Site‐Selective Approach to β‐Fluorination: Photocatalyzed Ring Opening of Cyclopropanols

To expand upon the recent pioneering reports of catalyzed sp³ C?H fluorination methods, the next rational step is to focus on directing “radical‐based fluorination” more effectively. One potential solution entails selective C?C bond activation as a prelude to selective fluorination. Herein, we report the tandem photocatalyzed ring‐opening/fluorination reactions of cyclopropanols by 1,2,4,5‐tetracyanobenzene (TCB) and Selectfluor to afford a process tantamount to site‐selective β‐fluorination of carbonyl‐containing compounds. This new approach provides a synthetically mild and operationally simple route to otherwise difficult‐to‐prepare β‐fluorinated products in good yields and with good‐to‐excellent regioselectivity. Remarkably, substrates that contain other usually reactive (e.g., benzylic) sites undergo ring‐opening fluorination preferably. The versatility of this method to give cyclic β‐fluorides from tertiary cyclopropanols and γ‐fluoro alcohols is also highlighted.     

Site‐Selective Late‐Stage Aromatic [18F]Fluorination via Aryl Sulfonium Salts

Site‐selective functionalization of C?H bonds in small complex molecules is a long‐standing challenge in organic chemistry. Herein, we report a broadly applicable and site‐selective aromatic C?H dibenzothiophenylation reaction. The conceptual advantage of this transformation is further demonstrated through the two‐step C?H [¹⁸F]fluorination of a series of marketed small‐molecule drugs.     

Acyl Fluorides in Late‐Transition‐Metal Catalysis

In this Review, we summarize the current state of the art in late‐transition‐metal‐catalyzed reactions of acyl fluorides, covering both their synthesis and further transformations. In organic reactions, the relationship between stability and reactivity of the starting substrates is usually characterized by a trade‐off. Yet, acyl fluorides display a very good balance between these properties, which is mostly due to their moderate electrophilicity. Thus, acyl fluorides (RCOF) can be used as versatile building blocks in transition‐metal‐catalyzed reactions, for example, as an “RCO” source in acyl coupling reactions, as an “R” source in decarbonylative coupling reactions, and as an “F” source in fluorination reactions. Starting from the cleavage of the acyl C?F bond in acyl fluorides, various transformations are accessible, including C?C, C?H, C?B, and C?F bond‐forming reactions that are catalyzed by transition‐metal catalysts that contain the Group 9–11 metals Co, Rh, Ir, Ni, Pd, or Cu.     

A Convenient Photocatalytic Fluorination of Unactivated CH Bonds

Fluorination reactions are essential to modern medicinal chemistry, thus providing a means to block site‐selective metabolic degradation of drugs and access radiotracers for positron emission tomography imaging. Despite current sophistication in fluorination reagents and processes, the fluorination of unactivated C? H bonds remains a significant challenge. Reported herein is a convenient and economic process for direct fluorination of unactivated C? H bonds that exploits the hydrogen abstracting ability of a decatungstate photocatalyst in combination with the mild fluorine atom transfer reagent N‐fluorobenzenesulfonimide. This operationally straightforward reaction provides direct access to a wide range of fluorinated organic molecules, including structurally complex natural products, acyl fluorides, and fluorinated amino acid derivatives.     

The Fluorination of C−H Bonds: Developments and Perspectives

This Review summarizes advances in fluorination by C(sp²)?H and C(sp³)?H activation. Transition‐metal‐catalyzed approaches championed by palladium have allowed the installation of a fluorine substituent at C(sp²) and C(sp³) sites, exploiting the reactivity of high‐oxidation‐state transition‐metal fluoride complexes combined with the use of directing groups (some transient) to control site and stereoselectivity. The large majority of known methods employ electrophilic fluorination reagents, but methods combining a nucleophilic fluoride source with an oxidant have appeared. External ligands have proven to be effective for C(sp³)?H fluorination directed by weakly coordinating auxiliaries, thereby enabling control over reactivity. Methods relying on the formation of radical intermediates are complementary to transition‐metal‐catalyzed processes as they allow for undirected C(sp³)?H fluorination. To date, radical C?H fluorinations mainly employ electrophilic N?F fluorination reagents but a unique Mn^III‐catalyzed oxidative C?H fluorination using fluoride has been developed. Overall, the field of late‐stage nucleophilic C?H fluorination has progressed much more slowly, a state of play explaining why C?H ¹⁸F‐fluorination is still in its infancy.     

Silver‐Promoted Oxidative Benzylic C−H Trifluoromethoxylation

A silver‐promoted oxidative benzylic C?H trifluoromethoxylation has been reported for the first time. With trifluoromethyl arylsulfonate as the trifluoromethoxylation reagent, various arenes, having diverse functional groups, undergo trifluoromethoxylation of their benzylic C?H bonds to form trifluoromethyl ethers under mild reaction conditions. In addition, the trifluoromethoxylation and the fluorination of methyl groups of electron‐rich arenes have been achieved to prepare α‐fluorobenzyl trifluoromethyl ethers in one step.     

Benzylic Fluorination of Aza‐Heterocycles Induced by Single‐Electron Transfer to Selectfluor

A selective and mild method for the benzylic fluorination of aromatic azaheterocycles with Selectfluor is described. These reactions take place by a previously unreported mechanism, in which electron transfer from the heterocyclic substrate to the electrophilic fluorinating agent Selectfluor eventually yields a benzylic radical, thus leading to the desired C?F bond formation. This mechanism enables high intra‐ and intermolecular selectivity for aza‐heterocycles over other benzylic components with similar C?H bond‐dissociation energies.     

Iron(II)‐Catalyzed Site‐Selective Functionalization of Unactivated C(sp3)−H Bonds Guided by Alkoxyl Radicals

An alkoxyl radical guided strategy for site‐selective functionalization of unactivated methylene and methine C?H bonds enabled by an Fe^II‐catalyzed redox process is described. The mild, expeditious, and modular protocol allows efficient remote aliphatic fluorination, chlorination, amination, and alkynylation of structurally and electronically varied primary, secondary, and tertiary hydroperoxides with excellent functional‐group tolerance. The application for one‐pot 1,4‐hydroxyl functionalization of non‐oxygenated alkane substrates initiated by aerobic C?H oxygenation is also demonstrated.     

Ortho‐Functionalized Aryltetrazines by Direct Palladium‐Catalyzed C−H Halogenation: Application to Fast Electrophilic Fluorination Reactions

A general catalyzed direct C?H functionalization of s‐tetrazines is reported. Under mild reaction conditions, N‐directed ortho‐C?H activation of tetrazines allows the introduction of various functional groups, thus forming carbon–heteroatom bonds: C?X (X=I, Br, Cl) and C?O. Based on this methodology, we developed electrophilic mono‐ and poly‐ortho‐fluorination of tetrazines. Microwave irradiation was optimized to afford fluorinated s‐aryltetrazines, with satisfactory selectivity, within only ten minutes. This work provides an efficient and practical entry for further accessing highly substituted tetrazine derivatives (iodo, bromo, chloro, fluoro, and acetate precursors). It gives access to ortho‐functionalized aryltetrazines which are difficult to obtain by classical Pinner‐like syntheses.     

Silver‐Catalyzed Oxidative Activation of Benzylic CH Bonds for the Synthesis of Difluoromethylated Arenes

A mild and catalytic method to form difluoromethylated arenes through the activation of benzylic C? H bonds has been developed. Utilizing AgNO₃ as the catalyst, various arenes with diverse functional groups undergo activation/fluorination of benzylic C? H bonds with commercially available Selectfluor reagent as a source of fluorine in aqueous solution. The reaction is operationally simple and amenable to gram‐scale synthesis.     

Visible‐Light Photocatalysis of C(sp3)‐H Fluorination by the Uranyl Ion: Mechanistic Insights

The uranyl dication shows photocatalytic activity towards C(sp³)?H bonds of aliphatic compounds, but not towards those of alkylbenzenes or cyclic ketones. Theoretical insights into the corresponding mechanisms are still limited. Multi‐configurational ab initio calculations including relativistic effects reveal the inherent electron‐transfer mechanism for the uranyl catalyzed C?H fluorination under blue light. Along the reaction path of the triplet state it was found that the hydrogen atom abstraction triggered by the electron‐rich oxygen of the uranyl moiety is the rate‐limiting step. The subsequent steps, that is, N?F and O?H bond breakage in a manner of concerted asynchronicity, generation of the targeted fluorinated product, and recovery of the photocatalyst are nearly barrierless. Moreover the single electron transfer between the reactive substrates plays a fundamental role during the whole photocatalytic cycle.     

Iodine Catalysis for C(sp3)–H Fluorination with a Nucleophilic Fluorine Source

Iodine catalysis was developed for aliphatic fluorination through light‐promoted homolytic C?H bond cleavage. The intermediary formation of amidyl radicals enables selective C?H functionalization via carbon‐centered radicals. For the subsequent C?F bond formation, previous methods have typically been limited by a requirement for electrophilic fluorine reagents. We here demonstrate that the intermediary instalment of a carbon–iodine bond sets the stage for an umpolung, thereby establishing an unprecedented nucleophilic fluorination pathway.     

Modification of ultra‐high‐molecular weight polyethylene by various fluorinating routes

Chemical–physical properties of ultra‐high‐molecular weight polyethylene (UHMWPE) treated by direct fluorination, direct fluorination accompanied with UV irradiation, by XeF₂ and by TbF₄, were tested by FTIR spectroscopy, visible spectroscopy, 19F and 13C NMR, scanning electron microscopy, XRD, and EPR. Surface energy measurements were carried out. The direct fluorination of UHMWPE is a diffusion‐controlled process, but treatment with XeF₂ is a kinetically controlled one. Direct fluorination and direct fluorination accompanied with UV irradiation results mainly in a formation of ? CF₂? groups. On the contrary, ? CHF? groups are prevailing in UHMWPE treated with XeF₂ and TbF₄. Surface texture of UHMWPE treated with XeF₂ and with F₂ is quite different. Direct fluorination results in a higher polarity of the polymer surface when compared with treatment with XeF₂. For the case of direct fluorination, both long‐lived peroxy and fluoroalkylradicals are formed. For the case of treatment with XeF₂, only fluoroalkylradicals were detected. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 49:3559–3573, 2011     

AgF‐Mediated Fluorinative Cross‐Coupling of Two Olefins: Facile Access to α‐CF3 Alkenes and β‐CF3 Ketones

A AgF‐mediated fluorination with a concomitant cross‐coupling between a gem‐difluoroolefin and a non‐fluorinated olefin is reported. This highly efficient method provides facile access to both α‐CF₃ alkenes and β‐CF₃ ketones, which otherwise remain challenging to be directly prepared. The application of this method is further demonstrated by the synthesis of bioactive isoxazoline derivatives. This approach represents a conceptually novel route to trifluoromethylated compounds that combines the in situ generation of the CF₃ moiety and a C? H functionalization in a single reaction system.     

Molecular Self‐Recognition: Rotational Spectra of the Dimeric 2‐Fluoroethanol Conformers

Fluoroalcohols show competitive formation of intra‐ and intermolecular hydrogen bonds, a property that may be crucial for the protein‐altering process in a fluoroalcohol/water solution. In this study, we examine the intra‐ and intermolecular interactions of 2‐fluoroethanol (FE) in its dimeric conformers by using rotational spectroscopy and ab initio calculations. Three pairs of homo‐ and heterochiral dimeric FE conformers are predicted to be local minima at the MP2/6‐311++G(d,p) level of theory. They are solely made of the slightly distorted most stable G+g?/G?g+ FE monomer units. Jet‐cooled rotational spectra of four out of the six predicted dimeric conformers were observed and unambiguously assigned for the first time. All four observed dimeric conformers have compact geometries in which the fluoromethyl group of the acceptor tilts towards the donor and ensures a large contact area. Experimentally, the insertion of the O? H group of one FE subunit into the intramolecular O? H???F bond of the other was found to lead to a higher stabilisation than the pure association through an intermolecular O? H???O? H link. The hetero‐ and homochiral combinations were observed to be preferred in the inserted and the associated dimeric conformers, respectively. The experimental rotational constants and the stability ordering are compared with the ab initio calculations at the MP2 level with the 6‐311++G(d,p) and aug‐cc‐pVTZ basis sets. The effects of fluorination and the competing inter‐ and intramolecular hydrogen bonds on the stability of the dimeric FE conformers are discussed.     

Gold‐Catalyzed Fluorination–Hydration: Synthesis of α‐Fluorobenzofuranones from 2‐Alkynylphenol Derivatives

The Au^I‐catalyzed fluorination–hydration of 2‐alkynylphenol derivatives in the presence of Selectfluor [1‐chloromethyl‐4‐fluoro‐1,4‐diazoniabicyclo‐[2.2.2]octane bis(tetrafluoroborate)] has been developed. This method provides straightforward access to α‐fluorobenzofuranones with the construction of C?O, C=O, and C?F bonds in a single step on the basis of an Au^I/Au^III redox catalytic cycle. Several control experiments, including the asymmetric variant of this reaction, were also conducted to gain insight into the reaction mechanism.     

Rhodium(III)‐Catalyzed ortho‐Heteroarylation of Phenols through Internal Oxidative CH Activation: Rapid Screening of Single‐Molecular White‐Light‐Emitting Materials

Reported herein is the first example of a transition‐metal‐catalyzed internal oxidative C? H/C? H cross‐coupling between two (hetero)arenes through a traceless oxidation directing strategy. Without the requirement of an external metal oxidant, a wide range of phenols, including phenol‐containing natural products, can undergo the coupling with azoles to assemble a large library of highly functionalized 2‐(2‐hydroxyphenyl)azoles. The route provides an opportunity to rapidly screen white‐light‐emitting materials. As illustrative examples, two bis(triphenylamine)‐bearing 2‐(2‐hydroxyphenyl)oxazoles, which are difficult to access otherwise, exhibit bright white‐light emission, high quantum yield, and thermal stability. Also presented is the first example of the white‐light emission, in a single excited‐state intramolecular proton transfer system, of 2‐(2‐hydroxyphenyl)azoles, thus highlighting the charm of C? H activation in the discovery of new organic optoelectronic materials.     

Intramolecular Hydrogen Bonds in Low‐Molecular‐Weight Polyethylene Glycol

We used static DFT calculations to analyze, in detail, the intramolecular hydrogen bonds formed in low‐molecular‐weight polyethylene glycol (PEG) with two to five repeat subunits. Both red‐shifted O?H???O and blue‐shifting C?H???O hydrogen bonds, which control the structural flexibility of PEG, were detected. To estimate the strength of these hydrogen bonds, the quantum theory of atoms in molecules was used. Car–Parrinello molecular dynamics simulations were used to mimic the structural rearrangements and hydrogen‐bond breaking/formation in the PEG molecule at 300 K. The time evolution of the H???O bond length and valence angles of the formed hydrogen bonds were fully analyzed. The characteristic hydrogen‐bonding patterns of low‐molecular‐weight PEG were described with an estimation of their lifetime. The theoretical results obtained, in particular the presence of weak C?H???O hydrogen bonds, could serve as an explanation of the PEG structural stability in the experimental investigation.     

Introduction of Fluorine and Fluorine‐Containing Functional Groups

Over the past decade, the most significant, conceptual advances in the field of fluorination were enabled most prominently by organo‐ and transition‐metal catalysis. The most challenging transformation remains the formation of the parent C? F bond, primarily as a consequence of the high hydration energy of fluoride, strong metal—fluorine bonds, and highly polarized bonds to fluorine. Most fluorination reactions still lack generality, predictability, and cost‐efficiency. Despite all current limitations, modern fluorination methods have made fluorinated molecules more readily available than ever before and have begun to have an impact on research areas that do not require large amounts of material, such as drug discovery and positron emission tomography. This Review gives a brief summary of conventional fluorination reactions, including those reactions that introduce fluorinated functional groups, and focuses on modern developments in the field.     

Toward product control in ring‐opening oligomerization of 9H‐9‐borafluorenes

To get deep insights into the structure–reactivity relationship for ring‐opening oligomerization reactions toward targeted design of novel main‐chain boron‐containing materials, detailed DFT B97D/TZVP calculations are carried out to compare the ring‐opening oligomerization of both unsubstituted and tert‐butyl (tBu)‐substituted 9H?9‐borafluorenes. In contrast to substituent exchange between normal boranes, such reactions are initiated by substituent exchanges involving double B? C? B bridged intermediates. On tBu‐substitution, the B? C? B, and B? H? B bridged dimer intermediate is stabilized mainly due to enhanced barrier of 18.1 kcal/mol toward further trimerization channel and higher isomerization barrier of 22.5 kcal/mol toward the double B? H? B bridged dimer. In good agreement with available experiments, it is clearly shown that various product channels can be efficiently controlled by bulky substitution and by reaction temperatures, pointing out the way toward desired higher oligomers with improved thermal stability. © 2014 Wiley Periodicals, Inc.