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.

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

The emergence of the C–H functionalization strategy in medicinal chemistry and drug discovery

The functionalization of C-H bonds in organic molecules containing functional groups has been one of the holy grails of catalysis. One synthetically important approach to the diverse functionalization of C-H bonds is the catalytic silylation or borylation of C-H bonds, which enables a broad array of downstream transformations to afford diverse structures. Advances in both undirected and directed methods for the transition-metal-catalyzed silylation and borylation of C-H bonds have led to their rapid adoption in early-, mid-, and late-stage of the synthesis of complex molecules. In this Review, we review the application of the transition-metal-catalyzed silylation and borylation of C-H bonds to the synthesis of bioactive molecules, organic materials, and ligands. Overall, we aim to provide a picture of the state of art of the silylation and borylation of C-H bonds as applied to the synthesis and modification of diverse architectures that will spur further application and development of these reactions. 

Transition-Metal-Catalyzed Silylation and Borylation of C-H Bonds for the Synthesis and Functionalization of Complex Molecules.

The kinetics and mechanism of the base-catalyzed hydrolysis (ArB(OR)2 → ArB(OH)2) and protodeboronation (ArB(OR)2 → ArH) of a series of boronic esters, encompassing eight different polyols and 10 polyfluoroaryl and heteroaryl moieties, have been investigated by in situ and stopped-flow NMR spectroscopy (19F, 1H, and 11B), pH-rate dependence, isotope entrainment, 2H KIEs, and KS-DFT computations. The study reveals the phenomenological stability of boronic esters under basic aqueous-organic conditions to be highly nuanced. In contrast to common assumption, esterification does not necessarily impart greater stability compared to the corresponding boronic acid. Moreover, hydrolysis of the ester to the boronic acid can be a dominant component of the overall protodeboronation process, augmented by self-, auto-, and oxidative (phenolic) catalysis when the pH is close to the pKa of the boronic acid/ester.

Protodeboronation of (Hetero)Arylboronic Esters: Direct versus Prehydrolytic Pathways and Self-/Auto-Catalysis.

Positron emission tomography (PET) has become an invaluable tool for drug discovery and diagnosis. The positron-emitting radionuclide fluorine-18 is frequently used in PET radiopharmaceuticals due to its advantageous characteristics; hence, methods streamlining access to 18F-labelled radiotracers can make a direct impact in medicine. For many years, access to 18F-labelled radiotracers was limited by the paucity of methodologies available, and the poor diversity of precursors amenable to 18F-incorporation. During the last two decades, 18F-radiochemistry has progressed at a fast pace with the appearance of numerous methodologies for late-stage 18F-incorporation onto complex molecules from a range of readily available precursors including those that do not require pre-functionalisation. Key to these advances is the inclusion of new activation modes to facilitate 18F-incorporation. Specifically, new advances in late-stage 19F-fluorination under transition metal catalysis, photoredox catalysis, and organocatalysis combined with the availability of novel 18F-labelled fluorination reagents have enabled the invention of novel processes for 18F-incorporation onto complex (bio)molecules. This review describes these major breakthroughs with a focus on methodologies for C–18F bond formation. This reinvigorated interest in 18F-radiochemistry that we have witnessed in recent years has made a direct impact on 19F-chemistry with many laboratories refocusing their efforts on the development of methods using nucleophilic fluoride instead of fluorination reagents derived from molecular fluorine gas.

/pdf/closing-the-gap-between-19f-and-18f-chemistry-3n955hv4ep.pdf

Closing the gap between 19F and 18F chemistry

Copper-mediated radiofluorination (CMRF) is emerging as the method of choice for the formation of aromatic C–18F bonds. This minireview examines proof-of-concept, preclinical, and in-human imaging studies of new and established imaging agents containing aromatic C–18F bonds synthesized with CMRF. An exhaustive discussion of CMRF methods is not provided, although key developments that have enabled or improved upon the syntheses of fluorine-18 imaging agents are discussed. A comprehensive literature search from April 2014 onwards of the Web of Science and PubMed library databases was performed to find reports that utilize CMRF for the synthesis of fluorine-18 radiopharmaceuticals, and these represent the primary body of research discussed in this minireview. Select conference proceedings, previous reports describing alternative methods for the synthesis of imaging agents, and preceding fluorine-19 methodologies have also been included for discussion. CMRF has significantly expanded the chemical space that is accessible to fluorine-18 radiolabeling with production methods that can meet the regulatory requirements for use in Nuclear Medicine. Furthermore, it has enabled novel and improved syntheses of radiopharmaceuticals and facilitated subsequent PET imaging studies. The rapid adoption of CMRF will undoubtedly continue to simplify the production of imaging agents and inspire the development of new radiofluorination methodologies.

Copper-Mediated Late-stage Radiofluorination: Five Years of Impact on Pre-clinical and Clinical PET Imaging.

This article describes a sequential Ir/Cu-mediated process for the meta-selective C-H radiofluorination of (hetero)arene substrates. In the first step, Ir-catalyzed C(sp2)-H borylation affords (hetero)aryl pinacolboronate (BPin) esters. The intermediate organoboronates are then directly subjected to copper-mediated radiofluorination with [18F]tetrabutylammonium fluoride to afford fluorine-18 labeled (hetero)arenes in high radiochemical yield and radiochemical purity. This entire process is performed on a benchtop without Schlenk or glovebox techniques and circumvents the need to isolate (hetero)aryl boronate esters. The reaction was automated on a TracerLab FXFN module with 1,3-dimethoxybenzene and a meta-tyrosine derivative. The products, [18F]1-fluoro-3,5-dimethoxybenzene and an 18F-labeled meta-tyrosine derivative, were obtained in 37 ± 5% isolated radiochemical yield and >99% radiochemical purity and 25% isolated radiochemical yield and 99% radiochemical purity, and 0.52 Ci/μmol (19.24 GBq/μmol) molar activity (Am), respectively.

Sequential Ir/Cu-Mediated Method for the Meta-Selective C-H Radiofluorination of (Hetero)Arenes

In the US, EU and elsewhere, basic clinical research studies with positron emission tomography (PET) radiotracers that are generally recognized as safe and effective (GRASE) can often be conducted under institutional approval. For example, in the United States, such research is conducted under the oversight of a Radioactive Drug Research Committee (RDRC) as long as certain requirements are met. Firstly, the research must be for basic science and cannot be intended for immediate therapeutic or diagnostic purposes, or to determine the safety and effectiveness of the PET radiotracer. Secondly, the PET radiotracer must be generally recognized as safe and effective. Specifically, the mass dose to be administered must not cause any clinically detectable pharmacological effect in humans, and the radiation dose to be administered must be the smallest dose practical to perform the study and not exceed regulatory dose limits within a 1-year period. In our experience, the main barrier to using a PET radiotracer under RDRC approval is accessing the required information about mass and radioactive dosing. The University of Michigan (UM) has a long history of using PET radiotracers in clinical research studies. Herein we provide dosing information for 55 radiotracers that will enable other PET Centers to use them under the approval of their own RDRC committees. The data provided herein will streamline future RDRC approval, and facilitate further basic science investigation of 55 PET radiotracers that target functionally relevant biomarkers in high impact disease states.

/pdf/use-of-55-pet-radiotracers-under-approval-of-a-radioactive-3klcxidkev.pdf

Use of 55 PET radiotracers under approval of a Radioactive Drug Research Committee (RDRC)

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Copper-Mediated Late-stage Radiofluorination: Five Years of Impact on Pre-clinical and Clinical PET Imaging.

Sequential Ir/Cu-Mediated Method for the Meta-Selective C-H Radiofluorination of (Hetero)Arenes

Use of 55 PET radiotracers under approval of a Radioactive Drug Research Committee (RDRC)