal oxides with expansive diversity in terms of their composition, structure, nuclearity and charge. Within this vast collection of compounds are dominant structural motifs (POM platforms), that are amenable to significant chemical tuning with minimal perturbation of the inorganic oxide molecular structure. Consequently, this enables the systematic investigation of these compounds as inorganic additives within materials whereby structure and charge can be tuned independently i.e. [PW₁₂O₄₀]³⁻vs. [SiW₁₂O₄₀]⁴⁻ while also investigating the impact of varying the charge balancing cations on self-assembly. The rich surface chemistry of POMs also supports their functionalisation by organic components to yield so-called inorganic–organic hybrids which will be the key focus of this perspective. We will introduce the modifications possible for each POM platform, as well as discussing the range of nanoparticles, microparticles and surfaces that have been developed using both surfactant and polymer building blocks. We will also illustrate important examples of POM-hybrids alongside their potential utility in applications such as imaging, therapeutic delivery and energy storage.

Polyoxometalates are anionic molecular metal oxides with diversity in composition, structure, nuclearity and charge. Their adaptable chemistry leads to potential for self-assembly with other building blocks into a variety of hybrid structures.     

Plasmonic O2 dissociation and spillover expedite selective oxidation of primary C–H bonds

Manipulating O₂ activation via nanosynthetic chemistry is critical in many oxidation reactions central to environmental remediation and chemical synthesis. Based on a carefully designed plasmonic Ru/TiO_2−x catalyst, we first report a room-temperature O₂ dissociation and spillover mechanism that expedites the “dream reaction” of selective primary C–H bond activation. Under visible light, surface plasmons excited in the negatively charged Ru nanoparticles decay into hot electrons, triggering spontaneous O₂ dissociation to reactive atomic ˙O. Acceptor-like oxygen vacancies confined at the Ru–TiO₂ interface free Ru from oxygen-poisoning by kinetically boosting the spillover of ˙O from Ru to TiO₂. Evidenced by an exclusive isotopic O-transfer from ¹⁸O₂ to oxygenated products, ˙O displays a synergistic action with native ˙O₂⁻ on TiO₂ that oxidizes toluene and related alkyl aromatics to aromatic acids with extremely high selectivity. We believe the intelligent catalyst design for desirable O₂ activation will contribute viable routes for synthesizing industrially important organic compounds.

Room-temperature O₂ dissociation and spillover, as driven by plasmonic Ru on oxygen-deficient TiO₂, expedite the selective oxidation of primary C–H bonds in alkyl aromatics for synthesizing industrially important organic compounds.     

Organocatalytic enantioselective SN1-type dehydrative nucleophilic substitution: access to bis(indolyl)methanes bearing quaternary carbon stereocenters

A highly general and straightforward approach to access chiral bis(indolyl)methanes (BIMs) bearing quaternary stereocenters has been realized via enantioconvergent dehydrative nucleophilic substitution. A broad range of 3,3′-, 3,2′- and 3,1′-BIMs were obtained under mild conditions with excellent efficiency and enantioselectivity (80 examples, up to 98% yield and >99 : 1 er). By utilizing racemic 3-indolyl tertiary alcohols as precursors of alkyl electrophiles and indoles as C–H nucleophiles, this organocatalytic strategy avoids pre-activation of substrates and produces water as the only by-product. Mechanistic studies suggest a formal S_N1-type pathway enabled by chiral phosphoric acid catalysis. The practicability of the obtained enantioenriched BIMs was further demonstrated by versatile transformation and high antimicrobial activities (3al, MIC: 1 μg mL⁻¹).

A highly general and straightforward approach to access chiral bis(indolyl)methanes (BIMs) bearing quaternary stereocenters has been realized via enantioconvergent dehydrative nucleophilic substitution.     

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.     

A general strategy for the synthesis of α-trifluoromethyl- and α-perfluoroalkyl-β-lactams via palladium-catalyzed carbonylation

β-Lactam compounds play a key role in medicinal chemistry, specifically as the most important class of antibiotics. Here, we report a novel one-step approach for the synthesis of α-(trifluoromethyl)-β-lactams and related products from fluorinated olefins, anilines and CO. Utilization of an advanced palladium catalyst system with the Ruphos ligand allows for selective cycloaminocarbonylations to give diverse fluorinated β-lactams in high yields.

β-Lactam compounds play a key role in medicinal chemistry, specifically as the most important class of antibiotics.     

Pinkment: a synthetic platform for the development of fluorescent probes for diagnostic and theranostic applications

Reaction-based fluorescent-probes have proven successful for the visualisation of biological species in various cellular processes. Unfortunately, in order to tailor the design of a fluorescent probe to a specific application (i.e. organelle targeting, material and theranostic applications) often requires extensive synthetic efforts and the synthetic screening of a range of fluorophores to match the required synthetic needs. In this work, we have identified Pinkment-OH as a unique “plug-and-play” synthetic platform that can be used to develop a range of ONOO⁻ responsive fluorescent probes for a variety of applications. These include theranostic-based applications and potential material-based/bioconjugation applications. The as prepared probes displayed an excellent sensitivity and selectivity for ONOO⁻ over other ROS. In vitro studies using HeLa cells and RAW 264.7 macrophages demonstrated their ability to detect exogenously and endogenously produced ONOO⁻. Evaluation in an LPS-induced inflammation mouse model illustrated the ability to monitor ONOO⁻ production in acute inflammation. Lastly, theranostic-based probes enabled the simultaneous evaluation of indomethacin-based therapeutic effects combined with the visualisation of an inflammation biomarker in RAW 264.7 cells.

Pinkment, a resorufin based ONOO⁻ selective and sensitive ‘plug and play’ fluorescence-based platform for in vitro and in vivo use, enables facile functionalisation for various imaging and theranostic applications.     

Unravelling the last milliseconds of an individual graphene nanoplatelet before impact with a Pt surface by bipolar electrochemistry

Contactless interactions of micro/nano-particles near electrochemically or chemically active interfaces are ubiquitous in chemistry and biochemistry. Forces arising from a convective field, an electric field or chemical gradients act on different scales ranging from few microns down to few nanometers making their study difficult. Here, we correlated optical microscopy and electrochemical measurements to track at the millisecond timescale the dynamics of individual two-dimensional particles, graphene nanoplatelets (GNPs), when approaching an electrified Pt micro-interface. Our original approach takes advantage of the bipolar feedback current recorded when a conducting particle approaches an electrified surface without electrical contact and numerical simulations to access the velocity of individual GNPs. We evidenced a strong deceleration of GNPs from few tens of μm s⁻¹ down to few μm s⁻¹ within the last μm above the surface. This observation reveals the existence of strongly non-uniform forces between tens of and a thousand nanometers from the surface.

The velocity of single GNP is monitored by contactless bipolar electrochemical feedback over the last hundreds of nm before collision on an electrode, and the variations shed light on the balance of forces acting on these objects near an interface.     

Nonspherical anion sequestration by C–H hydrogen bonding

Macrocyclic arenes laid the foundations of supramolecular chemistry and their study established the fundamentals of noncovalent interactions. Advancing their frontier, here we designed rigidified resorcin[4]arenes that serve as hosts for large nonspherical anions. In one synthetic step, we vary the host''s anion affinity properties by more than seven orders of magnitude. This is possible by engineering electropositive aromatic C–H bond donors in an idealized square planar geometry embedded within the host''s inner cavity. The hydrogen atom''s electropositivity is tuned by introducing fluorine atoms as electron withdrawing groups. These novel macrocycles, termed fluorocages, are engineered to sequester large anions. Indeed, experimental data shows an increase in the anion association constant (K_a) as the number of F atoms increase. The observed trend is rationalized by DFT calculations of Hirshfeld Charges (HCs). Most importantly, fluorocages in solution showed weak-to-medium binding affinity for large anions like [PF₆]⁻ (10²< K_a <10⁴ M⁻¹), and high affinity for [MeSO₃]⁻ (K_a >10⁶).

Fluorocages: new class of rigidified host utilizing nontraditional C–H hydrogen bonds to capture the nonspherical anions.     

Catalyst control of selectivity in the C–O bond alumination of biomass derived furans

Non-catalysed and catalysed reactions of aluminium reagents with furans, dihydrofurans and dihydropyrans were investigated and lead to ring-expanded products due to the insertion of the aluminium reagent into a C–O bond of the heterocycle. Specifically, the reaction of [{(ArNCMe)₂CH}Al] (Ar = 2,6-di-iso-propylphenyl, 1) with furans proceeded between 25 and 80 °C leading to dearomatised products due to the net transformation of a sp² C–O bond into a sp² C–Al bond. The kinetics of the reaction of 1 with furan were found to be 1st order with respect to 1 with activation parameters ΔH^‡ = +19.7 (±2.7) kcal mol⁻¹, ΔS^‡ = −18.8 (±7.8) cal K⁻¹ mol⁻¹ and ΔG^‡_{298 K} = +25.3 (±0.5) kcal mol⁻¹ and a KIE of 1.0 ± 0.1. DFT calculations support a stepwise mechanism involving an initial (4 + 1) cycloaddition of 1 with furan to form a bicyclic intermediate that rearranges by an α-migration. The selectivity of ring-expansion is influenced by factors that weaken the sp² C–O bond through population of the σ*-orbital. Inclusion of [Pd(PCy₃)₂] as a catalyst in these reactions results in expansion of the substrate scope to include 2,3-dihydrofurans and 3,4-dihydropyrans and improves selectivity. Under catalysed conditions, the C–O bond that breaks is that adjacent to the sp²C–H bond. The aluminium(iii) dihydride reagent [{(MesNCMe)₂CH}AlH₂] (Mes = 2,4,6-trimethylphenyl, 2) can also be used under catalytic conditions to effect a dehydrogenative ring-expansion of furans. Further mechanistic analysis shows that C–O bond functionalisation occurs via an initial C–H bond alumination. Kinetic products can be isolated that are derived from installation of the aluminium reagent at the 2-position of the heterocycle. C–H alumination occurs with a KIE of 4.8 ± 0.3 consistent with a turnover limiting step involving oxidative addition of the C–H bond to the palladium catalyst. Isomerisation of the kinetic C–H aluminated product to the thermodynamic C–O ring expansion product is an intramolecular process that is again catalysed by [Pd(PCy₃)₂]. DFT calculations suggest that the key C–O bond breaking step involves attack of an aluminium based metalloligand on the 2-palladated heterocycle. The new methodology has been applied to important platform chemicals from biomass.

Non-catalysed and catalysed reactions of aluminium reagents with furans, dihydrofurans and dihydropyrans were investigated and lead to ring-expanded products due to the insertion of the aluminium reagent into a C–O bond of the heterocycle.     

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.     

Torsional strain inversed chemoselectivity in a Pd-catalyzed atroposelective carbonylation reaction of dibenzothiophenium

A palladium-catalyzed enantioselective ring-opening/carbonylation of cyclic diarylsulfonium salts is reported. In comparison to thioethers, the sulfonium salts displayed high reactivity and enabled the reaction to be performed under mild conditions (room temperature). The steric repulsion of the two non-hydrogen substituents adjacent to the axis led cyclic diarylsulfonium salts to be distorted, which enabled the ring-opening reaction to proceed with significant preference for breaking the exocyclic C–S bond.

Torsional strain inversed chemoselectivity: from bond a to bond b.     

Low power threshold photochemical upconversion using a zirconium(iv) LMCT photosensitizer

The current investigation demonstrates highly efficient photochemical upconversion (UC) where a long-lived Zr(iv) ligand-to-metal charge transfer (LMCT) complex serves as a triplet photosensitizer in concert with well-established 9,10-diphenylanthracene (DPA) along with newly conceived DPA–carbazole based acceptors/annihilators in THF solutions. The initial dynamic triplet–triplet energy transfer (TTET) processes (ΔG ∼ −0.19 eV) featured very large Stern–Volmer quenching constants (K_SV) approaching or achieving 10⁵ M⁻¹ with bimolecular rate constants between 2 and 3 × 10⁸ M⁻¹ s⁻¹ as ascertained using static and transient spectroscopic techniques. Both the TTET and subsequent triplet–triplet annihilation (TTA) processes were verified and throughly investigated using transient absorption spectroscopy. The Stern–Volmer metrics support 95% quenching of the Zr(iv) photosensitizer using modest concentrations (0.25 mM) of the various acceptor/annihilators, where no aggregation took place between any of the chromophores in THF. Each of the upconverting formulations operated with continuous-wave linear incident power dependence (λ_ex = 514.5 nm) down to ultralow excitation power densities under optimized experimental conditions. Impressive record-setting η_UC values ranging from 31.7% to 42.7% were achieved under excitation conditions (13 mW cm⁻²) below that of solar flux integrated across the Zr(iv) photosensitizer''s absorption band (26.7 mW cm⁻²). This study illustrates the importance of supporting the continued development and discovery of molecular-based triplet photosensitizers based on earth-abundant metals.

The LMCT photosensitizer Zr(^MesPDP^Ph)₂ paired with DPA-based acceptors enabled low power threshold photochemical upconversion with record-setting quantum efficiencies.     

Carbon–carbon bond activation by B(OMe)3/B2pin2-mediated fragmentation borylation

Selective carbon–carbon bond activation is important in chemical industry and fundamental organic synthesis, but remains challenging. In this study, non-polar unstrained Csp²–Csp³ and Csp²–Csp² bond activation was achieved by B(OMe)₃/B₂pin₂-mediated fragmentation borylation. Various indole derivatives underwent C2-regioselective C–C bond activation to afford two C–B bonds under transition-metal-free conditions. Preliminary mechanistic investigations suggested that C–B bond formation and C–C bond cleavage probably occurred in a concerted process. This new reaction mode will stimulate the development of reactions based on inert C–C bond activation.

Non-polar unstrained Csp²–Csp³ and Csp²–Csp² bond activation was achieved via B(OMe)₃/B₂pin₂-mediated fragmentation borylation, in which C–C bond activation occurred regioselectively at the C2-position in various substituted indoles.     

Intramitochondrial co-assembly between ATP and nucleopeptides induces cancer cell apoptosis

Mitochondria are essential intracellular organelles involved in many cellular processes, especially adenosine triphosphate (ATP) production. Since cancer cells require high ATP levels for proliferation, ATP elimination can be a unique target for cancer growth inhibition. We describe a newly developed mitochondria-targeting nucleopeptide (MNP) that sequesters ATP by self-assembling with ATP inside mitochondria. MNP interacts strongly with ATP through electrostatic and hydrogen bonding interactions. MNP exhibits higher binding affinity for ATP (−637.5 kJ mol⁻¹) than for adenosine diphosphate (ADP) (−578.2 kJ mol⁻¹). To improve anticancer efficacy, the small-sized MNP/ADP complex formed large assemblies with ATP inside cancer cell mitochondria. ATP sequestration and formation of large assemblies of the MNP/ADP–ATP complex inside mitochondria caused physical stress by large structures and metabolic disorders in cancer cells, leading to apoptosis. This work illustrates a facile approach to developing cancer therapeutics that relies on molecular assemblies.

Mitochondria-targeting nucleopeptide (MNP) can sequester ATP by self-assembling with ATP. A small nanosized MNP/ADP complex forms a large assembly with ATP. Thus, intramitochondrial co-assembly causes stress by large structures and apoptosis.     

Sequential C–O decarboxylative vinylation/C–H arylation of cyclic oxalates via a nickel-catalyzed multicomponent radical cascade

A selective, sequential C–O decarboxylative vinylation/C–H arylation of cyclic alcohol derivatives enabled by visible-light photoredox/nickel dual catalysis is described. This protocol utilizes a multicomponent radical cascade process, i.e. decarboxylative vinylation/1,5-HAT/aryl cross-coupling, to achieve efficient, site-selective dual-functionalization of saturated cyclic hydrocarbons in one single operation. This synergistic protocol provides straightforward access to sp³-enriched scaffolds and an alternative retrosynthetic disconnection to diversely functionalized saturated ring systems from the simple starting materials.

A selective, sequential C–O decarboxylative vinylation/C–H arylation of cyclic alcohol derivatives enabled by visible-light photoredox/nickel dual catalysis has been described.     

Photoinduced metal-free borylation of aryl halides catalysed by an in situ formed donor–acceptor complex

Organoboron compounds are very important building blocks which can be applied in medicinal, biological and industrial fields. However, direct borylation in a metal free manner has been very rarely reported. Herein, we described the successful direct borylation of haloarenes under mild, operationally simple, catalyst-free conditions, promoted by irradiation with visible light. Mechanistic experiments and computational investigations indicate the formation of an excited donor–acceptor complex with a −3.12 V reduction potential, which is a highly active reductant and can facilitate single-electron-transfer (SET) with aryl halides to produce aryl radical intermediates. A two-step one-pot method was developed for site selective aromatic C–H bond borylation. The protocol''s good functional group tolerance enables the functionalization of a variety of biologically relevant compounds, representing a new application of aryl radicals merged with photochemistry.

We reported a facile metal-free conversion of aryl halides to the corresponding boronic esters catalysed by an in situ formed donor–acceptor complex. A two-step one-pot method was also developed for site selective aromatic C–H bond borylation.