Tritiation of aryl thianthrenium salts with a molecular palladium catalyst.

Tritium labelling is a critical tool for investigating the pharmacokinetic and pharmacodynamic properties of drugs, autoradiography, receptor binding and receptor occupancy studies1. Tritium gas is the preferred source of tritium for the preparation of labelled molecules because it is available in high isotopic purity2. The introduction of tritium labels from tritium gas is commonly achieved by heterogeneous transition-metal-catalysed tritiation of aryl (pseudo)halides. However, heterogeneous catalysts such as palladium supported on carbon operate through a reaction mechanism that also results in the reduction of other functional groups that are prominently featured in pharmaceuticals3. Homogeneous palladium catalysts can react chemoselectively with aryl (pseudo)halides but have not been used for hydrogenolysis reactions because, after required oxidative addition, they cannot split dihydrogen4. Here we report a homogenous hydrogenolysis reaction with a well defined, molecular palladium catalyst. We show how the thianthrene leaving group-which can be introduced selectively into pharmaceuticals by late-stage C-H functionalization5-differs in its coordinating ability to relevant palladium(II) catalysts from conventional leaving groups to enable the previously unrealized catalysis with dihydrogen. This distinct reactivity combined with the chemoselectivity of a well defined molecular palladium catalyst enables the tritiation of small-molecule pharmaceuticals that contain functionality that may otherwise not be tolerated by heterogeneous catalysts. The tritiation reaction does not require an inert atmosphere or dry conditions and is therefore practical and robust to execute, and could have an immediate impact in the discovery and development of pharmaceuticals.

Site-selective and versatile aromatic C-H functionalization by thianthrenation.

Direct C-H functionalization can quickly increase useful structural and functional molecular complexity1-3. Site selectivity can sometimes be achieved through appropriate directing groups or substitution patterns1-4-in the absence of such functionality, most aromatic C-H functionalization reactions provide more than one product isomer for most substrates1,4,5. Development of a C-H functionalization reaction that proceeds with high positional selectivity and installs a functional group that can serve as a synthetic linchpin for further functionalization would provide access to a large variety of well-defined arene derivatives. Here we report a highly selective aromatic C-H functionalization reaction that does not require a particular directing group or substitution pattern to achieve selectivity, and provides functionalized arenes that can participate in various transformations. We introduce a persistent sulfur-based radical to functionalize complex arenes with high selectivity and obtain thianthrenium salts that are ready to engage in different transformations, via both transition-metal and photoredox catalysis. This transformation differs fundamentally from all previous aromatic C-H functionalization reactions in that it provides direct access to a large number of derivatives of complex small molecules, quickly generating functional diversity with selectivity that is not achievable by other methods.

Ruthenium Phenoxo Complexes: An Isolobal Ligand to Cp with Improved Properties.

Catalytic π-arene activation is based on catalysts that allow for arene exchange. To date, cyclopentadiene (Cp)-derived catalysts are the most commonly used in π-arene activation despite their low arene exchange rates. Herein, we report the synthesis, analysis, and catalytic application of Ru(II) complexes supported by phenoxo ligands, which are isolobal alternatives to Cp. The phenoxo complexes exhibit arene exchange rates significantly faster than those of the corresponding Cp complexes. The rate can be further increased through the choice of appropriate counterions. The mechanism of the arene exchange process is elucidated by kinetic and computational analyses. We demonstrate the utility of the new catalysts through an SNAr reaction between fluorobenzene and alcohols, including secondary alcohols that could not be used previously in related reactions. Moreover, the catalytic thermal decarboxylation of phenylacetic acids is presented.

Palladium-catalysed electrophilic aromatic C-H fluorination.

Aryl fluorides are widely used in the pharmaceutical and agrochemical industries, and recent advances have enabled their synthesis through the conversion of various functional groups. However, there is a lack of general methods for direct aromatic carbon-hydrogen (C-H) fluorination. Conventional methods require the use of either strong fluorinating reagents, which are often unselective and difficult to handle, such as elemental fluorine, or less reactive reagents that attack only the most activated arenes, which reduces the substrate scope. A method for the direct fluorination of aromatic C-H bonds could facilitate access to fluorinated derivatives of functional molecules that would otherwise be difficult to produce. For example, drug candidates with improved properties, such as increased metabolic stability or better blood-brain-barrier penetration, may become available. Here we describe an approach to catalysis and the resulting development of an undirected, palladium-catalysed method for aromatic C-H fluorination using mild electrophilic fluorinating reagents. The reaction involves a mode of catalysis that is unusual in aromatic C-H functionalization because no organometallic intermediate is formed; instead, a reactive transition-metal-fluoride electrophile is generated catalytically for the fluorination of arenes that do not otherwise react with mild fluorinating reagents. The scope and functional-group tolerance of this reaction could provide access to functional fluorinated molecules in pharmaceutical and agrochemical development that would otherwise not be readily accessible.

1,4-Aminoarylation of Butadienes via Photoinduced Palladium Catalysis.

A visible-light-induced, three-component palladium-catalyzed 1,4-aminoarylation of butadienes with readily available aryl halides and aliphatic amines has been developed, affording allylamines with excellent E-selectivity. The reaction exhibits exceptional control over chemo-, regio-, and stereoselectivity, a broad substrate scope, and high functional group compatibility, as demonstrated by the late-stage functionalization of bioactive molecules. Mechanistic investigations are consistent with a photoinduced radical Pd(0)-Pd(I)-Pd(II)-Pd(0) Heck-Tsuji-Trost allylation cascade.

Photoinduced Copper-Catalyzed Late-Stage Azidoarylation of Alkenes via Arylthianthrenium Salts.

The arylethylamine pharmacophore is conserved across a range of biologically active natural products and pharmaceuticals, particularly in molecules that act on the central nervous system. Herein, we present a photoinduced copper-catalyzed azidoarylation of alkenes at a late stage with arylthianthrenium salts, allowing access to highly functionalized acyclic (hetero)arylethylamine scaffolds that are otherwise difficult to access. A mechanistic study is consistent with a rac-BINAP-CuI-azide (2) as the photoactive catalytic species. We show the utility of the new method by the expedient synthesis of racemic melphalan in four steps through C-H functionalization.

Bicyclopentylation of Alcohols with Thianthrenium Reagents.

Herein we present the first method for the synthesis of bicyclo[1.1.1]pentyl (BCP) alkyl ethers from alcohols. The reaction uses BCP-thianthrenium reagents and is catalyzed by a dual copper/photoredox catalyst system. Unlike known alkylations of tertiary alcohols via carbocation intermediates, our Cu-mediated radical process circumvents the labile BCP carbocations. The approach demonstrates a broad tolerance for functional groups when applied to primary, secondary, and even tertiary alcohols. In addition, we highlight the utility of this method in late-stage functionalizations of both natural products and pharmaceuticals as well as in the rapid construction of BCP analogs of known pharmaceuticals that would otherwise be difficult to access.

Electron-Transfer-Enabled Concerted Nucleophilic Fluorination of Azaarenes: Selective C-H Fluorination of Quinolines.

Direct C-H fluorination is an efficient strategy to construct aromatic C-F bonds, but the cleavage of specific C-H bonds in the presence of other functional groups and the high barrier of C-F bond formation make the transformation challenging. Progress for the electrophilic fluorination of arenes has been reported, but a similar transformation for electron-deficient azaarenes has remained elusive due to the high energy of the corresponding Wheland intermediates. Nucleophilic fluorination of electron-deficient azaarenes is difficult owing to the identity of the Meisenheimer intermediate after fluoride attack, from which fluoride elimination to regenerate the substrate is favored over hydride elimination to form the product. Herein, we report a new concept for C-H nucleophilic fluorination without the formation of azaarene Meisenheimer intermediates through a chain process with an asynchronous concerted F--e--H+ transfer. The concerted nucleophilic aromatic substitution strategy allows for the first successful nucleophilic oxidative fluorination of quinolines.

Nickel Meets Aryl Thianthrenium Salts: Ni(I)-Catalyzed Halogenation of Arenes.

Herein, a regioselective, late-stage two-step arene halogenation method is reported. We propose how unusual Ni(I)/(III) catalysis is enabled by a combination of aryl thianthrenium and Ni redox properties that is hitherto unachieved with other (pseudo)halides. The catalyst is accessed in situ from inexpensive NiCl2·6(H2O) and zinc without the need of supporting ligands.

Synthesis of α-Branched Enones via Chloroacylation of Terminal Alkenes.

Here, we show the conversion of unactivated alkenes into α-branched enones via regioselective chloroacylation with acyl chlorides. The method relies upon the initial in situ generation of chlorine radicals directly from the acyl chloride precursor under cooperative nickel/photoredox catalysis. Subsequent HCl elimination provides enones and α,ß-unsaturated esters that are not accessible via the conventional acylation approaches that provide the other, linear constitutional isomer.

Reductive Cross-Coupling of a Vinyl Thianthrenium Salt and Secondary Alkyl Iodides.

We report the first reductive vinylation of alkyl iodides. The reaction uses a vinyl thianthrenium salt, a palladium catalyst, and an alkyl zinc intermediate formed in situ to trap the Ln PdII (vinyl) complex formed after oxidative addition before it undergoes undesired homocoupling to form butadiene.

A Perspective on Late-Stage Aromatic C-H Bond Functionalization.

Late-stage functionalization of C-H bonds (C-H LSF) can provide a straightforward approach to the efficient synthesis of functionalized complex molecules. However, C-H LSF is challenging because the C-H bond must be functionalized in the presence of various other functional groups. In this Perspective, we evaluate aromatic C-H LSF on the basis of four criteria─reactivity, chemoselectivity, site-selectivity, and substrate scope─and provide our own views on current challenges as well as promising strategies and areas of growth going forward.

Concerted nucleophilic aromatic substitution with (19)F(-) and (18)F(-).

Nucleophilic aromatic substitution (SNAr) is widely used by organic chemists to functionalize aromatic molecules, and it is the most commonly used method to generate arenes that contain (18)F for use in positron-emission tomography (PET) imaging. A wide range of nucleophiles exhibit SNAr reactivity, and the operational simplicity of the reaction means that the transformation can be conducted reliably and on large scales. During SNAr, attack of a nucleophile at a carbon atom bearing a 'leaving group' leads to a negatively charged intermediate called a Meisenheimer complex. Only arenes with electron-withdrawing substituents can sufficiently stabilize the resulting build-up of negative charge during Meisenheimer complex formation, limiting the scope of SNAr reactions: the most common SNAr substrates contain strong π-acceptors in the ortho and/or para position(s). Here we present an unusual concerted nucleophilic aromatic substitution reaction (CSNAr) that is not limited to electron-poor arenes, because it does not proceed via a Meisenheimer intermediate. We show a phenol deoxyfluorination reaction for which CSNAr is favoured over a stepwise displacement. Mechanistic insights enabled us to develop a functional-group-tolerant (18)F-deoxyfluorination reaction of phenols, which can be used to synthesize (18)F-PET probes. Selective (18)F introduction, without the need for the common, but cumbersome, azeotropic drying of (18)F, can now be accomplished from phenols as starting materials, and provides access to (18)F-labelled compounds not accessible through conventional chemistry.

α-Thianthrenium Carbonyl Species: The Equivalent of an α-Carbonyl Carbocation.

Here we report an α-thianthrenium carbonyl species, as the equivalent of an α-carbonyl carbocation, which is generated by the radical conjugate addition of a trifluoromethyl thianthrenium salt to Michael acceptors. The reactivity allows for the synthesis of Cα -tetrasubstituted α- and ß-amino acid analogues via a Ritter reaction by addition of acetonitrile. Addition of hydroxide, methoxide, and even fluoride can afford α-heteroatom substituted α-phenylpropanoates.

Meerwein-type Bromoarylation with Arylthianthrenium Salts.

Herein, we report a photocatalyzed Meerwein-type bromoarylation of alkenes with stable arylthianthrenium salts, formed by site-selective C-H thianthrenation. This protocol can be applied to late-stage functionalization of a variety of biomolecules that are difficult to access by other aryl coupling reagents. Halogen introduction allows for a variety of follow-up transformations, affording numerous biologically active skeletons.

Radical Decarboxylative Carbometalation of Benzoic Acids: A Solution to Aromatic Decarboxylative Fluorination.

Abundant aromatic carboxylic acids exist in great structural diversity from nature and synthesis. To date, the synthetically valuable decarboxylative functionalization of benzoic acids is realized mainly by transition-metal-catalyzed decarboxylative cross couplings. However, the high activation barrier for thermal decarboxylative carbometalation that often requires 140 °C reaction temperature limits both the substrate scope as well as the scope of suitable reactions that can sustain such conditions. Numerous reactions, for example, decarboxylative fluorination that is well developed for aliphatic carboxylic acids, are out of reach for the aromatic counterparts with current reaction chemistry. Here, we report a conceptually different approach through a low-barrier photoinduced ligand to metal charge transfer (LMCT)-enabled radical decarboxylative carbometalation strategy, which generates a putative high-valent arylcopper(III) complex, from which versatile facile reductive eliminations can occur. We demonstrate the suitability of our new approach to address previously unrealized general decarboxylative fluorination of benzoic acids.

Vinyl Thianthrenium Tetrafluoroborate: A Practical and Versatile Vinylating Reagent Made from Ethylene.

The use of vinyl electrophiles in synthesis has been hampered by the lack of access to a suitable reagent that is practical and of appropriate reactivity. In this work we introduce a vinyl thianthrenium salt as an effective vinylating reagent. The bench-stable, crystalline reagent can be readily prepared from ethylene gas at atmospheric pressure in one step and is broadly useful in the annulation chemistry of (hetero)cycles, N-vinylation of heterocyclic compounds, and palladium-catalyzed cross-coupling reactions. The structural features of the thianthrene core enable a distinct synthesis and reactivity profile, unprecedented for other vinyl sulfonium derivatives.

Site-Selective C-H alkylation of Complex Arenes by a Two-Step Aryl Thianthrenation-Reductive Alkylation Sequence.

Herein, we present an undirected para-selective two-step C-H alkylation of complex arenes useful for late-stage functionalization. The combination of a site-selective C-H thianthrenation with palladium-catalyzed reductive electrophile cross-coupling grants access to a diverse range of synthetically useful alkylated arenes which cannot be accessed otherwise with comparable selectivity, diversity, and practicality. The robustness of this transformation is further demonstrated by thianthrenium-based reductive coupling of two complex fragments.

Trifluoromethyl Thianthrenium Triflate: A Readily Available Trifluoromethylating Reagent with Formal CF3+, CF3•, and CF3- Reactivity.

Here we report the synthesis and application of trifluoromethyl thianthrenium triflate (TT-CF3+OTf-) as a novel trifluoromethylating reagent, which is conveniently accessible in a single step from thianthrene and triflic anhydride. We demonstrate the use of TT-CF3+OTf- in electrophilic, radical, and nucleophilic trifluoromethylation reactions.

High Site Selectivity in Electrophilic Aromatic Substitutions: Mechanism of C-H Thianthrenation.

The introduction of thianthrene as a linchpin has proven to be a versatile strategy for the C-H functionalization of aromatic compounds, featuring a broad scope and fast diversification. The synthesis of aryl thianthrenium salts has displayed an unusually high para regioselectivity, notably superior to those observed in halogenation or borylation reactions for various substrates. We report an experimental and computational study on the mechanism of aromatic C-H thianthrenation reactions, with an emphasis on the elucidation of the reactive species and the nature of the exquisite site selectivity. Mechanisms involving a direct attack of arene to the isolated O-trifluoracetylthianthrene S-oxide (TT+-TFA) or to the thianthrene dication (TT2+) via electron transfer under acidic conditions are identified. A reversible interconversion of the different Wheland-type intermediates before a subsequent, irreversible deprotonation is proposed to be responsible for the exceptional para selectivity of the reaction.