Photo-/electro-chemical catalysis: a promising toolkit for late-stage functionalization of alkene-containing natural products†

Ji-Wei Sang ^ab, Yu Zhang ^c, Zhimin Hu *^a, Jinxin Wang *^a and Wei-Dong Zhang *^abcd
aDepartment of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, P. R. China. E-mail: 13021941113@163.com; jxwang2013@126.com; wdzhangy@hotmail.com
^bState Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, NMPA Key Laboratory for Research and Evaluation of Innovative Drug, Henan Normal University, Henan 453007, P. R. China
^cShanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P. R. China
^dInstitute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, P. R. China

First published on 1st August 2025

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Ji-Wei Sang

Ji-Wei Sang received his MS degree from Henan Normal University in 2021 under the supervision of Prof. Hai-Ming Guo. He completed his PhD training in the group of Prof. Wei-Dong Zhang through a joint program between the Naval Medical University and Henan Normal University. He is currently a Postdoctoral Researcher in the group of Assistant Professor Runze Mao at Tsinghua Shenzhen International Graduate School. His research interests focus on synthetic chemistry and synthetic biology.

Yu Zhang

Yu Zhang received his MSc degree in Medicinal Chemistry from the School of Pharmacy, Shanghai Jiao Tong University in 2017. He obtained his PhD from the Georg-August-Universität Göttingen in 2020. In 2021, he became a Postdoctoral Researcher at the University of Antwerp. In January 2022, he became an Associate Professor at the Shanghai University of Traditional Chinese Medicine. His research focuses on natural medicinal chemistry and drug discovery. He has published around 30 papers in well-known journals such as Chem, Nature Protocols, Nature Communications, Advanced Science, and ACS Central Science in the fields of organic synthesis and medicinal chemistry (ORCID: 0000-0002-7230-3575).

Zhimin Hu

Zhimin Hu received her BSc and MSc degrees from the School of Pharmaceutical Sciences at Peking University in 2017 and 2019. She obtained her PhD in Traditional Chinese Pharmacy at China Academy of Chinese Medical Sciences (2022). Since 2022, she began her research career in the research group of Prof. Wei-dong Zhang at the School of Pharmacy at Naval Medical University. Her research interests focus on the biosynthesis and chemo-enzymatic synthesis of bioactive natural products.

Jinxin Wang

Jinxin Wang earned his BS from the School of Traditional Chinese Pharmacy at China Pharmaceutical University in 2013. He received his PhD in Medicinal Chemistry in 2019 from Naval Medical University under the supervision of Prof. Wei-dong Zhang. During this time, he completed joint PhD studies at Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences with Prof. Ang Li. He began his independent career at the school of Pharmacy at Naval Medical University in 2020. His research interests include the development of synthesis methods that could lead to privileged skeletons and chemo-enzymatic synthesis and structural modification of bioactive natural products.

Wei-Dong Zhang

Prof. Wei-Dong Zhang obtained his bachelor's and master's degrees in Natural Medicinal Chemistry from the Second Military Medical University in 1988 and 1991, respectively. He received his PhD in Natural Medicinal Chemistry from the Shanghai Institute of Pharmaceutical Industry (1998), under the supervision of Professor HuiTing Li. He is currently a Professor at the Shanghai University of Traditional Chinese Medicine and Second Military Medical University. His research mainly focuses on Chinese medicine formulas, isolation, structural identification and modification, total synthesis, and structure–activity relationships in bioactive natural products.

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1. Introduction

Natural products (NPs) are the outcome of nature's extensive exploration of biologically significant chemical domains via evolution, constituting a valuable wellspring of bioactive small molecules for application in the fields of chemical biology and medicinal chemistry.¹ Despite the mounting competition from pharmaceutical and synthetic chemistry and the expansion of chemical biology, drugs derived from NPs have maintained a consistent presence in the pharmaceutical landscape over recent decades. Over the past four decades, approximately 40% of the pharmaceutical compounds that received approval from the U.S. Food and Drug Administration (FDA) has been derived from NPs, with a significant focus on antibiotics and antineoplastic agents.² NPs have been serving as valuable reservoirs of bioactive scaffolds and will continue to play a key role in successful molecular discovery endeavors. Nonetheless, NPs are restricted to evolutionary constraints, leaving numerous biologically fascinating NPs yet to be unearthed, thereby confining their presence to a mere fraction of the theoretical NP-like chemical spaces; thus, depending exclusively on nature as the source of bioactive molecules has its inherent limitations.³ Therefore, the pursuit of structural modifications to inspire the discovery of new bioactive chemical entities is highly promising.⁴ Moreover, the utilization of structural modification of NPs in the realm of drug discovery is multifaceted, encompassing activities such as unraveling the mechanisms of action, repurposing of drugs, streamlining the structures, enhancing the metabolic stability, and optimizing the solubility.⁵

Structural modification of diverse NPs through synthetic chemistry can lead to novel biological activities and the discovery of new molecular entities. While these newly generated scaffolds often retain the biological relevance of their parent NPs, they lie beyond the reach of known biosynthetic pathways. This strategy has enabled the development of NP-derived drugs such as artemisinin (antimalarial), taxol (anticancer), morphine (analgesic), and quinine (antiviral), highlighting how synthetic diversification can unlock therapeutic properties inaccessible through biosynthesis alone.⁶

Undoubtedly, alkene-containing NPs, including terpenes, alkaloids, steroids, and fatty acids, are abundantly present in plants, animals, and microorganisms. These compounds exhibit diverse structures and functionalities, exerting significant impacts on organisms and ecosystems. In recent decades, alkene-involved reactions have played a central role in organic synthesis.⁷ Through systematic design and meticulous control, these reactions facilitate a spectrum of chemical transformations, unlocking novel avenues for broadening the chemical landscape in science and technology. Traditional types of alkene reactions include addition reactions, oxidation reactions, cyclization reactions, and isomerization reactions. Nevertheless, the development of alkene-involved reactions characterized by gentler conditions, environmental friendliness, and heightened selectivity remains an ongoing exploration for synthetic chemists.⁸ Strategic carbon–carbon double bond (CC) modification of NPs not only aids in unraveling intricate mechanisms and cellular targets but also generates diverse chemical libraries, enriching scaffold, stereochemistry and appendage variations, thereby swiftly expanding the realm of chemical space. Simultaneously, these modifications bolster the metabolic stability of NPs, contributing to overcoming drug resistance, enhancing their bioavailability, and prolonging their in vivo biological efficacy. For example, Oridonin, a complex ent-kaurane diterpenoid, demonstrates remarkable antitumor activities. Through CC modification, it has been established that the α,β-unsaturated ketone fragment serves as the key pharmacophore responsible for both the anticancer activity and uptake of oridonin (Fig. 1A).^9a Esculetin, abundant in Fraxinus chinensis Roxb. and various other plants, exhibits anti-inflammatory and antitumor activities. Its antitumor efficacy is particularly enhanced against myeloid cell leukemia-1 after undergoing CC containing NP modification (Fig. 1B).^9b Following the implementation of late-stage functionalization (LSF) on a series of alkene-containing NPs via electrocatalysis, there was a significant enhancement in the anticancer activity of the resulting compounds (Fig. 1C).^9c

Over the past 15 years, visible-light photocatalysis¹⁰ and electrochemical catalysis¹¹ have emerged as two highly esteemed approaches for catalyzing chemical reactions. At the heart of photocatalysis lies the remarkable ability of light energy to engage open-shell reaction pathways with high efficiency and remarkable gentleness. In fact, intermediates with unpaired electrons (radicals) typically exhibit significantly enhanced reactivity compared to, or in an orthogonal fashion to, closed-shell species. Furthermore, the widespread availability of transition metal complexes or organic dyes (see Table 1 in the ESI†) and standardized equipment, including photo reactors and light sources, has substantially diminished the barriers to the practical application of this technology. Concurrently, the resurgence of radical chemistry has ignited a revival of synthetic electrochemistry. The extensive spectrum and precision of redox potentials, unmatched by conventional chemical reagents, combined with the ready accessibility of electrical energy, make electrochemistry an exceedingly appealing method. Within the broader realm of electrochemistry, electrocatalysis stands out as an especially advantageous technique in synthetic chemistry, employing reusable electron mediators to govern interactions between substrates and electrodes. Electrocatalysis offers a multitude of benefits, encompassing the capacity to modulate selectivity, enhance electron transfer kinetics, and mitigate the risk of electrode passivation. Nevertheless, in the process of photochemical conversion, not all energy can be effectively harnessed by photocatalysts, as non-radiative routes within the system can result in energy dissipation, posing challenges in the activation of unreactive chemical bonds. Owing to the intricate nature of electrochemical devices and the utilization of additives, electrochemical organic reactions have not entirely satisfied the demands of organic synthesis. As a result, these methods necessitate adaptable utilization contingent on the specific characteristics of the reaction at hand.¹² It is worth emphasizing that these radical-mediated strategies have indeed altered the conventional transformation patterns of alkenes. They reduce dependence on stringent reaction conditions, showcasing more green and efficient characteristics.

Over the years, numerous articles have been published, providing concise summaries of remarkable advancements in the fields of photo-organic synthesis, electro-organic synthesis, and LSF, respectively. These contributions have predominantly focused on the exploration of chemical reactivity, often neglecting a thorough examination of the potential and feasibility for NPs.¹³ There exists a notable gap in the literature, with no comprehensive review addressing the photo-/electro-chemical direct LSF of alkene-containing NPs. Therefore, we summarize a series of carefully chosen instances illustrating the photo-/electro-chemical LSF of alkene-containing NPs from the last decade, including hydrofunctionalization of alkenes, difunctionalization of alkenes, conversion to functionalized vinylic systems, formation of cyclic systems, functionalization of allylic positions and isomerization of alkenes (Fig. 1D). We have compiled a list of alkene-containing NPs including alkaloids, steroids, and terpenes from these reactions to demonstrate the extensive diversity of the recent successful application (Fig. 2). It is noteworthy to clarify that, in this article, we define the LSF of alkenes as the direct, site-selective, and chemoselective functionalization of NPs characterized by endogenous CC groups. The scope of this review excludes the modification of NPs and the addition of pendant groups for the purpose of guiding reactivity or serving as reaction centers. The presence of protecting groups, despite potentially increasing the synthetic effort in a sequence, falls within the purview of this review. This review is organized according to the reaction types of alkenes, and we aim to elucidate the pathways for the LSF of NPs, exploring their synthetic potential and delineating the limitations of specific reaction classes. This review encompasses original articles published from 2013 to December 2024. Despite the authors' conscientious efforts to incorporate all pertinent reports within the field, any unintentional omissions are sincerely regretted. To facilitate a quick overview of the scope of alkene functionalization, a summary of representative functional groups that can be installed on alkenes under photo- or electro-chemical conditions is provided (see Tables 2–7 in the ESI†), along with the corresponding reaction types, key conditions, and references. To comply with the journal's page limit, we provide a summary of representative reaction schemes for each class of reactions at the beginning of each chapter in the main text, enabling readers to quickly grasp the common framework of various reactions. Meanwhile, we discuss in detail the different types of reaction mechanisms in a graphical format in the ESI Section† to ensure the integrity and readability of the content.

2. Hydrofunctionalization of alkenes

The distinctive SOMO characteristics of alkenes render them ideal substrates for radical-mediated LSF in photo-/electro-catalytic systems. The general reaction paradigm commences with radical addition to the alkene, generating a stabilized carbon-centered radical intermediate. Subsequent reaction pathways bifurcate into four distinct mechanistic manifolds (Fig. 3): (1) radical–radical cross-coupling: direct homolytic coupling between the carbon-centered radical and a secondary radical species through spin-pairing interactions. (2) Nucleophilic radical–electrophile coupling: the nucleophilic carbon-centered radical engages with an electrophilic partner, forming a cation radical intermediate. Subsequent single-electron transfer (SET) processes facilitate charge neutralization, ultimately yielding the functionalized product. (3) Ionic intermediate pathway: the carbon-centered radical undergoes SET oxidation or reduction, generating either a carbocation or a carbanion intermediate. These ionic species subsequently participate in classical two-electron processes with nucleophiles or electrophiles, respectively. (4) Bimolecular homolytic substitution (S_H2): the carbon-centered radical interacts with transition metal complexes through a concerted three-center transition state, enabling formal substitution while preserving the radical character.

2.1 Hydrogenation of alkenes

The hydrogenation of alkenes commonly employs conventional approaches, typically requiring high-pressure hydrogen gas along with heterogeneous catalysts that are often costly and potentially toxic. Hence, there is a crucial need to develop environmentally friendly and mild methods for the hydrogenation of alkenes.¹⁴ In 2021, Matsunaga's group introduced a novel approach that utilizes a cobalt/photoredox catalysis system, allowing for ascorbic acid-mediated hydrogen atom transfer (HAT) hydrogenation of alkenes in aqueous media. Although aqueous conditions were primarily advantageous for the hydrogenation of polar substrates, substrates lacking polar functional groups were also efficiently hydrogenated, yielding synthetically valuable products. This catalytic system not only offers enhanced sustainability and a markedly improved safety profile compared to conventional hydrogen atom transfer (HAT) approaches, but simultaneously exhibits unprecedented tolerance towards diverse functional groups, well-suited for the late-stage hydrogenation of amino acid derivatives, natural products, and drug molecules, including compounds such as antioxidant dihydrolinalool, anticancer citronellol, antiviral isopulegol, capsaicin (neuroprotection), and antiviral mycophenolic acid. This method provides a unique advantage by enabling the direct conversion of unprotected sugar derivatives and achieving HAT hydrogenation of unprotected C-glycosides with significantly improved yields in comparison to previously reported HAT hydrogenation protocols (Scheme 1A).¹⁵ In 2023, Lam and co-workers presented a versatile, practical, and mild electrochemical process for the hydrogenation and deuteration of unsaturated compounds, employing hydrazine as a cost-effective source of H₂. This method provides a valuable complement to conventional hydrogenation techniques. This metal-free methodology efficiently reduced a wide range of alkenes and alkynes, yielding the corresponding alkanes in moderate to excellent yields. The mild reaction conditions demonstrated a high degree of tolerance for various functional groups. Notably, this method remained compatible with certain NPs, encompassing compounds such as sclareol, isopulegol, linalool, and capsaicin (Scheme 1B).¹⁶ More recently, Fu group developed a robust hydrogen-free electrochemical hydrogenation protocol, which uses a simple and bench-stable nickel salt as the catalyst. Enabled by the electrochemical Ni-catalysis, it is applicable to alkene substrates with diverse substitution patterns and electronic properties, including electron-deficient alkenes, styrenes and unactivated alkenes. The method exhibits remarkable regioselectivity, allowing for the reduction of α-olefins while leaving 1,2- and 1,1-disubstituted alkenes alone. The good functional group tolerance was also showcased in the LSF of NPs such as linalool, progesterone and testosterone converted into corresponding products in good yields (Scheme 1C).¹⁷

2.2 Hydrofluoroalkylation of alkenes

In recent decades, there has been a growing interest in the photo-/electro-chemically mediated hydrofunctionalization of alkenes and their diverse applications. Recent research endeavors reveal a notable trend of an increasing number of annual publications each year.¹⁸

Introducing fluoroalkyl moieties into small molecules selectively is a commonly employed technique to enhance characteristics such as bioavailability and metabolic stability. This approach is highly effective in the development of novel pharmaceuticals and the enhancement of the effectiveness of pre-existing drugs. As a result, numerous pharmaceuticals and bioactive compounds incorporate fluoroalkyl moieties.¹⁹ In 2021, Molander's group reported a method for the photochemically mediated defluoroalkylation of ethyl trifluoroacetate. A novel mechanistic pathway for the hydroalkylation of diverse alkenes was discovered through the utilization of a diarylketone HAT catalyst. Additionally, electrochemical investigations demonstrated the potential functionalization of the trifluoroacetamide radical precursor through synergistic Lewis acid/photochemical activation. This methodology offers a streamlined synthesis approach for novel geminal difluoro analogs of CC-containing NPs. As an example of NPs, (−)-limonene oxide, anxiolytic linalool oxide, (−)-carvone (acetylcholinesterase inhibitor) and (−)-longifolene, respectively, smoothly reacted with ethyl trifluoroacetate to obtain compounds (Scheme 2A).²⁰ In 2023, Dilman and co-workers introduced mild hydrofluoroalkylation, in which alkenes undergo a reaction with trifluoroacetic esters to yield difluorinated products under visible light irradiation. This process incorporates the use of easily accessible trimethyltriazine as a reducing agent, generating a diamino-substituted alkyl radical that serves as a potent electron donor. The scope of internal alkenes was tested on complex scaffolds such as limonene (antimicrobial) and terpineol (antifungal) (Scheme 2B).²¹ In 2022, Xie's group disclosed manganese-catalyzed hydrofluoroalkylation and hydropolyfluoroarylation of alkenes using white LEDs. This methodology exhibited a wide substrate scope, excellent functional group compatibility, and extensive late-stage diversification, emphasizing the protocol's synthetic robustness, as demonstrated with pregnenolone (neurosteroid). Both experimental and computational mechanism studies elucidated the vital role of a bidentate phosphine ligand in enhancing the stability and reactivity of the light-induced manganese-central radical (Scheme 2C).²²

In 2016, Qing's group introduced a pioneering approach for the visible-light-mediated hydrodifluoromethylation of alkenes with bromodifluoromethylphosphonium bromide. This innovative method uses H₂O and THF as hydrogen sources. Significantly, this difluoromethylation process stands out for its gentle reaction conditions, the ready accessibility of reagents, and its remarkable tolerance towards a diverse array of functional groups (Scheme 3A).²³ In 2023, the same group achieved an advancement by pioneering the hydrofluoromethylation of unactivated alkenes using fluoroiodomethane and hydrosilanes. This method was realized through the integration of photoredox catalysis and silane-mediated deiodination processes. Prominent characteristics of this methodology encompass the employment of H₂O as the solvent, strategically chosen to enhance the reactivity of CH₂F radicals towards unactivated alkenes. Furthermore, ICH₂F serves as the CH₂F radical source and PhSiH₃ functions as the H-donor in the process (Scheme 3B).²⁴ In 2022, Wu's group described photocatalytic hydrodifluoromethylation of unactivated alkenes using the inexpensive industrial chemical chlorodifluoromethane (ClCF₂H, Freon-22). This protocol involves merging tertiary amine-ligated boryl radical-induced halogen atom transfer (XAT) under blue light irradiation in a metal-free manner. A diverse range of readily available alkenes, encompassing various functional groups as well as drug and natural product motifs, could be selectively difluoromethylated with high efficiency (Scheme 3C).²⁵ More recently, the same group has provided an elegant methodology for the synthesis of difluorinated compounds from alkenes. This approach used the easily accessible reagent, ClCF₂SO₂Na, acting as a versatile “difluoromethylene” building block. Various difluorinated compounds were successfully synthesized by employing an organophotoredox-catalyzed hydrochlorodifluoromethylation of alkenes, followed by a ligated boryl radical-facilitated XAT process. To further prove the robustness of this protocol, the LSF of some complex drugs and NPs was reported, among which the NPs containing alkenes are anti-inflammatory nootkatone, anticarcinogenic sclareol, insecticide rotenone, cholesterol (estrogen-related receptor α agonist), pregnenolone, (+)-dihydrocarvone, antiproliferative camphene and more (Scheme 3E).²⁶

In 2013, Gouverneur's group unveiled a photoredox-induced hydrotrifluoromethylation of unactivated alkenes, employing the Umemoto reagent as the CF₃ source and MeOH as the reductant. The process is distinguished by its operational simplicity and exceptional functional group tolerance, encompassing various pharmaceutical scaffolds and natural product motifs as substrates. Notable examples include cholecalciferol (Vitamin D3), anti-malarial quinine, and carvone (Scheme 4A).²⁷ In 2014, Scaiano and co-workers documented a significant development involving the visible-light-induced utilization of methylene blue as a photosensitizer for catalytic radical trifluoro- and hydrotrifluoro-methylation reactions. This innovative approach extends to electron-rich heterocycles, as well as terminal alkenes and alkynes. These reactions exhibit moderate to good yields even at low catalyst concentrations, with short irradiation times, all while eliminating the necessity for potentially toxic transition-metal catalysts (Scheme 4B).²⁸ More recently, West and co-workers have unveiled a comprehensive catalytic protocol for the hydrofluoroalkylation of alkyl and aryl alkenes with varying fluoroalkyl carboxylic acids through the cooperative iron photocatalysis and thiol-catalyzed XAT. This innovative approach enables the efficient hydrotrifluoro-, difluoro-, monofluoro-, and perfluoro-alkylation under a unified pathway. The demonstrated methodology exhibits a broad scope, operates under mild redox-neutral conditions, and showcases the potential for LSF. It overcomes limitations observed in previous synthetic methods, including issues with scope tolerance, the superstoichiometric use of potent oxidants, and the necessity of noble metal catalysts. Crucially, this innovative approach enables the direct utilization of cost-effective feedstock chemicals, exemplified by TFA, possessing exceptionally high redox potentials, as the CF₃ source. This circumvents the formidable challenges associated with redox potential considerations by harnessing the catalytic prowess of an earth-abundant and economical iron catalyst in conjunction with a redox-active organic thiol cocatalyst. This collaborative approach will be an asset for assembling fluoroalkylated compounds modularly and speeding up the synthesis of analogs to commercially available drugs and NPs (Scheme 4C).²⁹ Malapit's group has developed an unprecedented electroreductive hydro-trifluoromethylation strategy for unactivated olefins through voltage-gated electrosynthesis. This transition metal-free methodology employs trifluoromethyl thianthrenium salt (TT⁺CF₃BF₄⁻) as the CF₃ radical precursor, which undergoes cathodic reduction to generate electrophilic trifluoromethyl radicals. The reaction proceeds via a radical-polar crossover mechanism: initial CF₃ radical addition to olefins forms carbon-centered radicals that undergo subsequent cathodic reduction to carbanions rather than conventional HAT, followed by protonation from the acetone solvent. Critical to success was the implementation of MgBr₂ as a sacrificial reductant, enabling operation in undivided cells while suppressing competitive dibromination pathways through precise voltage control (ΔE ≈ 1.00 V). The methodology demonstrates exceptional functional group tolerance, successfully modifying pharmaceutically relevant NPs, including quinine. This work establishes a paradigm for selective olefin functionalization through voltage-regulated redox pairing, expanding synthetic accessibility to trifluoromethylated bioactive molecules (Scheme 4D).³⁰

2.3 Hydroalkylation of alkenes

Incorporating ester structures into drugs serves several primary objectives, including enhancing the drug's stability, as shown in the case of vitamin A, reducing drug-induced irritation, as exemplified by benoxate, and enabling a change in the route of administration, such as oral delivery, as demonstrated by cefuroxime axetil.³¹ In 2018, Murakami and co-workers presented a practical approach for the synthesis of elongated aliphatic esters from alkenes. This method involves the generation of an (alkoxycarbonyl)methyl radical species under visible-light irradiation of an ester-stabilized phosphorus ylide in the presence of a photoredox catalyst. This radical species adds to the CC of alkenes, resulting in the formation of elongated aliphatic esters. The broad substrate scope and the accommodating reaction conditions encompassing a variety of functional groups render this method highly valuable for the synthesis of elongated aliphatic esters from alkenes (Scheme 5A).³² In 2023, Kobayashi's group devised a remarkably efficient method for catalytic α-alkylation of active methylene and methine compounds using nonactivated alkenes under blue-light irradiation. This breakthrough employed an organophotocatalyst in conjunction with lithium thiophenoxide, acting as a multifunctional catalyst that serves as a Lewis acid and Brønsted base, and participates in HAT. By implementing a continuous-flow system, this system was able to scale up the production, yielding multigram scales of the desired products. This innovative approach opens up new avenues for highly efficient and practical α-alkylation reactions involving active methylene and methine compounds. Furthermore, this method found application in the LSF of NPs and drug molecules. Limonene, caryophyllene and cholesterol were successfully functionalized through the alkylation reaction, resulting in the production of the corresponding products with moderate yields (Scheme 5B).³³ More recently, Melchiorre and co-workers reported a straightforward protocol that utilizes an inexpensive thiol catalyst to unite two alkenes, forming a new C–C bond under a photoredox catalyst. An electron-poor alkene is reduced by the photoredox catalyst to generate, upon protonation, a carbon radical, which is then captured by a neutral alkene. This intermolecular cross-coupling process serves as a valuable tool for the rapid synthesis of sp³-dense molecules from alkenes, employing an unconventional disconnection. Notably, this method exhibits high tolerance for functional groups, making it suitable for the LSF of biorelevant compounds such as antimicrobial β-pinene, anti-inflammatory caryophyllene oxide, and gibberellic acid (Scheme 5C).³⁴ A catalytic strategy was developed by Zeng's group for the C–H bond functionalization of polyethylene glycols (PEGs) through ammonium ion-mediated noncovalent interactions. This photoinduced co-catalysis system employs iridium complex [Ir(dF(CF₃)ppy)₂(dtbbpy)]PF₆ and quinuclidine under visible light irradiation, enabling efficient alkylation of PEGs with diverse acrylates via a radical-mediated pathway. Mechanistic studies reveal a sequential process involving hydrogen atom abstraction by quinuclidine radical, direct reduction of α-carbon radicals adjacent to oxygen atoms by Ir(II), and subsequent Michael-type nucleophilic addition to acrylates. Notably, DFT calculations and experimental evidence confirm the critical role of supramolecular interactions between PEG chains and quinuclidinium species in facilitating proton transfer and stabilizing reactive intermediates. The methodology demonstrates remarkable versatility in biofunctionalization, successfully incorporating therapeutic agents, including isoalantolactone and parthenolide, into PEG backbones through LSF strategies (Scheme 5D).³⁵ In 2024, MacMillan and co-workers presented the first C(sp³)–C(sp³) coupling of metal-HAT (MHAT)-activated alkenes with alcohols via deoxygenative hydroalkylation using triple co-catalysis. By leveraging synergistic pathways involving Ir photoredox, Mn MHAT, and Ni radical sorting, this branch-selective protocol facilitates the coupling of diverse olefins with methanol or primary alcohols, showcasing remarkable tolerance toward functional groups. This methodology enables the rapid construction of complex aliphatic frameworks of medicinal relevance (Scheme 5E).³⁶

2.4 Hydroamination of alkenes

Alkene hydroamination represents an ideal approach for synthesizing aliphatic amines, as it enables the direct combination of alkenes with simple N–H functional groups in a manner that is both direct and atom-economical.³⁷ In 2018, Knowles and co-workers disclosed a catalytic approach for achieving intermolecular anti-Markovnikov hydroamination of unactivated alkenes using simple sulfonamides under visible-light irradiation. This innovative method is made possible by the activation of the sulfonamide N–H bond via proton-coupled electron transfer (PCET). The mild reaction conditions showcased a remarkable tolerance towards a diverse range of functional groups (Scheme 6A).³⁸ In 2019, Studer and co-workers pioneered a photoredox and thiol co-catalyzed approach for the radical hydroamidation of a wide array of unactivated and electron-rich alkenes, all conducted under practical and mild conditions. The method's exceptional functional group tolerance was further exemplified in the late-stage hydroamidation of NPs, such as sclareol, anti-tumor linalool, camphene and antibacterial α-pinene, which were converted into various Cbz-protected amines in good to excellent yields (Scheme 6B).³⁹ In 2023, Knowles's group presented a light-driven approach for achieving intermolecular anti-Markovnikov hydroamination of alkenes using primary heteroaryl amines. In this methodology, electron transfer occurs between an amine substrate and an excited-state iridium photocatalyst, leading to the formation of an aminium radical cation (ARC) intermediate. This ARC species subsequently engages in C–N bond formation with a nucleophilic alkene. This practical and cost-effective technique has found broad applicability across various alkenes and heteroaryl amines. The derivatization yields for linalool and (+)-α-pinene were reported as 90% and 88%, respectively (Scheme 6C).⁴⁰ Alexanian's group have developed a cobalt-catalyzed hydroaminocarbonylation reaction that enables the direct synthesis of amides from alkenes and amines under mild, light-promoted conditions. This methodology employs unmodified Co₂(CO)₈ as a precatalyst, operating at low CO pressure (1–5 atm) and ambient to moderate temperatures under 390 nm LED irradiation. Mechanistic studies suggest that the photodissociation of a carbonyl ligand generates a catalytically active hydridocobalt species HCo(CO)₃, which facilitates alkene hydrocobaltation, migratory CO insertion, and subsequent nucleophilic attack by amines. The process exhibits exceptional regioselectivity, favoring linear amides via chain-walking of transient alkylcobalt intermediates, particularly with acyclic substrates. Notably, the reaction demonstrates broad applicability to structurally diverse alkenes, including terminal, di-, tri-, and tetra-substituted variants, as well as complex NPS. The successful functionalization of β-citronellol, (–)-sclareol, cholesterol, quinine, and brucine highlights its compatibility with sterically demanding and polar-functionalized substrates. The methodology addresses longstanding challenges in carbonylative coupling by circumventing traditional limitations of metal hydride stability in the presence of Lewis basic alkylamines, thereby expanding access to medicinally relevant amides (Scheme 6D).⁴¹

2.5 Hydroheteroarylation of alkenes

Functionalized (hetero) aromatic units are important structural elements in bioactive small molecules that span a wide range of applications.⁴² In 2015, Weaver and co-workers disclosed the photocatalytic reductive coupling of aryl bromides with unactivated alkenes. This process entailed light-triggered electron transfer from a tertiary amine to an aryl bromide, resulting in cleavage and formation of an aryl radical. This radical then proceeded to react with the alkene, leading to the formation of a C(sp²)–C(sp³) bond. Additionally, amines acted as the final reductant in this transformation. This methodology exhibited high functional group tolerance, exceptional selectivity, and proved versatile for synthesizing complex molecules such as anticancer (+)-perillyl alcohol, camphene, carvone, cholesterol, α-pinene, terpineol and (−)-caryophyllene oxide (Scheme 7A).⁴³ In 2023, Ye and co-workers introduced a light-induced hydroarylation reaction of unactivated alkenes utilizing 4-hydroxycoumarin as the arylating reagent. The nucleophilic 4-hydroxycoumarin undergoes conversion into electrophilic carbon radicals through photocatalytic arene oxidation, effectively bypassing the polarity mismatch issue commonly encountered under ionic conditions. Moreover, a [2 + 2] cycloaddition was successfully achieved, generating a cyclobutane-fused pentacyclic product with a high yield and diastereoselectivity, achieved by altering the photocatalyst. These methodologies hold significant synthetic potential in medicinal chemistry and are poised to expedite the discovery of biologically active 4-hydroxycoumarin derivatives (Scheme 7B).⁴⁴ More recently, Zhang and co-workers have introduced a mild photocatalysis approach using stable and readily prepared aromatic N-heterocyclic pyridinium salts as vital nitrogen-centered radical precursors. This method enables the effective conversion of diverse alkyl alkenes into pharmaceutically relevant alkylated N-heterocyclic amines. Mechanistic studies suggest the involvement of a triplet EnT pathway in the process (Scheme 7C).⁴⁵ Doyle's group has developed a cooperative phosphine–photoredox catalytic system enabling intermolecular anti-Markovnikov hydroamination of unactivated olefins with diverse N–H azoles. The mechanism proceeds through sequential SET tricyclohexylphosphine to a photoexcited iridium catalyst, generating a phosphine radical cation that undergoes nucleophilic attack by the azole substrate. Subsequent α-scission of the resulting phosphoranyl radical intermediate liberates a nitrogen-centered radical (NCR), which adds to the olefin followed by HAT to complete the catalytic cycle. This methodology demonstrates remarkable functional group tolerance and site selectivity, particularly evidenced in the LSF of bioactive compounds, including nootkatone and linalool. The protocol successfully modifies medicinally relevant nitrogen heterocycles such as purines (adenine, guanine derivatives), benzimidazoles, and 7-azaindoles, achieving exclusive N7-alkylation in purine systems and regioselective N1-functionalization of triazoles/pyrazoles (Scheme 7D).⁴⁶

2.6 Hydrohalogenation and hydronitrooxylation of alkenes

In 2023, Ritter's group developed the anti-Markovnikov addition of aqueous HCl and HNO₃ to unactivated alkenes. The conversion is accomplished through in situ generation of photoredox-active ion pairs, derived from acridine and mineral acids, acting as a charge and phase transfer combination catalyst. Introducing a HAT catalyst enables bypassing the chain propagation of HCl and HNO₃ caused by high bond dissociation energy. Concurrently, a range of structurally diverse products were obtained with high yields and notable functional group tolerance. This is underscored by the successful functionalization of bioactive compounds nootkatone and carvone in LSF (Scheme 8A).⁴⁷ In 2024, Ohmiya's group demonstrated hydrohalogenation of aliphatic alkenes with collidine·HX salts through dual photoredox/cobalt catalysis. The dual catalysis enables the conversion of a proton and a halide anion from collidine·HX salt to a nucleophilic hydrogen radical equivalent and an electrophilic halogen radical equivalent and their delivery to an alkene moiety. This protocol allows for the introduction of fluorine, chlorine, bromine, or iodine atom to alkene, producing highly functionalized alkyl halides (Scheme 8B).⁴⁸

2.7 Hydrocarboxylation of alkenes

A broad and general radical hydrocarboxylation reaction offers a powerful complement to transition-metal-catalyzed methods.⁴⁹ In 2021, Li and co-workers disclosed a formate salt-based photoredox activation method for carboxylation. This innovative approach uses a formate salt as both the reductant and carbonyl source, along with a HAT reagent. A diverse array of alkenes undergoes a carboxyl group transfer strategy, leading to acid products in an additive-free manner. Mechanistic studies show that radical anion species including CO₂˙⁻ and carbon radical anions were derived from alkene reduction, as pivotal intermediates in this transformation. The method offers high catalytic efficiency and features a straightforward catalytic system, positioning it as a promising strategy for potential industrial applications (Scheme 9).⁵⁰

2.8 Hydrooxygenation of alkenes

In 2017, Lei's group achieved a visible-light-induced anti-Markovnikov addition of H₂O to alkenes, employing an organic photoredox catalyst in collaboration with a redox-active H-donor. This approach eliminates the requirement for a transition-metal catalyst, stoichiometric borane, as well as an oxidant. The versatility of this method is evident as it accommodates both terminal and internal olefins, affording primary and secondary alcohols with high yields and single regioselectivity. Moreover, the scalability of this procedure has been demonstrated up to gram scale (Scheme 10A).⁵¹ In 2022, Glorius's group devised a gentle visible-light-promoted approach for achieving anti-Markovnikov hydrooxygenation of alkenes. They designed and synthesized a pyridinium salt capable of selectively forming an alkoxycarbonyloxyl radical after reduction. Using 2-phenylmalononitrile, they efficiently abstracted H atoms and initiated radical chain propagation. This protocol exhibited versatility in functionalizing a diverse range of bioactive compounds. Notably, it enabled the conversion of various unactivated alkenes, including camphene, showcasing broad functional group tolerance (Scheme 10B).⁵²

2.9 Hydroazidation of alkenes

Organic azides are integral components of a variety of pharmacophore molecules and chemical probes. They also play a crucial role in the synthesis of NPs, pharmaceuticals, and agricultural chemicals.⁵³ In 2023, Carreira and co-workers demonstrated a visible-light-initiated anti-Markovnikov hydroazidation of unactivated alkenes with NaN₃ facilitated by FeCl₃·6H₂O. Notably, this reaction showcased excellent resistance to air and moisture. Mechanistic investigations elucidated the crucial role of water in iron hydrate, acting as a source of H atoms. The transformation displayed wide functional group tolerance, accommodating both terminal alkenes and highly substituted alkenes, thus rendering it suitable for the functionalization of complex molecules, such as camphene (Scheme 11).⁵⁴

In this subsection, we provide a summary of the research conducted over the past decade on the photo-/electro-catalytic hydrofunctionalization of alkene-containing NPs. These transformations demonstrate significant potential in synthesizing a variety of valuable intermediates, bioactive molecules, and pharmaceutical compounds. The wide applicability of nonactivated alkenes further extends the utility of this reaction in the context of NPs. Moreover, the exploration and synthesis of more diverse chiral ligands for photo-/electro-catalytic enantioselective hydrofunctionalization of alkenes present broader research prospects.

3. Difunctionalization of alkenes

3.1 Amination of alkenes

In recent years, the difunctionalization of alkenes, involving the incorporation of two functional groups onto a CC bond, has emerged as a potent tool in organic synthesis. This method proves instrumental in constructing highly functionalized skeletons, elevating molecular complexity and paving the way for unconventional bond formations through streamlined processes. As a result, it has consistently garnered attention from chemists, becoming an area of ongoing exploration and innovation.^55,56

Alkene aminoarylation using a single or bifunctional reagent is a succinct synthetic strategy.⁵⁷ β-Amino acids are commonly encountered as crucial constituents in a wide array of biologically active molecules, pharmaceuticals, and NPs.⁵⁸ In 2022, Glorius's group pioneered a bifunctional oxime oxalate ester capable of simultaneously generating C-centered ester and N-centered imine radicals. This innovative approach used a metal-free, highly regioselective intermolecular aminocarboxylation reaction, enabling the efficient installation of amine and ester functionality into alkenes or (hetero)arenes in a single step via the EnT process. Notably, this mild method exhibited a broad substrate scope and excellent tolerance to sensitive functional groups, presenting a practical and versatile route for the synthesis of β-amino acid derivatives. The universality and effectiveness of this protocol were further underscored by successfully converting alkene-based NPs into their respective β-amino acid derivatives. Noteworthy examples include perillyl alcohol, antidepressant perillaldehyde, nootkatone, tulipalin A, limonene, carvone, and pinocarveol (Scheme 12A).⁵⁹ Soon after, the same group showcased an innovative approach for the photosensitized dearomative unsymmetrical diamination of a variety of electron-rich (hetero)arenes and alkenes under mild conditions without the need for transition metals or additives. The success of this achievement can be attributed to the meticulous design of bifunctional nitrogen-radical precursors, which simultaneously generate two distinct N-centered radicals through an EnT process. Remarkably, the resulting vicinal diamines possess two distinct amino functionalities, allowing for the convenient and independent conversion of either imine or amide units into unprotected amines. This feature greatly facilitates subsequent transformations. This method offers a straightforward, efficient, and practical means to access unsymmetrical vicinal diamines, making it valuable in both academic research and industrial applications (Scheme 12B).⁶⁰ At the same time, Xia's group developed bifunctional α-imino-oxy acid oxime esters, a molecule capable of simultaneously generating two distinct and reactive nitrogen-centered radicals. This approach harnessed metal-free, highly regioselective intermolecular cyanoalkylamination, enabling efficient integration of amino and cyanoalkyl functionalities into alkene substrates in a single step through the EnT process. This mild method exhibited excellent tolerance to sensitive functional groups. Its potential was further underscored by application in the LSF of complex drugs and NPs, as exemplified by anti-inflammation coumarin (Scheme 12C).⁶¹ Notably, inspired by these advancements, strategies for advancing the radical–radical vicinal difunctionalization of alkenes using bifunctional reagents via a triplet EnT pathway have been further developed.⁶²

In 2019, Yang and co-workers unveiled a novel application of the oxime phosphonate-derived phosphorus reagent. They successfully harnessed it in an intermolecular cascade radical addition reaction of alkenes, resulting in the formation of β-aminophosphonates. This transformation was achieved through visible-light-induced N-centered iminyl radical-mediated processes and redox-neutral, selective C–P bond cleavage within an active phosphorus radical pathway. Remarkably, this strategy exhibited broad tolerance for a diverse array of alkenes (Scheme 12D).⁶³ In 2023, Guin and co-workers disclosed a metal-free photocatalysis strategy employing sulfonyl-oxime-ethers as bifunctional reagents for the oximesulfonylation of olefins. Through simultaneous formation of C–S and C–C bonds, this process allows for the integration of oxime and sulfonyl groups into olefins in a fully atom-economic manner, offering efficient access to multi-functionalized β-sulfonyl oxime ethers with excellent yields and stereoselectivity. Mechanistic insights from the study indicated a radical chain mechanism initiated by photochemical HAT-mediated N–O bond cleavage. The efficacy of this method was further demonstrated through late-stage oximesulfonylation of natural compounds, exemplified by linalool and β-pinene (Scheme 12E).⁶⁴ In 2023, Li's group described an electrochemical approach for a “green” aminochlorination of alkenes, in which solvent acetonitrile and inorganic salt MgCl₂ readily functioned as sources of nitrogen and chlorine, respectively. Furthermore, benzimidazole was revealed to function as a reactivity modulator for chlorine radicals within the reaction. Through the in situ generation of diverse N-chlorobenzimidazole species, it was possible to achieve adjustable reactivity, chemoselectivity, and stereoselectivity in the four-component reaction. Moreover, the slowly releasing chlorinating reagent demonstrated enhanced robustness and reliability compared to an isolated reagent, and it exhibited tolerance for the aminochlorination of alkynes. A variety of activated and unactivated alkenes were amenable to this reaction, and its practicality was highlighted by the late-stage aminochlorination of NPs, including pregnenolone and camphene (Scheme 12F).⁶⁵

3.2 Azidation of alkenes

Among the current strategies for the synthesis of vicinal diamines, alkene diazidation emerges as a compelling method, as the organic azide functional groups can be readily reduced to yield the corresponding amines, thereby enabling direct access to the diamine motif.⁶⁶ In 2019, Lin's group introduced a novel aminoxyl radical catalyst, CHAMPO, designed for the electrochemical diazidation of alkenes. By utilizing an anodically generated charge-transfer complex in the form of CHAMPO–N₃, they successfully achieved radical diazidation across a wide range of alkene substrates, eliminating the necessity for a transition metal catalyst or a chemical oxidizing agent. Mechanistic data provide evidence for the aminoxyl's dual catalytic role, serving as both a single-electron oxidant and a radical group transfer agent. The method's gentle and practical attributes were additionally illustrated through its straightforward scalability and efficient application in the late-stage diazidation of various NPs. Examples include carvone, limonene oxide, and citronella (Scheme 13A).⁶⁷ In 2022, West and co-workers presented a diazotization of alkenes utilizing iron-mediated ligand-to-metal charge transfer (LMCT) and radical ligand transfer under the irradiation of 427 nm blue light. By capitalizing on the fusion of these two reaction pathways, this methodology employs a cost-effective and stable iron salt to serve dual roles as a radical initiator and terminator. In this process, the nucleophilic azide source undergoes transformation into its radical form through iron-mediated LMCT. Subsequently, the azide radical adds to a diverse array of alkenes to generate a carbon-centered radical. This mild approach showed the broad applicability of alkenes and showcased the feasibility of conducting the reaction in continuous-flow reactors. The good functional group tolerance was also showcased in the LSF of NPs such as oleic acid and mycophenolic acid converted into corresponding products in good yields (Scheme 13B).⁶⁸ In 2014, Masson and co-workers documented a photoredox-induced three-component azidotrifluoromethylation of alkenes. Using Umemoto's reagent as the CF₃ source, a diverse set of both alkyl and aryl alkenes could be readily difunctionalized, resulting in the formation of β-trifluoromethylated azides with good yields (Scheme 13C).⁶⁹ In 2023, Wu's group reported a versatile and pragmatic photoredox/iron dual catalytic system, which provides a gateway to highly privileged 1,2-aryl(alkenyl) heteroatomic pharmacophores with remarkable efficiency and precision in site selectivity. This method demonstrated an expansive applicability, enabling the direct utilization of a diverse range of commodities or commercially accessible (hetero)arenes, alongside activated and unactivated alkenes bearing a plethora of functional groups, drug frameworks, and natural product motifs as substrates, including examples nootkatone, (−)-carvone and (+)-dihydrocarvone. Through the integration of iron catalysis into the photoredox cycle, an extensive array of alkene 1,2-aryl(alkenyl) functionalization products, featuring adjacent azido, amino, halo, thiocyano, and nitrooxy groups, were successfully synthesized. The scalability and the capacity to rapidly produce numerous bioactive small molecules from readily available starting materials underscore the practicality of this methodology (Scheme 13D).⁷⁰ More recently, Xu's group has introduced an innovative electrochemical approach for alkene azidocyanation, which is suitable for both activated and nonactivated alkenes. This achievement is made possible by using finely tuned anodic electron transfer and strategically selected copper/ligand complexes. Importantly, the mild and well-regulated electrochemical method ensures remarkable tolerance for diverse functional groups, making this method compatible with both terminal and internal alkyl alkenes (Scheme 13E).⁷¹

3.3 Halogenation of alkenes

Vicinal dihalogenated compounds have found broad utility in various fields, including pharmaceutical manufacturing, natural product synthesis, and material science.^72,73 In 2022, Waldvogel and co-workers established a straightforward electrochemical procedure to achieve the selective dibromination of naturally derived olefins, including terpenes. This approach elegantly circumvents the use of hazardous Br₂ or its analogues, opting instead for readily available, cost-effective, and environmentally friendly sodium bromide, which plays a dual role as a reagent and supporting electrolyte. Sustainable carbon-based electrodes were employed in conjunction with sodium bromide. The electrochemical approach yields the desired products including compounds such as limonene, perillaldehyde, carvone, anti-inflammation terpinen-4-ol, anti-invasive myrcene, citronellal, anti-nociceptive citral, safrole, and more. These compounds were obtained with yields ranging from good to excellent, reaching up to 82% in 10 representative examples. Scalability has been demonstrated through a fivefold scale-up. Importantly, this method yields higher yields and selectivity when compared to traditional bromination using Br₂ and the DMSO/HBr system. The resulting dibrominated compound is amenable to further functionalization, such as cyanation, following the Kolbe nitrile synthesis protocol (Scheme 14A).⁷⁴ In 2023, Oestreich and co-workers unveiled a visible-light-mediated transfer protocol characterized by its simplicity in operation and mild conditions. This protocol enables the vicinal dihalogenation of C–C bonds in alkenes, alkynes, and alkenes using readily available oxime-based dihalogen surrogates. This method exhibited remarkable tolerance and compatibility with various functional groups, offering significant benefits for the subsequent modification of biologically active molecules, thereby expanding the scope of biologically relevant chemical space, showcasing its potential for diverse applications. The vicinal dihalogenation process of the NPs cholesterol and B-rhodinol proceeded smoothly, yielding the corresponding adducts in excellent yields (Scheme 14B).⁷⁵ Dmitry Katayev and co-workers developed a photocatalytic strategy for vicinal dihalogenation of unsaturated hydrocarbons using bench-stable carbon-based functional group transfer reagents (FGTRs). The reaction operates through a distinctive SET mechanism facilitated by fac-Ir(ppy)₃ photocatalysis, triggering mesolytic cleavage of C–X bonds in FGTRs followed by radical 1,2-halide rearrangement. This process generates active dihalogen species (X₂ or X–X′) that undergo electrophilic addition to alkenes, alkynes, and allenes via a halonium ion intermediate. The protocol demonstrates exceptional functional group tolerance and regioselectivity, enabling late-stage dihalogenation of complex NPs, including pregnenolone acetate and cholesterol derivatives, while preserving sensitive hydroxyl groups. This FGTR platform provides a safer alternative to molecular halogens for constructing vicinal dihalides, bromochlorides, and tetrabrominated compounds with applications in pharmaceutical intermediates and flame retardants (Scheme 14C).⁷⁶

In 2014, Han and co-workers reported a vicinal chlorotrifluoromethylation of alkenes using visible-light-induced photoredox catalysis. By employing Ru(Phen)₃Cl₂ as a photoredox catalyst and CF₃SO₂Cl as a source for the CF₃ radical and chloride ion, they successfully converted a variety of terminal and internal alkenes into their respective vicinal chlorotrifluoromethylated derivatives. The use of NPs in obtaining the desired products suggests that this method could be a viable approach for LSF in drug discovery (Scheme 15A).⁷⁷ In 2018, Lin's group presented an electro-oxidative heterodifunctionalization of activated and unactivated alkenes, achieved by anodic oxidation of CF₃SO₂Na. The process involved capturing the anodically generated trifluoromethyl radical via its reaction with a terminal alkene, leading to the formation of a secondary alkyl radical intermediate. This intermediate was subsequently trapped by a chloride radical, resulting in the heterodifunctionalized product. The incorporation of catalytic Mn(OAc)₂ facilitated the electrochemical process by participating in the generation of a putative Mn(III)–Cl radical chlorinating agent, which facilitated the recombination of the chloride radical during the reaction. This anodically coupled electrocatalytic process was harnessed for the direct LSF of various NPs, including antimalarial cinchonidine and cholesterol (Scheme 15B).⁷⁸ More recently, Luo and co-workers devised and showcased an AC-driven heterodifunctionalization of alkenes, strategically addressing the limitations posed by the potential window and enhancing functional group compatibility. This was achieved through the reversible conversion of redox-active functional groups, including thioether, quinone, and pyrrole. Mechanistic investigations unveiled a radical reaction pathway governing the heterodifunctionalization reactions. This discovery introduces a novel approach to enhance functional group tolerance in electro-organic synthesis (Scheme 15C).⁷⁹ In 2016, Qing and co-workers introduced a method that utilized (difluoromethyl)-triphenylphosphonium bromide for the bromofluoromethylation of alkenes under visible-light photoredox conditions (Scheme 15D).⁸⁰ In 2014, Melchiorre and co-workers discovered that p-anisaldehyde serves as an efficient catalyst for the intermolecular atom-transfer radical addition (ATRA) of various haloalkanes to alkenes. This reaction occurs at ambient temperature and is initiated by illumination with a common household light bulb. Initial investigations suggest a mechanism in which the aldehydic catalyst photochemically generates the reactive radical species through the sensitization of organic halides via an EnT process (Scheme 15E).⁸¹ Gaunt and coworkers developed a modular dual-catalytic aryl-chlorination strategy, enabling efficient synthesis of structurally diverse 1-aryl-2-chloroalkanes through visible-light-mediated coupling of diaryliodonium salts, alkenes, and potassium chloride. The transformation employs two complementary catalytic systems: an iron(III)-based catalyst for non-activated aliphatic alkenes/styrenes and a rationally designed copper(II)–pyridylimine complex for electron-deficient alkenes. Mechanistic studies reveal a photocatalytic cycle generating aryl radicals that undergo regioselective alkene addition, followed by metal-mediated chlorine atom transfer from the respective Fe(III)–Cl or Cu(II)–Cl complexes to the transient homobenzylic radical intermediate. Notably, this methodology demonstrates chemoselective functionalization of isoalantolactone, an NP containing dual alkenes, exclusively modifying the electron-deficient α,β-unsaturated lactone moiety while preserving the isolated double bond. The strategic ligand engineering of bidentate N(sp²)-hybridized frameworks proved critical for optimizing chlorine transfer efficiency, particularly in managing competing pathways like Sandmeyer chlorination and radical oligomerization. This work establishes a versatile platform for constructing architecturally complex chloroalkanes with orthogonal functional handles for downstream transformations (Scheme 15F).⁸²

3.4 Alkylation of alkenes

Pyridines stand out as one of the most prevalent heterocycles in pharmaceuticals, finding extensive applications across a diverse spectrum of uses.⁸³ In 2018, Hong's group successfully developed a green, transition metal-free trifluoromethylative pyridylation of alkyl alkenes through visible-light-induced photoredox catalysis. This three-component method utilizes a pyridinium salt and CF₃SO₂Na in the presence of eosin Y as a photoredox catalyst. The overall process is believed to involve the selective addition of an electrophilic CF₃ radical to the alkene substrate, generating an alkyl radical intermediate that subsequently reacts with the pyridinium salt. This photocatalytic approach bypasses traditional multistep procedures and readily delivers valuable trifluoromethyl- and pyridyl-containing compounds (Scheme 16A).⁸⁴ In 2020, the same group observed that the photoreduction of N-alkenoxypyridinium salts resulted in the generation of α-carbonyl radicals through N–O bond cleavage. This innovative discovery enabled the simultaneous integration of α-keto and pyridyl groups across unactivated alkenes. During this process, the generated α-carbonyl radicals react with unactivated alkenes, forming alkyl radical intermediates ready for subsequent addition to pyridinium salts, which ultimately yields a diverse array of γ-pyridyl ketones. The versatility of this method was further showcased through late-stage carbopyridylation of CC-containing NPs, such as antibacterial eugenol (Scheme 16B).⁸⁵ C–C bonds form the basic structural framework of organic molecules, making their formation a critical aspect of synthetic chemistry.⁸⁶ In 2020, Zhu's group reported a photocatalytic “polarity umpolung” strategy for the radical alkylation of alkenes. This innovative approach flips the conventional reaction pattern on its head by substituting the inherently nucleophilic alkyl radicals with electrophilic sulfone-bearing surrogates. The reaction displays a wide functional group tolerance under mild conditions. Diverse types of alkenes, including many intricate NPs and pharmaceutical derivatives such as nootkatone, anticancer ocimene, and limonene, readily furnish valuable alkylation products through consecutive docking and migration pathways. This methodology presents an efficient means to broaden aliphatic scaffolds (Scheme 16C).⁸⁷ In 2024, Koh and co-workers presented a dual catalytic approach combining photoredox and nickel catalysis, enabling the simultaneous formation of two C(sp³)–C(sp³) linkages via trimolecular cross-coupling of alkenes with alkyl halides and hypervalent iodine-based reagents. The reaction operates through a bimolecular homolytic substitution (S_H2) mechanism and chemoselective XAT, facilitating the regioselective addition of electrophilic and nucleophilic alkyl radicals across unactivated alkenes. The utility of this method is showcased through late-stage (fluoro)alkylation and (trideutero)methylation of C–C bonds with different substitution patterns, providing straightforward access to drug-like molecules featuring sp³-hybridized carbon scaffolds (Scheme 16D).⁸⁸

3.5 Oximinosulfonamidation of alkenes

More recently, our group has reported the highly atom-economical production of diverse α-oximino sulfonamides via direct photo-mediated radical relay oximinosulfonamidation of activated or unactivated alkenes with N-nitrosamines triggered by DABSO. N-Nitrosamines worked as bifunctional reagents in this transformation, simultaneously generating aminyl radicals and NO radicals. The DABSO was designed to act as a radical decaging agent as well as a source of sulfonyl. Its strong radical capturing ability and affinity for alkenes enable the rapid capturing of the aminyl radicals, thereby inhibiting the rapid recombination of radical pairs in the solvent cage. The synthesized oxime units could also be easily converted into other functional groups, leading to selective downstream transformations. The mild photodegradation reaction of harmful N-nitrosoamines showed high functional group tolerance and compatibility, facilitating the LSF of NPs and drug molecules, expanding the biologically relevant chemical space (Scheme 17).⁸⁹

In summary, we summarized several methods for the direct difunctionalization of alkene-containing NPs. The difunctionalization of alkenes using a single bifunctional reagent provides an efficient and straightforward strategy for rapidly increasing molecular complexity, so further advancements are needed in the development of more practical and efficient bifunctional reagents. Additionally, the functionalization of alkenes often results in the creation of new chiral centers, so the asymmetric functionalization of alkenes represents a crucial and noteworthy research direction in the field.

4. Conversion to functionalized vinylic systems

The use of light/electricity to modify alkenes at specific C(sp²)–H bonds remains poorly developed. This limitation stems from two key challenges: (1) substrate compatibility issues: photo-/electro-generated alkyl radicals (electron-rich species) require specific alkenes to react efficiently, such as monosubstituted styrenes or electron-deficient olefins. However, these activated alkenes are rare in NPs and drug molecules because their high reactivity makes them unstable. (2) Thermodynamic limitations: after the radical is added to an alkene, the reaction must overcome an energy barrier to re-form the double bond. In aromatic systems, this step is driven by rearomatization (regaining their stable aromatic structure), but alkenes lack this driving force. Without such stabilization, the reaction becomes energetically unfavorable.

4.1 Formation of C(sp²)–C(sp²) bonds

Functionalized vinylic are important intermediates for building complex organic molecules.⁹⁰ In 2019, Chu and co-workers introduced a catalytic, branch-selective pyridylation of alkenes using sulfinate-assisted photoredox catalysis. This process involves the sequential steps of radical addition, coupling and elimination, making use of readily accessible sodium sulfinates as both reusable radical precursors and traceless elimination groups. This versatile and eco-friendly method procedure enables the introduction of valuable vinyl pyridines with exclusive branched selectivity, all achieved under mild reaction conditions. Moreover, this catalytic approach was effectively employed in the efficient synthesis of triprolidine (Scheme 18A).⁹¹ Chiral axes are fundamental frameworks in NPs, pharmaceutical cores, and chiral ligands.⁹² In 2022, Ackermann's group disclosed a catalyst-controlled atroposelective pallada-electrocatalyzed C–H activations, offering a route to the synthesis of synthetically valuable chiral anilides without the need for stoichiometric chemical oxidants under remarkably mild reaction conditions. By employing (S)-5-oxoproline as the chiral ligand, both activated and non-activated alkenes were shown to be amenable substrates. The optimal catalytic redox mediator was found to be 1,4-benzoquinone, and the reaction generated molecular hydrogen as the sole stoichiometric byproduct. The inclusion of sodium acetate as an additive served a dual role as both a base and an electrolyte. This strategic choice not only prevented the electrochemical degradation of the palladium catalyst but also maintained the desired enantioselectivity. The asymmetric electrocatalysis harnessed electricity as a sustainable oxidant and could even be performed using a standard commercial solar panel, relying solely on natural sunlight as the power source (Scheme 18B).⁹³

4.2 Formation of C(sp²)–C(sp³) bonds

In 2018, Wu's group discovered the direct synthesis of Heck-type products using alkyl carboxylic acids. This innovative approach accommodates an exceptionally wide range of substrates, yielding products in an external oxidant-free manner. The success of this methodology is attributed to the synergistic collaboration between an organo photo-redox catalyst and a cobaloxime catalyst in the presence of a catalytic amount of base. The pivotal factor in this success lies in the unique proton–electron-accepting ability of the cobaloxime catalyst, surpassing the capabilities of conventional oxidants. This dual catalysis protocol offers several advantages, including the use of widely available feedstocks, and the absence of both noble-metal catalysts and harmful byproducts. It is poised to find extensive applications in the synthesis of valuable disubstituted alkenes and the LSF of drugs (Scheme 19A).⁹⁴ In 2020, Leonori's group developed a method for easily obtaining α-aminoalkyl radicals from simple amines. Mechanistic results demonstrate that α-aminoalkyl radicals can effectively trigger the homolytic activation of carbon–halogen bonds, allowing alkyl or aryl halides to be transformed into carbon radicals through XAT. This strategy greatly facilitates the construction of sp³–sp³, sp³–sp², and sp²–sp² C–C bonds using alkyl and aryl halides under mild conditions, showcasing excellent chemical selectivity. During this process, methoxsalen underwent C(sp³)–C(sp²) coupling with alkyl halides, yielding the desired product in a 42% yield. The universality, tolerance toward diverse functional groups, and modularity of this carbon–halogen bond activation method are expected to pave the way for a new platform in the synthesis of pharmaceutically valuable molecules (Scheme 19B).⁹⁵ In 2019, Tsui and co-workers introduced a mild method for the visible-light-mediated trifluoromethylation of unactivated alkenes without the requirement for photocatalysts. The reaction conditions enable the direct synthesis of valuable trifluoromethylated (E)-alkenes from readily available alkene feedstocks, exhibiting excellent tolerance towards various functional groups (Scheme 19C).⁹⁶

4.3 Formation of fluorosulfonylated alkenes

In 2022, Liao and co-workers discovered a novel class of solid-state, redox-active fluorosulfonyl radical reagents, 1-fluorosulfonyl 2-aryl benzoimidazolium triflate salts. These reagents facilitate the radical fluorosulfonylation of alkenes under photoredox-induced conditions. In contrast to the established radical precursor, gaseous FSO₂Cl, the salts exhibit bench-stability and ease of handling, and deliver high yields in the radical fluorosulfonylation of alkenes, even with previously challenging substrates. This method holds promise for advancing research in chemical biology and drug discovery (Scheme 20).⁹⁷

In this section, we reviewed diverse methods for the photo-/electro-catalytic conversion of alkene-containing NPs to functionalized vinyl systems. These methods, centered around carbon–carbon bond activation, showcase notable versatility and exhibit a high tolerance for various functional groups. This characteristic opens avenues for the subsequent syntheses of molecules endowed with medicinal value. The notable advantage of employing photo-/electro-catalytic functionalization of alkenes lies in its capacity to operate primarily under mild and environmentally friendly conditions. However, it is crucial to recognize that the current methodologies are predominantly applicable at the (milli)gram scale, underscoring a substantial demand for scalable reaction platforms conducive to industrial-scale production.

5. Formation of cyclic systems

The cyclization of alkenes under photoelectrocatalytic conditions proceeds through four distinct mechanistic paradigms governed by spin-state dynamics and redox modulation (Fig. 4): (1) triplet diradical coupling: alkenes undergo concerted addition with diradical species or triplet carbenes, forming transient triplet diradical intermediates, ultimately yielding cyclized products through spin-coupled bond reorganization. (2) EnT-mediated cyclization: photoexcitation induces intersystem crossing to generate alkene triplet excitons. These activated species undergo addition with acceptors, forming triplet diradical adducts. The system subsequently achieves closed-shell products through spin-flip-mediated σ-bond formation. (3) Dicationic intermediate pathway: electro-/photochemical oxidation generates dicationic or cation-radical intermediates at the alkene moiety. Subsequent SET to nucleophilic partners initiates concerted ring-closure through nucleophilic attack, accompanied by charge equalization. (4) Radical cationic cyclization: photoelectrocatalysis generates catalytically activated radical-cation species. These electrophilic intermediates undergo regioselective addition to the alkene π-system, forming a transient charge-polarized adduct. A direct SET then yields the product.

5.1 Cyclopropanation of alkenes

In recent years, significant progress has been achieved in the field of photo-/electro-chemical cyclization using the allene functionality, owing to the unique structure and reactivity of allenes.^98,99 Cyclopropanes are key features in the synthesis of complex molecules and NPs.¹⁰⁰ In 2023, Giri's group developed a simple photo-/iodine-co-catalytic system to efficiently achieve intermolecular cyclopropanation reactions involving unactivated alkenes and active methylene compounds. In this system, iodine, a crucial component, can either be added directly as iodine molecules or generated in situ from alkyl iodides. Detailed mechanistic studies reveal the pivotal role of photosensitive O₂ in generating carbon-centered radicals. The transformation exhibits broad substrate compatibility and functional group tolerance, although styrene and 1,3-dienes are exceptions, not participating in this reaction. Notably, alkene substrates containing active molecular skeleton derivatives, such as dihydromyrcenol, anxiolytic linalool oxide, quinine, oleic acid, and cinchonidine, among others, can be successfully converted into the corresponding cyclopropylation products with yields ranging from 66% to 79%. This underscores the practicality of this transformation and introduces a novel avenue for the subsequent modification of these bioactive molecules (Scheme 21).¹⁰¹

5.2 Aziridination of alkenes

Given the distinctive pharmacological activities associated with nitrogen-containing heterocyclic groups, the synthesis of their structures has perennially remained a focal point within the domain of contemporary synthetic chemistry.¹⁰² In 2022, Zhu's research group achieved an efficient, mild, and environmentally friendly catalyst-free visible-light-induced aziridination reaction. This process involved ortho-methoxymethyl iminoiodinanes and a wide range of alkenes via a nitrene transfer mechanism. Notably, the reaction exhibited remarkable functional group tolerance, enabling intermolecular aziridination of numerous complexes of biologically active NPs. The exemplary results obtained with the aziridination of antiviral andrographolide, sclareol, pregnenolone, anti-apoptotic levomenol, and cholesterol underscore the excellence of this method (Scheme 22A).¹⁰³ In 2024, Parasram and co-workers introduced a novel method, in which readily accessible azoxy-triazenes act as nitrogen atom sources under visible light excitation for the phthalimido-protected aziridination of alkenes. This approach obviates the necessity for external oxidants, precious transition metals, and photocatalysts, representing a departure from conventional methodologies. The versatility of this transformation extends to the selective aziridination of both activated and unactivated multisubstituted alkenes, exhibiting varying electronic profiles. This new approach is expected to create a new platform for the synthesis of nitrogen-containing compounds for biologically relevant chemical space (Scheme 22B).¹⁰⁴ More recently, Lei's group has unveiled a practical approach for achieving aziridination of unactivated alkenes within an electrochemical flow cell with hydrogen evolution, eliminating the need for transition metal catalysts and additional oxidants. This innovative technology, driven by a distinct oxidative amine/alkene cross-coupling mechanism, showcases remarkable versatility by accommodating more than 15 types of NPs and drug derivatives, such as α-ionone, rose oxide, dehydroisoandrosterone, anticancer betulin, anti-HIV betulinic acid, and others. Moreover, subsequent synthetic transformations of aziridines and their applications in anticancer treatments underscore the potential of this electro-oxidative process in both the electrochemical and medical sectors. This method introduces a groundbreaking synthetic route for alkene aziridination, offering an alternative pathway to access potential drug candidates (Scheme 22C).^9c

In this chapter, we present an overview of studies focusing on the photo-/electro-catalytic cyclopropanation and aziridination of alkene-containing NPs. These reactions showcase substantial tolerance toward various functional groups. Notably, in the investigations conducted by Lei's group,^9c the modified molecules found application in anti-cancer treatment within cellular environments, demonstrating their potential in drug discovery. This underscores the significance of cross-collaboration between organic synthetic chemistry and chemical biology as a future developmental trend. Further exploration into cyclization reactions and the synthesis of diverse heterocyclic compounds holds promise and warrants continued development.

6. Functionalization of allylic positions

In the photo-/electro-catalytic functionalization of allylic positions in alkenes, the reaction mechanism initiates through HAT to generate an allylic radical intermediate. Three distinct catalytic pathways subsequently govern product formation (Fig. 5): (1) radical–radical coupling pathway: the allylic radical undergoes bimolecular coupling with a secondary radical species, yielding products through direct radical cross-coupling. (2) Oxidation-nucleophilic addition pathway: single-electron oxidation of the allylic radical generates a cationic intermediate. This carbocation undergoes nucleophilic attack, facilitated by the electrophilic character of the allylic position, producing substitution products. (3) Radical–polar crossover pathway: redox modulation induces radical-to-polar transition, forming a closed-shell π–allyl metal complex. This intermediate undergoes regioselective allylic substitution with nucleophiles, followed by catalyst regeneration.

6.1 Allylic C–H oxidation

Functionalized allylic systems offer the opportunity to access a range of well-established pharmacophores, which are molecular features responsible for a drug's mechanism of action. In this context, the oxidation of allylic systems has emerged as a prominent and widely employed method for C–H functionalization.¹⁰⁵ In 2016, Baran's group developed an electrochemical C–H oxidation approach that used Cl₄NHPI as a redox mediator, t-BuOOH as a co-oxidant, and LiClO₄ as the electrolyte. This method was conducted under constant-current conditions in an undivided cell, demonstrating a wide range of substrate compatibility, operational simplicity, and exceptional chemoselectivity. Numerous representative NPs were subjected to oxidation, affording a diverse array of corresponding products, including nootkatone, cyperone, rotundone, verbenone, theaspirone, carvone, and isolongifolenine. Notably, it makes use of affordable and easily obtainable materials and showcases a scalable approach to allylic C–H oxidation, as demonstrated with a 100 gram scale, making it feasible for this C–H oxidation strategy to be adopted in large-scale industrial applications with minimal environmental impact (Scheme 23A).¹⁰⁶ In 2022, Wu's group used genetically modified Escherichia coli in fermentation to obtain amorphadiene and antiallergic valencene via a metal-free visible-light photocatalysis strategy to additionally synthesize nootkatone, cis-nootkatol, and two hydration derivatives. During fermentation, employing a closed, anaerobic condition was instrumental in eliminating the need for an organic overlay, enhancing productivity, and streamlining the workup procedure. The incorporation of metal-free photocatalysis for hydration and allylic C–H oxidation was a strategic choice to enhance the overall environmental sustainability of the process. The study demonstrated that the anti-Markovnikov selectivity observed in photocatalyzed alkene hydration could be altered due to the presence of stereo-electronic and steric effects in intricate natural compounds. This synergistic approach of integrating bioprocessing with photocatalysis demonstrates promise in offering an efficient and more environmentally friendly pathway to diversify the chemical landscape for applications in the pharmaceutical, flavor, and fragrance industries (Scheme 23B).¹⁰⁷

6.2 Formation of allylic C(sp³)–C(sp³) bonds

In 2019, Liu's group introduced a remarkably efficient ketone carbonyl alkylation reaction, in which ketones are directly hydrocarbonation, yielding a diverse range of challenging tertiary alcohols. This transformation occurs through an intermolecular cross radical–radical coupling mechanism involving semi-persistent ketyl radicals and transient alkyl radicals generated via a HAT process, employing a thiol and photoredox catalysts. Significantly, this catalytic approach obviates the need for pre-functionalization steps and mitigates the use of stoichiometric quantities of environmentally harmful metal redox agents. The successful modification of NPs and drugs serves as a testament to the versatility and simplicity of this mild method, as evidenced by α-pinene, γ-terpinene, citronellol, etc. (Scheme 24A).¹⁰⁸ Simultaneously, Huang and co-workers developed a novel catalytic method for the direct alkylation of allylic sp³ C–H bonds within unactivated alkenes using imines, achieved through a synergistic combination of photoredox and organocatalysis. This mild reaction exhibits impressive tolerance towards a wide array of functional groups. The reactivity and applicability of this protocol are particularly highlighted in the LSF of allylic C–H bonds in various complex NPs including (−)-α-pinene, (−)-β-pinene, progesterone, and cholesterol. Mechanistic studies revealed that the reaction proceeds via the N-centered radical intermediate, which is formed by the allylic radical addition to the imine (Scheme 24B).¹⁰⁹

6.3 Formation of allylic C(sp³)–C(sp²) bonds

The direct arylation of nonfunctionalized allylic systems facilitates the synthesis of intricate drug molecules without the need to introduce additional functional groups. In 2015, MacMillan's group introduced a groundbreaking method enabling the direct functionalization and arylation of allylic sp³ C–H bonds, all while maintaining mild and operationally straightforward conditions. This innovative C–C bond formation process capitalizes on the mechanistic fusion of photoredox and thiol-based organic catalysis, readily accommodating a diverse array of unactivated alkene and electron-deficient arene coupling partners. A notable advantage of this gentle arylation protocol is its capacity for late-stage diversification of highly functionalized synthetic intermediates. To illustrate the effectiveness of this approach, they applied it to pregnenolone, a complex biologically active compound. In this context, the compound efficiently underwent fragment coupling with 1,4-dicyanobenzene in a highly regioselective and diastereoselective manner, yielding the aryl-functionalized steroid framework in 67% yield (Scheme 25A).¹¹⁰ In 2018, Kanai and co-workers showcased the novel application of sulfonamides as HAT catalysts. These sulfonamides were found to be suitable for allylic or benzylic C–H arylations in conjunction with a visible-light photoredox catalyst. The bond dissociation energy for N–H in diarylsulfonamide, a new HAT catalyst, was estimated to be 95 kcal mol⁻¹, indicating its potential for selective HAT processes without the random activation of strong C–H bonds in organic molecules. The method demonstrated compatibility with a broad range of alkyl and aryl alkenes (Scheme 25B).¹¹¹ In 2023, Wang's group disclosed a mild, efficient polycatalytic approach for the synthesis of β,γ-unsaturated ketones via allylic acylation of alkenes. This innovative method utilizes a triple co-catalytic strategy involving photoredox, NHC, and HAT catalysts to facilitate the single-electron reduction of acyl azolium intermediates. Subsequently, radical–radical coupling forms of C–C bonds, resulting in the generation of β,γ-unsaturated ketones. The starting materials for this approach are readily prepared and exhibit a wide substrate scope. The versatility of this technology is showcased through successful modifications of various NPs and pharmaceutical molecules, including isopulegol, terpineol, (+)-limonene, 3-carene, antinociceptive γ-terpinene, and (−)-β-citronellol. Additionally, the resulting products can be further selective downstream transformations, enhancing their potential applications (Scheme 25C).¹¹²

6.4 Formation of allylic C(sp³)–hetero bonds

In 2020, Che's group reported iron(III) porphyrin Fe(TF₄DMAP)Cl-catalyzed intermolecular sp³ C–H amination and alkene aziridination with selectivity, employing organic azides as the nitrogen source under visible-light irradiation. Mechanistic studies unveiled that Fe(TF₄DMAP)Cl served a dual role as both a photosensitizer and a catalyst, leading to the formation of a reactive iron–nitrene intermediate for the subsequent C–N bond formation. These photochemical reactions exhibit chemo- and regio-selectivity and are effective for the LSF of complex natural and bioactive compounds such as cholesterol, antiallergic diosgenin, and nootkatone (Scheme 26A).¹¹³ In 2020, Hong and co-workers presented a method for the direct allylic sp³ C–H thiolation using disulfides via visible-light photoredox catalysis. This approach addressed previous limitations associated with transition metal catalysis for direct allylic sp³ C–H thiolation. Visible-light photoredox catalysis was employed to induce selective HAT at the allylic position, along with a deprotonation strategy to prevent unwanted hydrothiolation reactions under basic conditions. The reaction accommodated a wide range of diaryl disulfides and alkenes, resulting in the efficient production of allyl thioethers. Mechanistic investigations revealed the pivotal role of the photocatalyst as a redox mediator in the conversion of the allyl radical into the allyl cation and subsequent ionic coupling processes (Scheme 26B).¹¹⁴

In this section, we present an overview of functionalization occurring at the allylic position of alkene-containing NPs. This category of reactions holds significant importance in organic synthesis, offering pathways to fundamental chemicals and more intricate compounds, including those derived from terpenes. Notably, these methods are characterized by their gentleness, environmental friendliness, broad functional group tolerance, and outstanding selectivity. A distinctive advantage lies in their elimination of the need for toxic and expensive oxidants or catalysts, diverging from classical methodologies. A noteworthy milestone is the electrochemical allylic C–H oxidation developed by Baran and co-workers,¹⁰⁶ which has demonstrated success at a 100 gram scale. This achievement underscores the heightened technical appeal of photo-/electro-catalysis for large-scale industrial applications, providing a glimpse into its potential for advancing industrial processes.

7. Isomerization of alkenes

The photo-/electro-catalytic isomerization of alkenes proceeds via three distinct mechanistic pathways, as outlined below: (1) positional isomerization via metal-hydride or π–allyl pathways: transition metal catalysts promote positional isomerization of alkenes through either metal–hydride intermediates or π–allyl coordination mechanisms. (2) Radical-mediated C–H activation and reductive elimination: HAT process generates an allylic radical species, which undergoes inner-sphere reduction by a transition metal to form a π–allyl–M complex. This organometallic intermediate subsequently undergoes reductive elimination through either concerted proton–electron transfer at the M–C bond or homolytic substitution, yielding the desired isomerized product. Regioselectivity is dictated by steric constraints during both the HAT and π–allyl–M formation steps. (3) Migratory insertion and radical-rebound catalysis: diene substrates participate in migratory insertion into a metal–hydride bond, generating an σ-allyl–M intermediate. Concurrently, radical species attack the metal center, triggering reductive elimination to release the isomerized product while regenerating the active catalyst (Fig. 6).

The isomerization of alkenes provides a direct and atom-economical method for synthesizing desired isomers, including those that may not be readily attainable through conventional techniques. The positional isomerization of CC double bonds stands as a potent strategy for interconverting regioisomers of alkenes.¹¹⁵ In 2019, König and co-workers unveiled a novel approach for achieving both thermodynamic and kinetic isomerization of alkenes via the combination use of visible light and cobalt catalysis. By employing xantphos as the ligand, the most stable isomers were obtained, whereas the selective isomerization of terminal alkenes over a single position could be precisely controlled by utilizing DPEphos as the ligand. The presence of 4CzIPN further accelerated the reaction. The efficient transformation of exocyclic alkenes into their corresponding endocyclic products was accomplished using 4CzIPN and Co(acac)₂ without the need for additional ligands. Spectroscopic and spectroelectrochemical studies provide compelling evidence of the participation of CoI in the generation of a Co hydride. This hydride species subsequently engages with alkenes, serving as the initiation point for the isomerization process. During the isomerization of exocyclic alkenes, a prominent constituent of pine resin, (−)-β-pinene underwent transformation resulting in (−)-α-pinene with a quantitative yield. Eugenol, as an allylbenzene derivative, underwent isomerization with excellent functional tolerance, resulting in the formation of the more stable trans-isomer in 93% yield (Scheme 27A).¹¹⁶ In 2022, Baran's group pioneered an innovative electroreductive approach involving Co-catalyzed regioselective isomerization of alkenes, utilizing transition-metal hydride intermediates. The process initiated with the cathodic reduction of high-valent Co(III) species, leading to the formation of low-valent Co(I) species. These Co(I) species effectively catalyzed the reduction of protons, generating Co(III)–H intermediates. These cobalt hydride intermediates, when exposed to terminal alkenes and alkynes, exhibited remarkable selectivity, transforming the former into internal alkenes and the latter into Z-alkenes. This straightforward and efficient method demonstrated its versatility and suitability for the modification of diverse substrates. It is particularly well suited for the late-stage derivatization of structurally complex organic architectures, including (−)-caryophyllene oxide (Scheme 27B).¹¹⁷ At the same time, Wendlandt and co-workers presented a novel photochemical dual-catalyst system enabling contra-thermodynamic positional isomerization of alkenes. This innovative protocol provides a direct route to the synthesis of terminal olefin isomers from conjugated internal olefin starting materials. The mechanism involves allylic hydrogen atom abstraction and subsequent radical addition to form an allylcobaloxime intermediate, followed by a regiospecific hydrogen atom substitution, resulting in the formation of the terminal alkene product isomer. The proposed mechanism aligns with a regiospecific S_H2 mechanism. Various strategies were employed in the synthesis of NPs, showcasing notable examples. α-Cedene underwent a transformation to yield anti-leukemic β-cedene with a yield of 41%. Additionally, the reaction of (+)-α-pinene resulted in a 58% yield of (+)-β-pinene on a 10 mol scale. Using (−)-linalool as a model substrate, the terminal isomer was obtained in 61% yield on a 10 mmol (1.5 g) scale, and then (−)-cyclonerodiol was successfully synthesized via subsequent reactions (Scheme 27C).¹¹⁸ In 2023, Cai's group achieved light-mediated direct N-allylation of azoles using a cobalt catalytic system. The reaction conditions are mild and circumvent the necessity for stoichiometric oxidants. A diverse array of N-allylic azole derivatives were synthesized with high atom economy and efficiency, employing easily accessible starting materials. The methodology exhibits extensive functional group tolerance and offers potential for further derivatization. Furthermore, effective last-stage N-allylation of NPs including limonene, terpineol, and linalool was also reported (Scheme 27D).¹¹⁹ In 2017, Rovis and co-workers reported a hydrogen-aminoalkylation reaction involving α-amino radicals generated through photoredox with conjugated dienes. This method utilizes a cobalt-catalyzed system to access a diverse range of valuable homoallylic amines using readily available starting materials. A series of meticulous mechanistic experiments provided substantial evidence supporting the involvement of Co-hydride intermediates, proceeding through diene insertion to generate Co–π–allyl species. This reactivity paradigm represents a significant advancement, opening up unprecedented possibilities for coupling π-rich functionalities with photoredox-generated radical intermediates. Linear dienes with intricate structures, such as the NPs myrcene, pseudoionone (juvenile hormone), and immune-modulating piperine, are also viable substrates, resulting in the desired adducts in good yields (Scheme 27E).¹²⁰ More recently, Teskey and co-workers introduced a photocatalytic method for the intermolecular reductive coupling of feedstock dienes with ketones. Under mild conditions, simultaneous formation of a Co–H species and single-electron reduction of ketones occurs. Selective HAT from Co–H generates an allylic radical, enabling selective coupling with the persistent radical-anion of the ketone. This radical–radical coupling avoids unfavorable steric interactions associated with ionic pathways and eliminates the unstable alkoxy radical encountered in previous radical alkene–carbonyl couplings, which were limited to aldehydes as a result. The applications of this uncomplicated approach extend to the efficient synthesis of drug molecules, NPS, and site-selective LSF (Scheme 27F).¹²¹

In this section, we provide an overview of isomerization involving various types of alkene-containing NPs, with a particular emphasis on the potency of Co-catalysis as the most effective tool for the rapid isomerization of alkenes. The involvement of Co–H species is pivotal to the success of the isomerization of alkenes. It is noteworthy that the research and application of transition metal hydrides have consistently been a vibrant area of activity in chemical research. Consequently, there is considerable promise for the further development of metal-catalyzed reactions applied to the functionalization of unsaturated C–C, C–O, and C–N bonds.

8. Conclusion

In the past decade, photo-/electro-chemical catalysis has emerged as a remarkable technology and has been acknowledged as a potent tool in molecular science. Significant advancements have been achieved in the application of photoelectrocatalytic LSF of alkene-containing NPs. In comparison to well-established alkene functionalization methods, radical approaches offer a complementary and extended avenue for the selective LSF of alkenes, owing to the high reactivity and site specificity of their shell-opening reaction pathway. This approach is particularly attractive in terms of environmental sustainability and economics. While significant progress has been achieved in photo-/electro-catalytic LSF of olefin-bearing natural products, key challenges remain yet to be addressed:

(1) Labeling or modification of peptides, proteins, and sugars plays a pivotal role in modern drug discovery. Currently, only a limited number of developed photo-/electro-chemical peptide/protein LSF methods exist, and further exploration into the photo-/electro-chemical modification of these elusive macromolecular compounds is warranted.¹²²

(2) A substantial number of drug molecules possess chiral structures, yet enantioselective photo-/electrochemical LSF, or photo-/electro-chemical asymmetric synthesis, has thus far encountered limited success. Consequently, the focal point of future research lies in the development of asymmetric photo-/electro-catalysis.¹²³

(3) The foremost consideration propelling future research is environmental awareness. A substantial obstacle hindering the widespread adoption of photo-/electro-catalytic LSF in drug discovery, development, and industrial applications undoubtedly stems from the lack of standardization and large-scale setups.¹²⁴ Furthermore, the utilization of artificial intelligence, automation, continuous-flow technology, and high-throughput screening technologies will expedite the discovery and optimization of novel reactions, streamlining the design-make-test-analyse cycles, and thereby, fostering the rapid development of this field.

(4) Currently, drug development is constrained by a deficiency in collaboration among synthetic chemistry, medicinal chemistry, and chemical biology. Future research endeavors are recommended to prioritize efforts to the diversification of reaction types, broadening the substrate scope, including direct modifications on complex NP skeletons, enhancing synthetic efficiency, and reinforcing the connection between synthetic chemistry and biomolecules. The advancement of innovative and robust catalysts and catalytic systems holds promise for opening new avenues in photo-/electro-catalytic LSF of NPs, thereby facilitating the exploration of conceptually novel strategies.

Through this overview, we anticipate that function-oriented synthetic methodologies will take center stage as the future direction, facilitating mutual feedback and collaboration between synthetic chemistry, medicinal chemistry and chemical biology. Such an approach is poised to equip NP chemists with more selective structural modification tools, thereby laying the foundation for significant advancements in drug development. We envision those partnerships between the life science industry and academia in the field hold great promise to spur breakthroughs in drug discovery.

9. Conflicts of interest

There are no conflicts to declare.

10. Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 82003624, 82141203, 82004003, and 82004215), Science and Technology Commission of Shanghai Municipality (No. 20YF1458700 and 23YF1457800), Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTDD-202004), Shanghai Frontiers Science Center of TCM Chemical Biology and Open Research Fund of School of Chemistry and Chemical Engineering, Henan Normal University (2024Y08, Y. Z.). We would like to acknowledge Shanghai Key Laboratory for Pharmaceutical Metabolites Research for their support.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d5np00030k

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