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Piperazine cores have long been identified as privileged scaffolds in the development of pharmaceutical compounds. Despite this, the facile synthesis of diverse C-substituted piperazines remains a challenge without prefunctionalized substrates/cores. Herein, we describe a programmable approach to highly diversifiable piperazine cores, which circumvents the typical need for radical precursors. The use of organic photoredox catalysis renders this method operationally simple, as direct substrate oxidation followed by 6- endo-trig radical cyclization with in situ generated imines may furnish the product. Additionally, the photoredox-catalyzed anti-Markovnikov hydroamination of readily accessible ene-carbamates provides a modular approach to functionalized diamine starting materials which are shown to generate more complex piperazine cores. A wide range of both carbonyl and amine condensation partners were shown to be compatible with this system in good to excellent yield.

Photoredox is a powerful synthetic tool in organic chemistry and has been widely used in various fields, including nuclear medicine and molecular imaging. In particular, acridinium-based organophotoredox radiolabeling has significantly impacted the production and discovery of positron emission tomography (PET) agents. Despite their extensive use in preclinical research, no PET agents synthesized by acridinium photoredox labeling have been tested in humans. [ 18 F]FDOPA is clinically used for tumor diagnosis and the evaluation of neuropsychiatric disorders, but its application is limited by complex synthesis methods, the need for expensive modules, and/or the high cost of consumable materials/cassettes. In this report, we integrated a photoredox labeling unit with an automated module and produced [ 18 F]FDOPA for human study. This research not only represents the first human study of a PET agent generated by acridinium-based organophotoredox reactions but also demonstrates the safety of this novel labeling method, serving as a milestone/reference for the clinical translation of other PET agents generated by this technique in the future.

To avoid the harsh conditions that are oftentimes adopted in direct radiofluorination reactions, conjugation of bioactive ligands with 18 F-labeled prosthetic groups has become an important strategy to construct novel PET agents under mild conditions when the ligands are structurally sensitive. Prosthetic groups with [ 18 F]fluoroarene motifs are especially appealing because of their stability in physiological environments. However, their preparation can be intricate, often requiring multistep radiosynthesis with functional group conversions to prevent the decomposition of unprotected reactive prosthetic groups during the harsh radiofluorination. Here, we report a general and simple method to generate a variety of highly reactive 18 F-labeled electrophiles via one-step organophotoredox-mediated radiofluorination. The method benefits from high step-economy, reaction efficiency, functional group tolerance, and easily accessible precursors. The obtained prosthetic groups have been successfully applied in PET agent construction and subsequent imaging studies, thereby demonstrating the feasibility of this synthetic method in promoting imaging and biomedical research., Competing Interests: The authors declare the following competing financial interest(s): We have filed a provisional patent on the invention in this manuscript., (© 2024 The Authors. Published by American Chemical Society.)

The C-H functionalization of remote, unactivated C-H bonds offers a unique method of garnering structural complexity in a synthesis. The use of directing groups has provided a means of enacting C-H functionalization on these difficult-to-access bonds; however, the installation and removal of directing groups on a substrate require additional synthetic manipulations, detracting from both the efficiency and economic feasibility of a transformation. The use of alkoxy radicals as transient directing groups for the functionalization of remote C-H bonds allows access to the synthesis of complex molecules without the need for additional functionality. Herein, we report a method for alkoxy radical formation from unactivated alcohols and reactivity mediated by photoredox-generated sulfoxide cation radicals. This protocol leverages the unique reactivity of alkoxy radicals to implement different reaction manifolds: 1,5-hydrogen atom transfer (HAT), cyclization, and β-scission. Furthermore, it was discovered that this methodology could be utilized to impose radical group transfer reactions via the β-scission pathway. Stern-Volmer analysis supports the formation of an alkoxy radical via the intermediacy of a sulfurane radical rather than a proton-coupled electron transfer (PCET) mechanism.

In this study, we introduce a practical methodology for the synthesis of PET probes by seamlessly combining flow chemistry with photoredox radiofluorination. The clinical PET tracer 6-[ 18 F]FDOPA was smoothly prepared in a 24.3% non-decay-corrected yield with over 99.0% radiochemical purity (RCP) and enantiomeric excess (ee), notably by a simple cartridge-based purification. The flow chemistry-enhanced photolabeling method supplies an efficient and versatile solution for the synthesis of 6-[ 18 F]FDOPA and for more PET tracer development.

The β-amino nitrile moiety and its derivatives frequently appear in natural product synthesis, in drug design, and as ligands in asymmetric catalysis. Herein, we describe a direct route to these complex motifs through the amino- and oxycyanation of olefins utilizing an acridinium photooxidant in conjunction with copper catalysis. The transformation can be rendered asymmetric by using a serine-derived bisoxazoline ligand. Mechanistic studies implicate olefin-first oxidation. The scope of amines for the aminocyanation reaction has been greatly expanded by undergoing a cation radical intermediate as opposed to previous N -centered radical-initiated aminocyanations. Furthermore, alkyl carboxylic acids were included as nucleophiles in this type of transformation for the first time without any decarboxylative side reactions.

Direct functionalization of alkynes under oxidative conditions is challenging, as alkynes are usually recalcitrant towards typical oxidants. Herein, we communicate a strategy for the divergent functionalization of alkynes with photoexcited acridinium organic dyes, presumably via the formation of vinyl cation radicals as key intermediates. Based on the nature of the nucleophiles, different types of difunctionalized products were obtained in moderate to good yields. Addition of lithium Lewis acids resulted in a surprising reversal of diastereocontrol., Competing Interests: Conflict of Interest The authors declare no conflict of interest.

As a non-invasive imaging technology, positron emission tomography (PET) plays a crucial role in personalized medicine, including early diagnosis, patient screening, and treatment monitoring. The advancement of PET research depends on the discovery of new PET agents, which requires the development of simple and efficient radiolabeling methods in many cases. As bioisosteres for halogen and carbonyl moieties, nitriles are important functional groups in pharmaceutical and agrochemical compounds. Here, we disclose a mild organophotoredox-catalyzed method for efficient cyanation of a broad spectrum of electron-rich arenes, including abundant and readily available veratroles and pyrogallol trimethyl ethers. Notably, the transformations not only are compatible with various affordable 12 C and 13 C-cyanide sources, but also could be applied to carbon-11 synthons to incorporate [ 11 C]nitriles into arenes. The aryl [ 11 C]nitriles can be further derivatized to [ 11 C]carboxylic acids, [ 11 C]amides, and [ 11 C]alkyl amines. The newly developed reaction can serve as a powerful tool for generating new PET agents., Competing Interests: DECLARATION OF INTERESTS The authors Z.L., D.A.N. and W.C. have filed a WO patent (patent applicant, the University of North Carolina at Chapel Hill, USA; inventors, Z.L, D.A.N and W.C.; patent no. WO 2020176804) related to part of the labelling methodology in this manuscript and is under review. Z.L. and D.A.N. are the cofounders of LED Radiofluidics. D.A.N. is a member of Chem’s advisory board. The remaining authors declare no competing interests.

Innovative labeling methods to incorporate the short-lived positron emitter carbon-11( 11 C) into bioactive molecules are attractive for positron emission tomography (PET) tracer discovery. Herein, we report a direct C-H radiocyanation method that incorporates [ 11 C]cyanide ( 11 CN - ) to a series of functional electron-rich arenes via photoredox catalysis. This photoredox-mediated radiocyanation can proceed in an aerobic environment and is not moisture sensitive, which allows for ease of reaction setup and for scalable synthesis of 11 C-aryl nitriles from readily available precursors.

A mechanistic investigation into the amination of electron-neutral and electron-rich arenes using organic photoredox catalysis is presented. Kinetic and computational data support rate-limiting nucleophilic addition into an arene cation radical using both azole and primary amine nucleophiles. This finding is consistent with both fluoride and alkoxide nucleofuges, supporting a unified mechanistic picture using cation radical accelerated nucleophilic aromatic substitution (CRA-S N Ar). Electrochemistry and time-resolved fluorescence spectroscopy confirm the key role solvents play in enabling selective arene oxidation in the presence of amines. The synthetic limitations of xanthylium salts are elucidated via photophysical studies. An alternative catalyst scaffold with improved turnover numbers is presented.

The alkylation and heteroarylation of unactivated tertiary, secondary, and primary C(sp 3 )-H bonds was achieved by employing an acridinium photoredox catalyst along with readily available pyridine N oxides as hydrogen atom transfer (HAT) precursors under visible light. Oxygen-centered radicals, generated by single-electron oxidation of the N oxides, are the proposed key intermediates whose reactivity can be easily modified by structural adjustments. A broad range of aliphatic C-H substrates with electron-donating or -withdrawing groups as well as various olefinic radical acceptors and heteroarenes were well tolerated., Competing Interests: The authors declare no competing financial interest.

Ketone-olefin coupling reactions are common methods for the formation of carbon-carbon bonds. This reaction class typically requires stoichiometric or super stoichiometric quantities of metal reductants, and catalytic variations are limited in application. Photoredox catalysis has offered an alternative method toward ketone-olefin coupling reactions, although most methods are limited in scope to easily reducible aromatic carbonyl compounds. Herein, we describe a mild, metal-free ketone-olefin coupling reaction using an excited-state acridine radical super reductant as a photoredox catalyst. We demonstrate both intramolecular and intermolecular ketone-olefin couplings of aliphatic and aromatic ketones and aldehydes. Mechanistic evidence is also presented supporting an " olefin first " ketone-olefin coupling mechanism.

Positron emission tomography (PET) is a powerful imaging technology that can visualize and measure metabolic processes in vivo and/or obtain unique information about drug candidates. The identification of new and improved molecular probes plays a critical role in PET, but its progress is somewhat limited due to the lack of efficient and simple labelling methods to modify biologically active small molecules and/or drugs. Current methods to radiofluorinate unactivated arenes are still relatively limited, especially in a simple and site-selective way. Here we disclose a method for constructing C- 18 F bonds through direct halide/ 18 F conversion in electron-rich halo(hetero)arenes. [ 18 F]F - is introduced into a broad spectrum of readily available aryl halide precursors in a site-selective manner under mild photoredox conditions. Notably, our direct 19 F/ 18 F exchange method enables rapid PET probe diversification through the preparation and evaluation of an [ 18 F]-labelled O-methyl tyrosine library. This strategy also results in the high-yielding synthesis of the widely used PET agent L-[ 18 F]FDOPA from a readily available L-FDOPA analogue., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The fields of C-H functionalization and photoredox catalysis have garnered enormous interest and utility in the past several decades. Many different scientific disciplines have relied on C-H functionalization and photoredox strategies including natural product synthesis, drug discovery, radiolabeling, bioconjugation, materials, and fine chemical synthesis. In this Review, we highlight the use of photoredox catalysis in C-H functionalization reactions. We separate the review into inorganic/organometallic photoredox catalysts and organic-based photoredox catalytic systems. Further subdivision by reaction class─either sp 2 or sp 3 C-H functionalization─lends perspective and tactical strategies for use of these methods in synthetic applications.