Direct photocatalyzed hydrogen atom transfer (d-HAT) can be considered a method of choice for the elaboration of aliphatic C-H bonds. In this manifold, a photocatalyst (PCHAT) exploits the energy of a photon to trigger the homolytic cleavage of such bonds in organic compounds. Selective C-H bond elaboration may be achieved by a judicious choice of the hydrogen abstractor (key parameters are the electronic character and the molecular structure), as well as reaction additives. Different are the classes of PCsHAT available, including aromatic ketones, xanthene dyes (Eosin Y), polyoxometalates, uranyl salts, a metal-oxo porphyrin and a tris(amino)cyclopropenium radical dication. The processes (mainly C-C bond formation) are in most cases carried out under mild conditions with the help of visible light. The aim of this review is to offer a comprehensive survey of the synthetic applications of photocatalyzed d-HAT.

Direct Photocatalyzed Hydrogen Atom Transfer (HAT) for Aliphatic C-H Bonds Elaboration

Organic compounds labeled with hydrogen isotopes play a crucial role in numerous areas, from materials science to medicinal chemistry. Indeed, while the replacement of hydrogen by deuterium gives rise to improved absorption, distribution, metabolism, and excretion (ADME) properties in drugs and enables the preparation of internal standards for analytical mass spectrometry, the use of tritium-labeled compounds is a key technique all along drug discovery and development in the pharmaceutical industry. For these reasons, the interest in new methodologies for the isotopic enrichment of organic molecules and the extent of their applications are equally rising. In this regard, this Review intends to comprehensively discuss the new developments in this area over the last years (2017-2021). Notably, besides the fundamental hydrogen isotope exchange (HIE) reactions and the use of isotopically labeled analogues of common organic reagents, a plethora of reductive and dehalogenative deuteration techniques and other transformations with isotope incorporation are emerging and are now part of the labeling toolkit.

Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules.

The emergence of modern photocatalysis, characterized by mildness and selectivity, has significantly spurred innovative late-stage C-H functionalization approaches that make use of low energy photons as a controllable energy source. Compared to traditional late-stage functionalization strategies, photocatalysis paves the way toward complementary and/or previously unattainable regio- and chemoselectivities. Merging the compelling benefits of photocatalysis with the late-stage functionalization workflow offers a potentially unmatched arsenal to tackle drug development campaigns and beyond. This Review highlights the photocatalytic late-stage C-H functionalization strategies of small-molecule drugs, agrochemicals, and natural products, classified according to the targeted C-H bond and the newly formed one. Emphasis is devoted to identifying, describing, and comparing the main mechanistic scenarios. The Review draws a critical comparison between established ionic chemistry and photocatalyzed radical-based manifolds. The Review aims to establish the current state-of-the-art and illustrate the key unsolved challenges to be addressed in the future. The authors aim to introduce the general readership to the main approaches toward photocatalytic late-stage C-H functionalization, and specialist practitioners to the critical evaluation of the current methodologies, potential for improvement, and future uncharted directions.

Photocatalytic Late-Stage C-H Functionalization.

Dearomatization reactions provide rapid access to structurally complex three-dimensional molecules from simple aromatic compounds. Plenty of reports have demonstrated their utilities in the synthesis of natural products, medicinal chemistry, and materials science in the last decades. Recently, visible-light mediated photocatalysis has emerged as a powerful tool to promote many kinds of transformations. The dearomatization reactions induced by visible-light have also made significant progress during the past several years. This review provides an overview of visible-light induced dearomatization reactions classified based on the manner in which aromaticity is disrupted.

Visible-light induced dearomatization reactions.

Substitution of a hydrogen atom with its heavy isotope deuterium entails the addition of one neutron to a molecule. Despite being a subtle change, this structural modification, known as deuteration, may improve the pharmacokinetic and/or toxicity profile of drugs, potentially translating into improvements in efficacy and safety compared with the non-deuterated counterparts. Initially, efforts to exploit this potential primarily led to the development of deuterated analogues of marketed drugs through a ‘deuterium switch’ approach, such as deutetrabenazine, which became the first deuterated drug to receive FDA approval in 2017. In the past few years, the focus has shifted to applying deuteration in novel drug discovery, and the FDA approved the pioneering de novo deuterated drug deucravacitinib in 2022. In this Review, we highlight key milestones in the field of deuteration in drug discovery and development, emphasizing recent and instructive medicinal chemistry programmes and discussing the opportunities and hurdles for drug developers, as well as the questions that remain to be addressed. Substituting a hydrogen atom with its heavy isotope deuterium may improve the pharmacokinetic and/or toxicity profile of a drug compared with its non-deuterated counterpart. This article highlights milestones in the field of deuteration in drug discovery and development, and discusses recent examples of its application, which have shifted towards deuteration of novel drug candidates instead of developing deuterated analogues of marketed drugs. 

/pdf/deuterium-in-drug-discovery-progress-opportunities-and-2vf7zlsi.pdf

Deuterium in drug discovery: progress, opportunities and challenges

Since the seminal work of Zhang in 2016, donor-acceptor cyanoarene-based fluorophores, such as 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN), have been widely applied in photoredox catalysis and used as excellent metal-free alternatives to noble metal Ir- and Ru-based photocatalysts. However, all the reported photoredox reactions involving this chromophore family are based on harnessing the energy from a single visible light photon, with a limited range of redox potentials from -1.92 to +1.79 V vs SCE. Here, we document the unprecedented discovery that this family of fluorophores can undergo consecutive photoinduced electron transfer (ConPET) to achieve very high reduction potentials. One of the newly synthesized catalysts, 2,4,5-tri(9H-carbazol-9-yl)-6-(ethyl(phenyl)amino)isophthalonitrile (3CzEPAIPN), possesses a long-lived (12.95 ns) excited radical anion form, 3CzEPAIPN•-*, which can be used to activate reductively recalcitrant aryl chlorides (Ered ≈ -1.9 to -2.9 V vs SCE) under mild conditions. The resultant aryl radicals can be engaged in synthetically valuable aromatic C-B, C-P, and C-C bond formation to furnish arylboronates, arylphosphonium salts, arylphosphonates, and spirocyclic cyclohexadienes.

Unveiling Extreme Photoreduction Potentials of Donor-Acceptor Cyanoarenes to Access Aryl Radicals from Aryl Chlorides

Deuterated organic compounds have widespread applications in many fields such as medicinal chemistry, mechanistic studies, and quantitative analyses. Traditionally, the incorporation of deuterium atoms into organic compounds can be achieved either by multistep synthesis from commercially available deuterated precursors or by a direct hydrogen isotope exchange (HIE) assisted by an acid/base or a transition metal. Recently, photocatalytic deuteration, normally bearing merits such as mild conditions, good site selectivity, and cheap and readily available deuterium sources, has emerged as a reliable platform for the generation of medicinally and synthetically valuable deuterated organic molecules, especially deuterated pharmaceutical compounds. This review summarizes the recent advances in visible-light photocatalytic deuteration reactions according to the type of bond deuterated in these reactions.

Recent advances in visible-light photocatalytic deuteration reactions

Metal-free hydrogen evolution cross-coupling enabled by synergistic photoredox and polarity reversal catalysis

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Unveiling Extreme Photoreduction Potentials of Donor-Acceptor Cyanoarenes to Access Aryl Radicals from Aryl Chlorides

Recent advances in visible-light photocatalytic deuteration reactions

Metal-free hydrogen evolution cross-coupling enabled by synergistic photoredox and polarity reversal catalysis