English

• 1. Introduction

  Nitrogen-containing heterocycles represent the most structurally diverse and important family of organic compounds. Among this family, phenanthridine and its derivatives are N-centered fused tricyclic aromatics that exhibit a diverse array of bioactivities including antibacterial, antifungal, antiseptic, antitumor, antiviral, cytotoxic effects, DNA intercalation and inhibition of glutamic dehydrogenase [1–7]. Notably, biologically active molecules, such as chelerythrine, fagaronine, nitidine, and hippadine feature the phenanthridine scaffold, which might be regarded as a pharmacophoric core, highlighting its pharmacological importance (Fig. 1). As formal hydrolysis products of such phenanthridinium salts, phenanthridinone derivatives, were also claimed to display extraordinary cytotoxicity against tumor cell lines [8].

  Figure 1

  

  Figure 1.  Examples of naturally occurring phenanthridine alkaloids.

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  Given their significant biological and chemical relevance, considerable efforts have been dedicated to their synthesis [9–27]. Recently, visible-light-induced radical cyclization has emerged as a powerful and environmentally benign strategy for the construction of phenanthridine frameworks. This approach leverages the advantages of photochemical processes, such as mild reaction conditions, high functional group tolerance, and efficient radical generation under visible light irradiation [28–30]. In this review, we summarize the recent progress in the photochemical synthesis of phenanthridines, focusing on radical cyclization strategies employing various acceptors and radical sources. The discussion is organized into four sections based on the nature of the radical acceptors and the corresponding reaction mechanisms: (ⅰ) tandem radical cyclization using o-isocyanobiaryls as the radical acceptors, categorized by the types of radicals involved; (ⅱ) cyclization reaction involving cyano group; (ⅲ) cyclization employing vinyl azides or vinyl benzotriazoles as radical acceptors; and (ⅳ) other photochemical cyclization reaction types. This review aims to provide a comprehensive overview of recent progress in this rapidly evolving field, offering valuable insights for researchers engaged in the photochemical synthesis of N-heterocycles. By summarizing key strategies and highlighting emerging trends, we hope to inspire further innovations and advances in this dynamic area of research.

  2. Visible-light-induced synthesis of phenanthridines involving 2-isocyanobiaryls

  Over the past decade, isocyanides have emerged as effective radical acceptors in the synthesis of complicate organic molecules through relatively few steps [31–36]. In particular, 2-isocyanobiaryls, which contain both an isocyanide group and a phenyl ring, have proven to be efficient for the radical cascade cyclization reactions that yield phenanthridines. In 1995, Nanni and colleagues first reported the preparation of 6-substituted phenanthridines by reacting readily accessible 2-isocyanobiphenyl 1a with some radicals generated from azobisisobutyronitrile (AIBN), tris(trimethylsilyl)silane (TTMSS), and dibenzoyl peroxide (DPB) (Scheme 1) [37].

  Scheme 1

  

  Scheme 1.  Reactions of 2-isocyanobiphenyl with AIBN, TTMSS, and DBP.

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  Since this pioneering study, the reactivity of 2-isocyanobiaryls with a wide range of radicals has been extensively investigated, with the view to introducing various important functional groups at the 6-position of the phenanthridine core. In 2015, Studer et al. published a review about the synthesis of N-heterocycles via radical cascade reactions occurring with isonitriles as radical acceptors, in which syntheses of 6-substituted phenanthridines employing 2-isocyanobiphenyls with various types of radicals were covered [38].

  In recent years, visible-light-induced cascade reactions have become instrumental in the synthesis of phenanthridines. Mechanistically, under visible light irradiation, a radical intermediate (R^•) is generated from a radical precursor via a single electron transfer (SET). The R^• radical then adds to the isonitrile, forming an imidoyl radical that subsequently undergoes intramolecular cyclization to produce a cyclohexadienyl radical. Finally, the latter intermediate undergoes oxidation and deprotonation to yield the desired product (Scheme 2).

  Scheme 2

  

  Scheme 2.  Mechanism for the construction of 6-substituted tricyclic heteroaromatic frameworks by radical isocyanide insertions.

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  2.1 Visible-light-induced synthesis of 6-alkylated phenanthridines

  In 2013, Yu and Zhang's group pioneered the visible-light-promoted synthesis of 6-alkylated phenanthridines 7 starting from 2-isocyanobiaryls 1 and α-bromoesters 6 (Scheme 3) [39], which demonstrated the feasibility of constructing phenanthridine scaffolds by an aza-Reformatsky-type reaction under mild photochemical conditions using Ir(ppy)₃ as photocatalyst.

  Scheme 3

  

  Scheme 3.  Activated alkyl bromides as radical precursors for the synthesis of 6-alkylated phenanthridines.

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  A broad substrate scope was explored, with 2-isocyanobiaryls reacting efficiently with a diverse range of alkyl radical precursors, including long-chain, branched, saturated, and cyclic ethyl 2-bromoesters, as well as perfluoroalkyl bromides. The corresponding phenanthridines 7 were obtained in 39%–94% yields.

  Building upon their initial findings, the same group further extended the substrate scope by employing inexpensive and readily available ethyl bromodifluoroacetate (EBDA) and ethyl bromofluoroacetate (EBDFA) as fluorine-containing radical precursors for the synthesis of mono- and difluoromethylated phenanthridines 8 and 9 (Scheme 4) [40]. This strategy involved radical cascade cyclization and subsequent removal of ester moiety to furnish the desired products. Notably, the authors developed a one-pot procedure, which significantly improved the overall efficiency of the transformation compared to the stepwise one.

  Scheme 4

  

  Scheme 4.  Synthesis of mono and difluoromethylated phenanthridines through radical alkylation and subsequent decarboxylation.

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  In 2018, Chen et al. reported a visible-light-induced synthetic route to phenanthridines from the reaction of trifluoromethylated tertiary bromides 11 and 2-isocyanobiaryls 1 (Scheme 5) [41]. A particularly notable aspect of this work is the use of trifluoromethylated tertiary bromides, which were synthesized from perfluoroisobutylene 10, an industrial waste product with significant environmental concerns. The reaction proved versatile, tolerating various substituents at the 2-isocyanobiaryls, and constructing a trifluoromethylated quaternary carbon center with high efficiency in good to excellent yields. Additionally, different substituents on the oxazolyl ring of the bromides did not hinder the reaction, further underscoring its broad functional group tolerance and practical applicability.

  Scheme 5

  

  Scheme 5.  Photocatalytic synthesis of 6-substituted phenanthridines with pendant trifluoromethyl and oxazoline groups by radical cascade reaction of trifluoromethylated tertiary bromides with 2-isocyanobiaryls.

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  To assess the utility of these compounds, the authors evaluated their bioactivity. Notably, compound 12a exhibited substantial antifungal activity, alongside moderate insecticidal and herbicidal activities. These findings suggest that these phenanthridines are potential to serve as multifunctional agrochemicals, with promising applications. This work not only advances synthetic organic methodology but also opens avenues for developing environmentally friendly agrochemicals.

  In the study of Barriault et al. [42], an innovative approach for generating alkyl radicals from non-activated bromoalkanes 13 was achieved using a photoexcited dimeric gold catalyst, [Au₂(dppm)₂]Cl₂ (Scheme 6). This method specifically targets simple bromoalkane reactants lacking electron-withdrawing groups at α-position, demonstrating the versatility of gold catalysts in radical chemistry.

  Scheme 6

  

  Scheme 6.  Photocatalytic alkylation of 2-isocyanobiaryls with bromoalkanes.

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  Mechanistically, upon photoexcitation, the dimeric gold catalyst generates significant excimeric Au−Au interactions, leading to the formation of an exciplex with haloalkanes. This interaction indeed facilitates an inner-sphere activation mechanism via photoinduced electron transfer from the excited state of the gold complex to the haloalkanes. This unique pathway offers a novel approach to activate haloalkanes using a gold(Ⅰ) complex with lower reduction potentials, in contrast to traditional methods that typically utilize Ru- and Ir-based polypyridyl complexes which rely on metal-to-ligand charge transfer. Once the alkyl radicals 15 are generated, they react with isonitriles 1a, producing sp²-hybridized radicals 16. These intermediates proceed through a cyclization with aryl group, yielding cyclohexadienyl radicals. The reaction is completed when these radicals are oxidized by the Au(Ⅲ) complex 17, yielding the desired phenanthridines. The protocol demonstrated tolerance for a diverse range of primary, secondary, and tertiary bromoalkanes, as well as various isonitriles. This enables an efficient synthesis of a wide variety of functionalized phenanthridines. The work not only introduces a novel synthetic approach to phenanthridines but also provides a compelling case for the continued exploration of gold catalysts in photoredox catalysis.

  In contrast to previous studies involving bromoalkanes, several research groups have made significant effort in developing reactions of alternative alkyl sources with 2-isocyanobiaryls.

  A notable contribution by She et al. focused on the single-electron oxidation of ethers facilitated by photoredox catalysis, enabling the synthesis of diverse phenanthridines (Scheme 7) [43]. This method exhibited wide compatibility with a range of 2-isocyanobiaryls bearing both electron-donating (such as Me-, i-Pr-, t-Bu-, pH-, MeS- and MeO-) and electron-withdrawing substituents (such as F-, Cl-, Br- and CF₃-), yielding the corresponding products in moderate to high yields. Simple ethers such as diethyl ether, 1,3-dioxolane, and tetrahydropyran also performed efficiently, further highlighting the versatility of the method and practical utility in functional group compatibility.

  Scheme 7

  

  Scheme 7.  Ethers as radical precursors for the synthesis of 6-alkylated phenanthridines.

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  Based on the control experimental observations, the authors proposed a plausible mechanism (Scheme 7). Under blue LED irradiation, the excited-state Ru(Ⅱ) species donates one electron to tert–butyl hydroperoxide (TBHP), generating a tert–butoxyl radical 20. This radical efficiently abstracts a hydrogen atom adjacent to the oxygen atom of tetrahydrofuran (THF) 18a, forming a α-oxo radical 21. The α-oxo radical then undergoes intermolecular addition to the isocyanide 1a to form an imidoyl radical 22, followed by intramolecular radical cyclization to provide a cyclohexadienyl-type radical 23. The oxidation of radical 23 by the Ru(Ⅲ) species affords a carbocation intermediate 24. Finally, the carbenium 24 undergoes aromatization through a deprotonation step, giving the desired product 19a.

  In 2019, a visible-light-mediated protocol was reported by Liu's group utilizing amino acid- and peptide-derived Katritzky pyridinium salts as the alkylating agents for the synthesis of 6-alkylated phenanthridines (Scheme 8) [44]. The reaction of 2-isocyanobiaryl (1), bearing either electron-withdrawing (e.g., F-, Cl-, CN-) or electron-donating (e.g., Me-, MeO-, CF₃O-) substituents, proceeded smoothly, affording the corresponding products in satisfactory yields. Notably, the reaction could be readily scaled up to the gram level, highlighting the method's robustness and practical utility. Different Katritzky salts were tolerated well, including those containing sulfide, ester, and amide functionalities, as well as unprotected hydroxyl group, providing the desired 6-substituted phenanthridines in good to excellent yields.

  Scheme 8

  

  Scheme 8.  Katritzky salts as radical precursors for the synthesis of 6-α-keto-alkylated phenanthridines.

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  A plausible mechanism for this transformation was proposed. Initially, a single electron reduction (SER) of the redox-active Katritzky salt 25 by the excited state of the ruthenium catalyst (*[Ru]²⁺), generates a dihydropyridine radical 27, followed by a fragmentation process to afford an alkyl radical 28. This alkyl radical then adds to the isocyanide 1a to form an imidoyl radical 29, which undergoes intramolecular cyclization to yield the cyclohexadienyl radical 30. Finally, oxidation of intermediate 30 by [Ru]³⁺ leads to the desired product 26 via aromaticity-driven deprotonation.

  Cyclopropanols, as readily accessible and versatile radical precursors due to their intrinsic ring strain, have gained significant interest in radical chemistry [45–55]. Ding et al. developed a novel visible-light-induced protocol for the synthesis of 6-β-ketoalkyl phenanthridines 32 from 2-isocyanobiaryls 1 and cyclopropanols 31 (Scheme 9) [56]. Mn(acac)₃ was utilized as the photocatalyst, representing a cost-effective and earth-abundant alternative to noble metal-based systems, which aligns with the current trend toward sustainable catalysis. This strategy showcases remarkable substrate scope, accommodating a range of electron-donating (e.g., Me-) and electron-withdrawing groups (e.g., Cl-, F-, CF₃-) on the 2-isocyanobiaryls, and providing the corresponding products in moderate to good yields. Moreover, both alkyl-and aryl-substituted cyclopropanols were well tolerated in the reaction with moderate to excellent yields.

  Scheme 9

  

  Scheme 9.  Cyclopropanols as radical precursors for the synthesis of 6-β-keto-alkylated phenanthridines.

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  Yatham et al. reported a general radical decarboxylative cascade alkylation strategy for the synthesis of 6-alkyl-substituted phenanthridines, utilizing alkyl N-hydroxyphthalimide (NHP) esters 33 as the alkyl radical precursors and inexpensive PPh₃/NaI system as the photocatalyst (Scheme 10) [57]. A diverse array of alkyl NHP esters reacted with various substituted 2-isocyanobiaryls to yield the corresponding products.

  Scheme 10

  

  Scheme 10.  Alkyl NHP esters as radical precursors for the synthesis of 6-alkylated phenanthridines.

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  Based ON/OFF light experiments, radical clock, UV–visible absorption spectroscopy, and precedent literature, the authors proposed a mechanism involving the formation of a charge transfer complex between PPh₃, NaI, and the NHP-ester [58]. Upon photodissociation of this complex, the key alkyl radical 35 and PPh₃-Ⅰ radical 36 are generated. The alkyl radical 35 then adds to 2-isocyanobiphenyl 1a, forming the iminyl radical 37, which can undergo intramolecular radical cyclization to produce intermediate 38. Further oxidation of the intermediate 38 by the PPh₃-Ⅰ radical results in the formation of the corresponding carbocation 39 and the regeneration of NaI and PPh₃. Ultimately, the carbocation 39 loses a proton to produce the desired alkyl-substituted phenanthridines.

  In 2020, Miranda et al. developed a novel protocol for the synthesis of 6-alkylated phenanthridines 41 using xanthates 40 as the radical precursors under visible light irradiation. The xanthates used contained various functional groups, including nitrile, aromatic and aliphatic ketone, malonates, amide, phthalimidomethyl, and benzylic groups (Scheme 11) [59]. The methodology tolerated a wide range of substituents on both aromatic rings of the 2-isocyanobiaryls 1, including alkyl, alkyloxy, methoxycarbonyl, halogen, and acetyl groups, affording the corresponding products in 28%–76% yields.

  Scheme 11

  

  Scheme 11.  Xanthates as radical precursors for the synthesis of functional 6-alkylated phenanthridines.

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  Wang and Miao developed a visible-light-induced decarboxylative cyclization/hydrogenation cascade reaction involving α-oxocarboxylic acids 42 and 2-isocyanobiaryls 1 to synthesize phenanthridin-6-ylmethanols in moderate to good yields (Scheme 12) [60]. This method demonstrated broad tolerance for a variety of 2-oxo-2-arylacetic acids and 2-isocyanobiaryls with alkyl, alkoxyl, and halogen substituents, producing the corresponding products 43.

  Scheme 12

  

  Scheme 12.  Decarboxylative cyclization/hydrogenation cascade reaction of α-oxocarboxylic acids and 2-isocyanobiaryls.

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  Through UV–vis absorption spectroscopy and Job's plot analysis, the authors proposed that the reaction was driven by a key photoactive electron donor-acceptor (EDA) complex, which mediated the sequential radical and cyclization events. Upon visible light irradiation, the photoactive EDA complex generates a radical-ion pair by SET. Fragmentation of the radical-ion pair then produces carboxylic radical 44 and a stabilized radical anion 45. The acyl radical 46 is formed by the release of CO₂ from the carboxylic radical 44, which subsequently reacts with the isonitrile to produce another radical intermediate 47. This radical 47 undergoes intramolecular radical cyclization to generate the cyclohexadienyl radical intermediate 48, which then undergoes reduction and dehydrogenation to form 6-acyl phenanthridine 50, while the anion 45 is protonated to the neutral radical 49. Finally, 6-acyl phenanthridine 50 is excited, then reduced by the H^• donors 49 and 42 to yield the corresponding alcohols 43. This protocol avoids the external photosensitizers, oxidants, or reductants, relying solely on visible light and the intrinsic properties of the EDA complex. This not only reduces waste but also aligns with green chemistry principles, making it a highly sustainable approach.

  2.2 Visible-light-induced synthesis of 6-fluoroalkylated phenanthridines

  The incorporation of fluorine-containing alkyl groups into molecular scaffolds has attracted significant interest among researchers over the past few decades due to the enhanced reactivity, increased lipophilicity, and improved bioactivity of these groups [61]. Among them, the trifluoromethyl (CF₃-) group is particularly valuable, prompting the development of a variety of elegant methods for its introduction into diverse molecular frameworks. Notably, Yu, Zhang and Liu's groups have independently reported the synthesis of 6-(trifluoromethyl)phenanthridines from 2-isocyanobiaryls. In these cases, trifluoromethyl radicals were generated from different sources using appropriate initiators under light irradiation.

  Yu's group pioneered a photoredox-catalyzed method to synthesize 6-(trifluoromethyl)phenanthridines, using Umemoto's reagent 51 as the CF₃ source at room temperature (Scheme 13a) [62]. This work represents a significant advance in CF₃ radical generation under mild visible light conditions, providing good functional group compatibility. Following this, Zhang's group reported a photocatalyst-free approach, involving the homolysis of CF₃SO₂Cl 52 to generate a CF₃ radical (Scheme 13b) [63]. The reaction was carried out under a 300 W Xe lamp at 0 ℃. A range of 6-(trifluoromethyl)phenanthridines containing diverse functional substituents, such as alkyl, alkoxyl, phenyl, chloro, bromo, acetyl, and cyano groups, were afforded in acceptable to good yields. Simple reaction conditions, combined with the absence of an external photocatalyst, represents a significant contribution to the field. Gram-scale synthesis obtained a comparable yield (65%) of the product with that of 0.2 mmol scale (69%), hinting the potential applicability of the protocol. Almost concurrently, Hu and coworkers introduced an innovative method for generating CF₃ radicals from fluorinated sulfones 68 and 69 using Ru-based complexes as the photoredox catalysts under visible light. Furthermore, Liu et al. disclosed a visible-light-promoted protocol for the synthesis of 6- tri-/di-/monofluoromethylated phenanthridines with R_fSO₂Na reactants (Scheme 13c) [64]. In this protocol, N-methyl-9-mesityl acridinium perchlorate (Mes-Acr⁺) served as the photosensitizer, and K₂S₂O₈ acted as an oxidant.

  Scheme 13

  

  Scheme 13.  Photoredox tri- and di-fluoromethylation of 2-isocyanobiaryls with different fluroalkyl reagents.

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  Li and coworkers unveiled an elegant visible-light-induced methodology for the synthesis of 6-(trifluoromethyl)phenanthridines, employing diacetyl and NaSO₂CF₃ to generate CF₃ radical (Scheme 14) [65]. Notably, this transformation accommodated 2-isocyanobiaryls with a wide range of functionalities under mild conditions at room temperature.

  Scheme 14

  

  Scheme 14.  Generation of CF₃ radical through diacetyl as the photooxidant for the synthesis of 6-trifluoromethylphenanthridines.

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  Based on UV–vis spectroscopy and the Stern-Volmer analysis, the authors proposed that the carbonyl group of diacetyl is promoted from its ground state to an excited state upon visible light irradiation, forming a diradical species 56. The excited diacetyl undergoes reductive quenching with NaSO₂CF₃, generating a CF₃ radical along with the release of 1 equiv. of SO₂. The CF₃ radical then attacks the terminal carbon of 1a, affording the iminyl radical 57. Subsequently, radical addition and intramolecular homolytic aromatic substitution (HAS) occurs to form a cyclohexadienyl radical 58, then the final product 54 being afforded through aromaticity-driven H^• abstraction by the diacetyl radical anion. The innovative use of diacetyl as both the light-absorbing species and an electron donor highlights the methodology's novelty and potential for broader applications in organic synthesis. This work not only expands the toolbox for trifluoromethylation of phenanthridines but also provides a novel pathway to generate CF₃ radical [66].

  In addition to trifluoromethylation, the development of novel methods for introducing the difluoromethyl group and its analogs at the 6-position of phenanthridines has gained significant attention. Among these, Liu et al. reported a photocatalytic phosphonodifluoromethylation using commercially available diethyl bromodifluoromethylphosphonate 59 under the visible light conditions (Scheme 15) [67]. The reaction proved to be robust and versatile, accommodating 2-isocyanobiphenyls with both electron-withdrawing and electron-donating groups, to give a diverse array of 6-(difluoromethylenephosphonyl)phenanthridines in moderate to high yields. The incorporation of a difluoromethylenephosphonyl group significantly enhances the structural diversity of phenanthridines, broadening the scope and potential applications of phosphonodifluoromethylation in organic synthesis.

  Scheme 15

  

  Scheme 15.  Visible-light-induced Ir-photocatalyzed synthesis of 6-phosphonodifluoromethylated phenanthridines.

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  Subsequently, Dolbier reported a photoredox-catalyzed difluoromethylation and 1,1-difluoroalkylation of 2-isocyanobiaryls using HCF₂SO₂Cl 61 and RCF₂X 62 as precursors (Scheme 16) [68]. Different radical sources have some differents in reactivity. When HCF₂SO₂Cl as difluoromethyl radical precursor, a small amount of H₂O was needed to achieve higher yields. When PhCF₂Br employed as the PhCF₂ radical precursor, a higher reaction temperature and 2 mol% loading of catalyst were required to obtain satisfactory yields. In general, this approach displayed broad functional group tolerance on the benzene ring of the 2-isocyanobiaryls, efficiently delivering the desired products in good to excellent yields.

  Scheme 16

  

  Scheme 16.  Visible-light-induced Ir-photocatalyzed synthesis of difluoroalkylated phenanthridines.

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  Hu's group reported an innovative strategy employing fluoroalkyl sulfones and their derivatives as radical fluoroalkylation agents through photoredox catalysis (Scheme 17a) [69]. Utilizing difluoromethyl sulfone 64 as the radical source, various 2-isocyanobiaryls 1 with either electron-donating or electron-withdrawing substituents on one of the aryl rings were effectively tolerated under the reaction conditions, affording the final products 63 in moderate to good yields. Additionally, other sulfones featuring 2-benzo[d]thiazolyl sulfone scaffolds 65–68, as well as 2-pyridyl scaffolds 69 and 70 also reacted smoothly with 1, producing the corresponding phenanthridines in good yields.

  Scheme 17

  

  Scheme 17.  Sulfones and sulfonium salt as radical precursors for the photocatalytic synthesis of difluoroalkylated phenanthridines.

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  Later, the S-(difluoromethyl)diarylsulfonium salt 71 demonstrated to be an effective difluoromethyl radical precursor in photoredox catalysis for the synthesis of a variety of difluoromethylated phenanthridines (Scheme 17b) [70]. In general, the reactivity of this salt resembles that of Hu's difluoroalkyl sulfones. KOH was added as a base to neutralize the acid generated during the reaction. PEG600 was employed as an additive, likely acting as a co-solvent to enhance miscibility of the KOH aqueous solution and dichloromethane. Notably, a DNA intercalator 6-(difluoromethyl)trispheridine 63b was thus regioselectively synthesized from 1b in a yield of 71%, illustrating the practicality and potential application of this method in medicinal chemistry and drug discovery. This work broadens the utility of fluoroalkyl sulfones as versatile radical precursors in constructing structurally diverse fluoroalkylated phenanthridines, which is promising for applications in pharmaceutical and materials chemistry.

  Chen and coworkers developed a mild and efficient photochemical method for the perfluoroalkylation of cost-effective perfluoroalkyl iodides 72 in the presence of Lewis bases, such as amines (Scheme 18) [71]. A key feature of this methodology is the absence of a photoredox catalyst. This method has been successfully applied to various substituted 2-isocyanobiphenyls. Both linear and branched perfluoroalkyl iodides of various chain lengths were well-tolerated, affording perfluoroalkyl phenanthridines in good-to-excellent yields with high regioselectivity. Furthermore, the reaction proceeds under a range of light sources, including a compact fluorescent lamp, low-intensity UV lamp, or even sunlight at ambient temperature, showcasing its operational simplicity and sustainability. Mechanistic studies were performed using ¹⁹F NMR titration and a Job's plot analysis, to confirm the formation of the 1:1 complex between NEt₃ and C₁₀F₂₁−Ⅰ, which promotes the photochemical reactivity of perfluoroalkyl iodides under low-intensity UV irradiation.

  Scheme 18

  

  Scheme 18.  Visible-light-induced photocatalyst-free synthesis of 6-perfluoroalkylated phenanthridines.

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  2.3 Visible-light-induced synthesis of 6-arylphenanthridines

  In 2014, Zhou and coworkers described a visible-light-induced radical cyclization of 2-isocyanobiaryls 1 with hydrazines 74 employing the organic dye Eosin B, a fluorescein derivative, as a radical initiator in the open air (Scheme 19) [72]. A variety of hydrazines, including different substituted phenyl hydrazines, alkyl hydrazines, benzoyl hydrazines, and ethyl carbazates (EtOC(O)NHNH₂), reacted smoothly with 1, affording the corresponding 6-alkyl-substituted phenanthridines in moderate to high yields. Additionally, 2-isocyanobiaryls with both electron-donating (such as Me-, MeO-) and electron-withdrawing (such as CF₃-, Cl-), substituents on the aromatic rings were well tolerated, indicating that the electronics of the 2-isocyanobiaryl substrates did not significantly affect the efficiency of the reaction. Instead of Ru- and Ir-based photosensitizers, the reaction employed an inexpensive and easily available organic dye as a photoredox catalyst, which would facilitate potential applications of this method in the synthesis of 6-substituted phenanthridines.

  Scheme 19

  

  Scheme 19.  Hydrazines as radical precursrs for the photochemical synthesis of 6-substituted phenanthridines.

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  Subsequently, several novel strategies were developed for synthesizing 6-arylphenanthridines from 2-isocyanobiaryls using various aryl radical precursors under visible light conditions (Scheme 20).

  Scheme 20

  

  Scheme 20.  Visible-light-induced synthesis of 6-arylated phenanthridines from 2-isocyanobiaryls and different aryl radical precursors.

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  Gu et al. reported a visible-light-catalyzed transformation of 2-isocyanobiaryls 1 with arylsulfonyl chlorides 76 (Scheme 20a) [73]. This approach leverages the reactivity of sulfonyl chlorides under visible light, offering an efficient and straightforward method to produce 6-arylphenanthridines. In a separate study, Yu's group described a photoredox method employing diaryliodonium salts 77 as aryl radical precursors, enabling the synthesis of 6-arylphenanthridines (Scheme 20b) [62]. Meanwhile, Li et al. demonstrated the use of aryl bromides (78) as aryl radical precursors in conjunction with the commercially available Rhodamine 6G (Rh-6G) photoredox catalyst (Scheme 20c) [74]. Iodonium ylides could also be employed as aryl radical precursors under photocatalytic conditions [75]. He's group introduced iodonium ylides 79 as aryl radical precursors for the synthesis of 6-arylphenanthridines 4 through a visible-light-induced cascade arylation/cyclization pathway (Scheme 20d) [76].

  These methods above enabled the preparation of 6-arylphenanthridines with a wide range of electron-rich and electron-deficient substituents, showcasing the broad substrate scope and versatility of these protocols. Mechanistically, these reactions all proceed via the photoreduction of aryl radical precursors to generate aryl radicals, which then undergo radical tandem cyclization with isocyanobiaryls to afford the target 6-arylated phenanthridines.

  2.4 Visible-light-induced synthesis of 6-acylphenanthridines

  After discovering that C(2)-substituted benzothiazolines 80 can absorb visible light, Xuan et al. investigated their photochemical reactivity as acyl radical precursors for the acylation of isonitriles, ultimately preparing acyl-substituted phenanthridines 81 (Scheme 21) [77]. This methodology exploits the direct photoexcitation of C(2)-substituted benzothiazolines, combined with acetoxybenziodoxole (BI-OAc) as an electron mediator and 2-isocyanobiaryls as radical acceptors.

  Scheme 21

  

  Scheme 21.  C2-acyl benzothiazolines as radical precursors for the photo-synthesis of 6-acylated phenanthridines.

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  Following several control experiments, the authors proposed that benzothiazoline undergoes photoexcitation to produce 80* under blue LED irradiation, which is a strong photoreductant (–1.68 V vs. SCE). Subsequently, a SET from 80* to BI-OAc affords radical cation 80^•+, which then fragments to yield the key acyl radical 83 along with 2-phenylbenzo[d]thiazole 82. Additionally, the acyl radical 83 can also be generated through direct homolytic cleavage of the C–CBz bond in 80*, which is however of relatively low efficiency.

  Wang and Chen's group published a novel strategy for the photoreduction of acyl chlorides to generate acyl radicals, facilitating the synthesis of various acylated phenanthridines (Scheme 22) [78]. The reaction demonstrated broad substrate compatibility, as diverse isocyanides and aryl acyl chlorides bearing either electron-donating or electron-withdrawing substituents underwent smooth transformations to afford the corresponding products in 48%−82% yields. This methodology was further utilized to construct a range of diverse N-heterocycles, including acylated oxindoles 85, tricyclic indoles 86 and 87, fused tetracyclic N-heterocycles 88 and 89, and coumarin derivative 90, all synthesized with high efficiency.

  Scheme 22

  

  Scheme 22.  Acyl chlorides as acyl radical precursors for the photo-synthesis of 6-carbonylated phenanthridines.

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  To further understand the reaction mechanism, UV−vis spectroscopy, ¹³C NMR titrations, radical-trapping experiments, and density functional theory (DFT)/time-dependent DFT (TD-DFT) computations were performed. These studies revealed that weak interactions between DIPEA and the carbonyl group of acyl chlorides enables the formation of a photoactive charge transfer complexes (CTC). Under blue light irradiation, acyl radicals were generated through SET from DIPEA to the acyl chlorides. This CTC-based strategy provides a cost-effective and operationally simple alternative for the photoreduction of acyl chlorides, avoiding the need for expensive photocatalysts that rely on specific redox potentials, transition metals, ligands, or additives.

  Later, the same group reported a photoreduction of acyl fluorides catalyzed by an N-heterocyclic nitrenium (NHN) iodide salt, enabling the synthesis of various 6-acylphenanthridines (Scheme 23) [79]. In this study, acyl fluorides served as acyl radical precursors, representing a rare and efficient use of this class of compounds in photoredox chemistry. Consistent with the group's previous work, the strategy was operationally simple, avoiding transition metals or oxidants.

  Scheme 23

  

  Scheme 23.  Acyl fluorides as radical sources for the photo-synthesis of 6-arylacyl-phenanthridines.

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  A series of mechanistic experiments were conducted, including UV–vis spectroscopy, Stern−Volmer analysis, and radical trapping studies, to explore the reaction mechanism. These investigations revealed two potential pathways for generating the NHN radical 92: either through SET from I⁻ (Scheme 23, path a) or SET from Et₃N (Scheme 23, path b) to the NHN catalyst under visible light. The resulting NHN radical 92 then reduces the acyl fluorides, affording the key acyl radical 83. This acyl radical subsequently reacts with the 2-isocyanobiaryls, forming an intermediate that undergoes intramolecular cyclization, followed by a second SET and deprotonation, ultimately producing the acylated phenanthridines.

  2.5 Visible-light-induced synthesis of other substituted phenanthridines

  Organophosphorous compounds play a pivotal role in organic synthesis, with diverse applications in medicinal chemistry, materials science, and catalysis. Several visible-light-mediated methods were developed for the preparation of 6-phosphinoylated phenanthridines over the past decade. In 2016, Lu et al. reported an effective photoredox-mediated tandem phosphorylation/cyclization reaction involving diphenylphosphine oxide 98 and 2-isocyanobiaryls 1, yielding 6-phosphinoyl-phenanthridines 99 in up to 85% yield at room temperature (Scheme 24) [80]. Various functional groups on the two phenyl rings of 1 were well tolerated, including Me-, OMe-, F-, Cl-, ^tBu-, and CF₃- groups. Additionally, the method allowed the use of various phosphinoyl sources, including di-p-tolylphosphine oxide, tert–butyl(phenyl)phosphine oxide and ethyl phenylphosphinate. However, no desired product was obtained when diethyl phosphonate was employed as a possible phosphonyl source.

  Scheme 24

  

  Scheme 24.  Synthesis of 6-phosphinoylated phenanthridines with Ir(ppy)₃ as a photocatalyst.

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  Yu and Chen's group designed and developed an organic dye, 2,4,5,6-tetrakis(3,6-di–tert–butyl–9H-carbazol-9-yl)-isophthalonitrile (4CzIPN-^tBu), which served as an efficient photocatalyst for a phosphorus radical-initiated cascade cyclization of isonitriles (Scheme 25) [81]. This strategy avoids the use of expensive and toxic transition-metal photocatalysts, offering a sustainable and cost-effective alternative. Under visible light irradiation, the 4CzIPN-^tBu catalyst enabled the synthesis of a wide variety of phosphinoylated N-heterocycles, including phenanthridines 99, quinolines, and benzothiazoles, via a proton-coupled electron transfer (PCET) mechanism.

  Scheme 25

  

  Scheme 25.  Synthesis of 6-phosphinoyl-phenanthridines with 4CzIPN-^tBu as a photocatalyst.

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  To gain deeper understanding of the reaction mechanism, a series of mechanistic studies were conducted, including radical scavenging experiments, intermolecular kinetic isotope effect (KIE) experiments, electron paramagnetic resonance (EPR) spectroscopy, luminescence quenching tests, and cyclic voltammetry (CV). The authors proposed that the reaction begins with the rapid equilibrium of diphenylphosphine oxide 98a with its minor tautomer, hydroxydiphenylphosphine 100. Upon visible light photoactivation, the photocatalyst (PC) is excited to its corresponding excited-state PC*. A SET occurs from 100 to PC*, coupled with proton transfer from 100 to the added weak base (NaHCO₃), generating the photocatalyst radical anion PC^•− and the phosphinoyl radical 101. The phosphinoyl radical reacts with the isocyano group of 1a, forming the imidoyl intermediate 102. In the presence of TBHP, the intermediate 102 undergoes an intramolecular cyclization and subsequent oxidation by in situ-generated ^tBuO^• to form ^tBuO⁻ and intermediate 104. In the presence of a base, the acidic proton of intermediate 105 dissociates to form the phosphine oxide 99a. Lastly, the photocatalyst is regenerated through a SET from PC^•− to TBHP, completing the catalytic cycle.

  Singh et al. developed a convenient, efficient, and metal-free method for the synthesis of 6-thiocyanatophenanthridines through a visible-light-induced radical cyclization of 2-isocyanobiaryls 1 with readily available and inexpensive NH₄SCN as the source of SCN radicals at room temperature (Scheme 26) [82].

  Scheme 26

  

  Scheme 26.  NH₄SCN as radical precursor for the Eosin Y-mediated photo-synthesis of 6-thiocyanatophenanthridines.

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  Based on fluorescence-quenching experiments, the authors proposed that a SET occurs between SCN⁻ and the excited state EY*, generating the SCN^• radical and the radical anion EY^∙−. The radical anion EY^∙− is subsequently oxidized to EY in the presence of O₂, thereby completing the catalytic cycle. Thus, the presence of air (O₂) is crucial for the reaction, as only trace amounts of product were observed under a nitrogen atmosphere. The generated SCN^• radical subsequently adds to 1a to afford the radical 107, which undergoes cyclization to yield 108. The cyclohexadienyl radical 108 is oxidized and further undergoes dehydrogenation by superoxide O₂^∙− to afford the target product 106a.

  Wang's group discovered an EDA complex formed by arylsulfinic acid as the electron donor and 2-isocyanobiaryls 1 as the electron acceptor (Scheme 27) [83]. This complex was utilized as a photocatalyst for a three-component reaction involving arylsulfinic acid, an alkyne, and 2-isocyanobiaryls, enabling the synthesis of 6-(vinylsulfonyl)phenanthridines. This tandem reaction exhibited high regio- and stereo-selectivity, selectively yielding E- or Z-products in good yields under blue LED or UV irradiation.

  Scheme 27

  

  Scheme 27.  Three-component reaction induced by an EDA complex for the photo-synthesis of 6-(vinylsulfonyl)phenanthridines.

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  Various substituted sulfinic acids with aryl, 2-thienyl, and aliphatic groups reacted efficiently to give the corresponding products in satisfactory yields. Aliphatic alkynes such as n-pentyl-, n-propyl-, n–butyl–, n-hexyl-, n-heptyl-, and cyclopropyl-acetylene were well tolerated. Under different light irradiation conditions, the ratio of E- and Z-isomers varies significantly. Specifically, blue LED irradiation predominantly yields the E-isomer, whereas UV irradiation results in the Z-isomer as the major product. The authors found that when E-product 111a was irradiated with UV light at 365 nm for 24 h, it could be efficiently converted into its Z-isomer in 93% yield. This finding highlights the distinct outcomes of the reaction under different irradiation conditions.

  Various aromatic alkynes with different functional groups, such as alkyl, methoxyl, and halogen on the phenyl rings reacted smoothly under N₂ atmosphere with 3 W UV or 3 W blue LED irradiation, producing Z-isomers only in good yields. Furthermore, 2-isocyanobiaryls containing substituents such as Me-, Cl-, CF₃-, and MeO₂C- were incorporated into the reaction with high efficiency.

  A possible mechanism was proposed for the reaction. With the assistance of pyridine and H₂O, an EDA complex 112 was formed from the arylsulfinate anion and isocyanide 1a. Upon light excitation, a SET process generates the dipolar species 113. Fragmentation of 113 produces an oxygen-centered radical 114 and a radical anion 115. The generated radical 114 can resonate with the sulfonyl radical form 114′. The sulfonyl radical then reacts with terminal alkyne 110 to afford a vinyl radical 116. Addition of the vinyl radical 116 to the terminal carbon of 1a generates the imidoyl radical 117, which then undergoes intramolecular HAS to yield the cyclohexadienyl radical 118. Finally, oxidation by O₂ and base-assisted deprotonation lead to the final product 111. On the other hand, resonance and a hydrogen cation abstraction of radical 115 can form an imidoyl radical to store a hydrogen radical. Under an O₂ atmosphere, the imidoyl radical can be captured by O₂^•− to produce 1a and HO₂⁻.

  Recently, Huang et al. developed a visible-light-induced photoredox/PPh₃ catalytic system for the intramolecular cyclization of 2-isocyanobiaryls 1, offering a straightforward, mild, and atom-economical method for synthesizing a series of phenanthridines (Scheme 28) [84].

  Scheme 28

  

  Scheme 28.  Visible-light-induced self-cyclization of 2-isocyanobiaryls to phenanthridines through a photoredox/PPh₃ catalytic system.

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  Through extensive mechanistic studies, including control experiments and isotopic labeling, the authors proposed two distinct reaction pathways.

  Initially, the Ir^Ⅲ complex is initially photoexcited to generate the strongly oxidative excited species Ir^Ⅲ*, which is subsequently reduced by PPh₃ to form a reducing Ir^Ⅱ complex and the phosphorus-radical cation 121. On one hand, the phosphorus-radical cation 121 directly adds to the isocyano group of 1a to access the radical cation intermediate 122. Intramolecular radical cyclization of 122 produces the cyclohexadienyl radical phosphonium 123, which is reduced by the Ir^Ⅱ complex to generate the zwitterionic phosphonium-cyclohexadienyl anion intermediate 124. This intermediate undergoes intramolecular 1,2-HAT, releasing PPh₃, and yielding the final product. The key hydride process was by the reaction result of deuterated 2-isocyanobiphenyl.

  Alternatively, the phosphorus-radical cation 121 enables hydroxylation with H₂O to form the (OH)Ph₃P^• radical 125. This adduct undergoes homolytic cleavage of its O—H bond to give a hydrogen radical and Ph₃P=O. The hydrogen radical then adds to 2-isocyanatobiphenyl 1a, initiating radical cyclization to form the cyclohexadienyl radical intermediate 127. Oxidation of 127 by the photocatalyst, followed by deprotonation, yields the phenanthridine 120a. Additionally, Ph₃P=O with [Ir]PF₆, undergoes photoexcitation enabling SER and subsequent protonation to regenerate the (OH)pH₃P^• radical adduct 125, completing the cycle. The authors replaced water with D₂O, resulting in a ratio of 27:73 (H-120a to D-120a). The result indicated that the proton at the C6 position of the phenanthridine predominantly originates from water, supporting the pathway as the major mechanistic pathway for the transformation.

  3. Visible-light-induced synthesis of phenanthridines involving nitriles

  Nitriles are versatile and valuable functional groups in organic synthesis, serving as crucial precursors for a wide array of transformations [85,86]. The cyano group can effectively function as a radical-bridging moiety, facilitating the synthesis of various substituted phenanthridines through radical cascade reactions (Scheme 29) [87–91]. In 2021, He's group summarized the process of the radical cascades using the cyano group as a radical acceptor for synthesis of ketones and N-heterocycles, in which synthesis of phenanthridines was included [92]. In this section, we summarize recent progress in the visible-light-induced preparation of phenanthridines utilizing cyano groups as radical acceptors in the last decade. These methods demonstrate the unique ability of nitriles to mediate radical cascade reaction under visible light initiation, offering efficient and practical strategies for accessing functionalized phenanthridines with diverse applications in medicinal chemistry and materials science.

  Scheme 29

  

  Scheme 29.  The cyano group as a radical acceptor for the preparation of annelated phenanthridines.

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  In 2017, Sun's group developed a novel visible-light-induced cascade alkoxycarbonylation and cyclization reaction of N-(o-cyanobiaryl)acrylamides 129. The method employed alkyl carbazates 130 as alkoxycarbonyl sources, allowing the synthesis of ester-functionalized pyrido[4,3,2-gh]phenanthridines 131 under metal-free conditions (Scheme 30) [93]. The reactions proceeded smoothly for the substrates featuring either electron-donating groups (e.g., alkyl, alkoxy, and alkylthio groups) or electron-withdrawing groups (e.g., halogen, ester, sulfonyl, cyano, and CF₃ groups), yielding moderate to good yields without significant electronic or steric hindrance effect.

  Scheme 30

  

  Scheme 30.  Alkyl carbazate as ester radical sources for the photo-synthesis of ester-functionalized pyrido[4,3,2-gh]phenanthridine derivatives in the presence of Eosin Y as photo-sensitizer.

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  Concurrently, the group reported a cascade reaction of N-(o-cyanobiaryl)acrylamides 129 initiated by active methylene radicals (Scheme 31) [94]. These radicals were generated from 2-bromoacetonitrile, ethyl 2-bromoacetate, or 2–bromo-N, N-dimethylacetamide, which subsequently added to the C=C bond of the N-arylacrylamides, forming 6-quaternary alkylated phenanthridines 133, produced in moderate to good yields under photoredox catalysis.

  Scheme 31

  

  Scheme 31.  Visible-light-induced synthesis of alkylated pyrido[4,3,2-gh]phenanthridines via methylene radicals.

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  Subsequently, the same group utilized aliphatic carboxylic acids 134 as alkyl sources to develop a visible-light-mediated synthesis of annelated alkylated phenanthridines 135 under transition metal-free conditions (Scheme 32) [95]. The (NH₄)₂S₂O₈/Eosin Y system functioned as a photoredox catalytic system to effectively promote the radical decarboxylation of the aliphatic carboxylic acids. Reactions with N-arylacrylamides featuring either electron-donating groups (e.g., Me-, MeO- and ^tBu-) or electron-drawing groups (e.g., pH-, F-, Cl-, Br-, CF₃-, CN-, MeSO₂- and EtO₂C-) on the benzene ring proceeded smoothly. Additionally, alkyl substituents on the nitrogen atom, such as n–butyl, i–butyl, and benzyl groups, were effectively transformed into their products. Various aliphatic carboxylic acids, including pivalic acid, isovaleric acid, 2-cyclohexylacetic acid, as well as primary and cyclic secondary carboxylic acids, were readily coupled with N-arylacrylamide, generating the tetracyclic products in good yields under the standard reaction conditions.

  Scheme 32

  

  Scheme 32.  Aliphatic carboxylic acids as radical precursors for the photo-synthesis of alkylated pyrido[4,3,2-gh]phenanthridines, in the presence of Eosin Y as photo-sensitizer.

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  The same group further developed a visible-light-induced synthesis of trifluoromethyl and difluoroalkyl phenanthridine derivatives 136 and 138, achieving moderate to good yields through a radical addition/insertion/cyclization process (Scheme 33) [96]. Three readily available fluoroalkylated reagents CF₃SO₂Cl, BrCF₂CO₂Et, and BrCF₂PO(OEt)₂ were employed as sources of fluoroalkyl radical, expanding the scope of radical-mediated phenanthridine functionalization.

  Scheme 33

  

  Scheme 33.  Visible-light-induced synthesis of trifluoroalkylated or difluoroalkylated pyrido[4,3,2-gh]phenanthridines.

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  Fu et al. found that difluoromethyl benzo[d]-thiazol-2-yl sulfone 64 was an effective difluoromethyl precursor for the preparation of CF₂H-substituted pyrido[4,3,2-gh]phenanthridines 139 under photoredox conditions (Scheme 34) [97]. N-(o-cyanobiaryl)acrylamides, bearing alkyl, methoxyl, halide, CF₃, CN and pH groups, demonstrated compatibility, affording the corresponding products in 43%−85% yields.

  Scheme 34

  

  Scheme 34.  Difluoromethyl benzo[d]-thiazol-2-yl sulfone as radical precursor for the photo-synthesis of HCF₂-substituted pyrido[4,3,2-gh]phenanthridines, in the presence of an Ir photocatalyst.

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  Wu's group reported a novel alkoxycarbonyl radical-triggered cascade cyclization involving N-(o-cyanobiaryl)acrylamides 129 and alkyloxalyl chlorides 140 (Scheme 35) [98]. A diverse array of N-(o-cyanobiaryl)acrylamides with different substituents including Me-, MeO-, ^tBu-, pH-, F-, Cl-, Br-, CF₃-, and CN- groups were explored. Furthermore, alkyloxalyl chlorides derived from common, especially long-chain primary alcohols, and chiral alcohols such as (+)-fenchol, menthol, (R)–tert-leucinol, and epiandrosterone, readily reacted with 129, affording the corresponding products 141 in up to 91% yield.

  Scheme 35

  

  Scheme 35.  Visible-light-induced synthesis of ester-containing phenanthridines via alkoxycarbonyl radicals, in the presence of a photo-sensitizer.

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  In 2023, Guo and coworkers reported a visible-light-induced cascade reaction for the preparation of cyanoalkyl-containing polyheterocycles 143, utilizing cyclic oxime esters 142 as radical sources (Scheme 36) [99]. This strategy demonstrates the versatility of cyclobutanone oximes derivatives as precursors for generating cyanoalkyl radicals, providing an efficient route to cyanoalkyl-containing molecules under mild and environmentally friendly conditions. This method exhibits excellent functional group compatibility, affording a diverse array of annelated phenanthridines 143, containing alkyl, alkyloxy, halogen, CN, SO₂Me groups in up to 80% yield.

  Scheme 36

  

  Scheme 36.  Cyclic oxime esters as radical precursors for the photo-synthesis of cyanoalkylpyrido[4,3,2-gh]phenanthridines, in the presence of an Ir photocatalyst.

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  Cycloalkanols and their derivatives have emerged as efficient keto-functionalized alkyl electrophiles within various catalytic systems. Recently, Guo et al. disclosed an efficient alkoxyl radical-mediated cascade transformation involving C—C bond cleavage and radical reactions (Scheme 37) [100]. This strategy provides a stepwise and atom-economical approach for the synthesis of pyrido[4,3,2-gh]phenanthridines 145 in 32%-72% yields with excellent functional group tolerance.

  Scheme 37

  

  Scheme 37.  Visible-light-induced synthesis of keto-alkylated pyrido[4,3,2-gh]phenanthridines, in the presence of fluorescein.

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  Unsaturated α-bromocarbonyls are highly versatile synthetic building blocks, capable of functioning as both radical donors and radical acceptors. Li and colleagues reported a tricyclization reaction utilizing unsaturated α-bromocarbonyls 147 with 3-ethynyl-[1,1′-biphenyl]−2-carbonitriles 146 under photoredox catalysis (Scheme 38) [101]. This reaction produces three C(sp³)−C(sp²) bonds, one C(sp²)−N bond, and three cycles in a single step under mild conditions, ultimately constructing dihydrobenzo[mn]-cyclopenta[b]acridines 148.

  Scheme 38

  

  Scheme 38.  Cascade cyclization of 3–ethynyl-[1,1′-biphenyl]−2-carbonitriles with unsaturated α–bromocarbonyls, in the presence of a Ru photocatalyst.

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  Mechanistically, the C-centered radical 149, generated by reduction of α-bromocarbonyl by the photocatalyst or by direct homolysis under visible light irradiation, undergoes radical addition to the C—C triple bond of ethynylbenzonitrile 146, leading to the alkenyl radical 150, which subsequently undergoes 5-exo-dig cyclization to form the alkyl radical 151. Then, the alkyl radical attacks the cyano group to produce iminyl radical 152, followed by an intramolecular cyclization with the aryl ring to afford the cycloghexadienyl radical 153. The intermediate 153 was the oxidized by a Ru(Ⅲ) species to give the cationic intermediate 154 and a Ru(Ⅱ) complex (path a). Oxidation of the bromo radical can also generate the same intermediate 154 (path b). Further deprotonation of 154 provides the annelated phenanthridine 148.

  Almost simultaneously, Yi and coworkers described a radical addition cyclization of N-(o-cyanobiaryl)acrylamides 129 with 2-benzyl-2-bromomalonates 155, providing the valuable functionalized pyrido[4,3,2-gh]phenanthridin derivatives 156 in moderate yields (Scheme 39) [102].

  Scheme 39

  

  Scheme 39.  Photochemical cascade cyclization of N-(o-cyanobiaryl)acrylamides with benzyl-2-bromomalonates, in the presence of the Eosin Y sodium salt as photo-sensitizer.

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  In addition to C-centered radicals, other types of radicals have been employed in the synthesis of functionalized phenanthridines. In 2020, a photoinduced sulfonylation/addition/cyclization reaction was developed for the synthesis of 4-sulfonated cyclopenta-[gh]phenanthridines 159 from 3-arylethynyl-[1,1′-biphenyl]−2-carbonitriles 157 (Scheme 40) [103]. This strategy employed aryldiazonium tetrafluoroborates 158 as the aryl sources and Na₂S₂O₅ as the source of sulfur dioxide, while proceeding under mild and environmentally friendly conditions. Notably, the reaction did not require a transition metal catalyst and demonstrated a broad substrate scope. The use of Na₂S₂O₅ as a sulfur dioxide source eliminates the need for handling gaseous SO₂, enhancing operational simplicity and safety.

  Scheme 40

  

  Scheme 40.  Three-component reaction for the photosynthesis of 4-sulfonated cyclopenta[gh]phenanthridine derivatives, in the presence of Eosin Y as photosensitizer.

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  The process is based on the photoinduced reduction of aryldiazonium tetrafluoroborates 158 to generate the aryl radical 160, which reacts with Na₂S₂O₅ to generate the sulfonyl radical 161. The radical addition of 161 to the carbon-carbon triple bond of 157 affords the intermediate 162, which subsequently undergoes intermolecular cyclization to form the iminyl radical 163. Finally, radical 163 adds to the aryl ring, leading to the cyclohexadienyl radical 164, which undergoes SET and deprotonation to deliver the target products.

  4. Visible-light-induced synthesis of phenanthridines involving vinyl azides and vinyl benzotriazoles

  Biaryl vinyl azides serve as versatile substrates in radical chemistry, as they can be efficiently attacked by radical species, leading to the formation of iminyl radicals. These highly reactive intermediates subsequently undergo HAS, resulting in the generation of 6-functionalized phenanthridines (Scheme 41).

  Scheme 41

  

  Scheme 41.  Reaction of biaryl vinyl azides with radicals.

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  In 2016, Yu's group developed an efficient strategy for synthesizing 6-alkylphenanthridine derivatives through the reaction of alkyl radicals from biaryl vinyl azides (Scheme 42) [104]. A variety of biaryl vinyl azides 166 reacted effectively with ethyl 2-bromopropanoate 5, affording the corresponding products 167 in good yields. This transformation demonstrated broad substrate compatibility with a range of alkyl bromides, including long-chained, branched, saturated, fluorinated, and malonate-derived bromoesters, as well as bromoketones. However, bromoamides and electron-deficient chlorides were unsuitable coupling partners under the same reaction conditions.

  Scheme 42

  

  Scheme 42.  Visible-light-induced synthesis of 6-alkylated phenanthridines using biaryl vinyl azides, in the presence of an Ir photocatalyst.

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  Guo et al. discovered that NHP esters 34 can undergo visible-light-promoted decarboxylative cyclization with biaryl vinyl azides 166 using Eosin Y as a photoredox catalyst (Scheme 43) [105]. This metal-free protocol demonstrated a broad substrate scope and excellent functional group tolerance, providing a straightforward and efficient method for synthesizing alkylated phenanthridines 168. A series of redox-active NHP esters, derived from structurally diverse aliphatic carboxylic acids with tertiary, secondary, and primary α-positions, readily reacted to form the corresponding products in moderate to good yields. Furthermore, biaryl vinyl azides containing various functional groups, such as Me-, MeO-, F-, Cl-, Br-, and CN-, on the aromatic rings were well tolerated.

  Scheme 43

  

  Scheme 43.  Visible-light-induced synthesis of alkylated phenanthridines using vinyl azides and NHP esters, in the presence of Eosin Y photosensitizer.

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  In 2021, Rastogi et al. reported an organophotocatalytic synthesis of 6-functionalized phenanthridines 170 from biaryl vinyl azides 166 and β-keto-α-diazo compounds 169 in the presence of a rhodamine photosensitizer (Scheme 44) [106]. The scope of the methodology was investigated and it was found that various substituted azides reacted efficiently with different α-diazo-β-ketophosphonates and α-diazo-β-ketocarboxylates to afford the desired products.

  Scheme 44

  

  Scheme 44.  β-Keto-α-diazos as radical precursors for the photo-synthesis of phenanthridines with o-aryl vinyl azides as radical acceptors, in the presence of Rh-6G.

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  Based on several control experiments, the authors proposed the reaction commenced with the generation of the Rh-6G radical anion Rh-6G^•‾ by SER of the excited Rh-6G* with Et₃N. This radical anion (Rh-6G^•‾) absorbs blue light and is further excited to form the corresponding Rh-6G^•‾* species. The excited species transfers an electron to the diazoenolate substrate 171, leading to nitrogen extrusion to generate the enolate vinyl radical 172 along with the regeneration of Rh-6G. The radical specie 172 then adds to the double bond of vinyl azide 166a, producing the iminyl radical 174 following N₂ elimination. Radical specie 174 undergoes intramolecular cyclization to generate the cyclohexadienyl radical 175. Upon successive oxidation by Et₃N^•+ and deprotonation, the enolate tautomer of 176 was produced, then further hydrolyzed to provide the phenanthridine product 170.

  Yu's group developed an efficient strategy for synthesizing 6-trifluoroalkylphenanthridine derivatives 177 through the reaction of biaryl vinyl azides and Umemoto's reagent 51 in moderate to good yields (56%−98%) (Scheme 45a) [104]. Subsequently, Liu and co-workers employed Umemoto's reagent (CF₃SO₂Na) as a trifluoromethyl radical precursor to obtain 6-(2,2,2-trifluoroethyl)phenanthridine (Scheme 45b) [107]. This approach effectively introduces trifluoromethyl groups into phenanthridine derivatives, showcasing the utility of Umemoto's reagent as a versatile trifluoromethyl radical source.

  Scheme 45

  

  Scheme 45.  Visible-light-induced synthesis of 6-trifluoroethylated phenanthridines using different radical precursors.

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  Yang's group reported a visible-light-induced sulfonylation/cyclization of biaryl vinyl azides 166 to synthesize a series of 6-(sulfonylmethyl)phenanthridines 179, employing readily available sulfonyl chlorides 178 as the sulfonylation reagents (Scheme 46a) [108]. Subsequently, Zhou's group employed hydrazine 180 as an alternative sulfonyl source to develop a similar method for synthesizing 179 (Scheme 46b) [109]. Both strategies exhibited a broad substrate scope and high functional group tolerance, producing the same target products with comparable yields. Importantly, gram-scale experiments were performed by both research groups and afforded the products in good yields, which demonstrates the scalability and practical applicability of the two reactions for potential industrial applications.

  Scheme 46

  

  Scheme 46.  Synthesis of 6-(sulfonylmethyl)phenanthridines with (a) sulfonyl chlorides and (b) hydrazines as radical precursors, in the presence of a Ru photocatalyst.

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  Khan et al. reported a novel three-component synthesis of 6-alkylsulfonylmethyl phenanthridines 182 under both thermal and photochemical conditions (Scheme 47) [110]. The strategy employs 4-alkyl-1,4-dihydropyridines (DHPs, 181) to generate alkylradicals, with DABSO or Na₂S₂O₅ acting as the respective SO₂ surrogate. The method exhibits distinct substrate scope and reactivate depending on the reaction conditions.

  Scheme 47

  

  Scheme 47.  Three-component reaction for the synthesis of 6-alkylsulfonylmethylated phenanthridines using biaryl vinyl azide, DHPs and SO₂ surrogates, under thermal and photochemical conditions.

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  Under thermal conditions (80 ℃), DHPs with primary alkyl substituents at the C-4 position efficiently yielded the desired 6-alkylsulfonylmethyl phenanthridine products 182. However, this type of DHPs were unreactive under photocatalytic conditions. Conversely, DHPs with secondary and tertiary alkyl substituents, both acyclic or cyclic, those containing distal functionalities or heterocycles, displayed superior reactivity under both thermal and photochemical conditions, delivering the sulfonylated products in comparable yields. Notably, benzyl-substituted DHPs underwent radical cascade cyclizations but failed to fix SO₂, resulting in non-sulfonylated derivatives under both conditions. Vinyl azides with mono- and disubstituted electron-donating and electron-withdrawing groups were well-tolerated in both thermal and photocatalytic processes.

  Moreover, the synthetic utility for 6-alkylsulfonylmethyl phenanthridine targets was highlighted through a series of diverse chemical transformations of compound 182a. These transformations demonstrate the versatility of the sulfonylmethyl group as a functional handle for further derivatization, expanding the applicability of the phenanthridine framework in complex molecule synthesis.

  Subsequently, the same group reported a simple and efficient protocol for the synthesis of phosphorus-containing phenanthridines 187 through the reaction of biaryl vinyl azides 166 and commercially available diarylphosphine oxide 98 as the phosphinoylation reagent (Scheme 48) [111]. This reaction operates under mild conditions, delivering moderate to good yields. The reaction exhibited broad substrate scope and functional group tolerance. A variety of biaryl vinyl azides, with electron-deficient or electron-donating groups on the two benzene rings, reacted smoothly with diphenylphosphine oxide, producing the corresponding phenanthridines in good to excellent yields. Furthermore, less reactive phosphorus sources, such as electron-rich diarylphosphine oxide, di–tert-butylphosphine oxide, ethyl phenylphosphinate and methyl phenylphosphinate, demonstrated reasonable tolerance in the reaction, facilitating the conversion of biaryl vinyl azides to the desired phenanthridines, albeit in lower yields.

  Scheme 48

  

  Scheme 48.  Photochemical synthesis of 6-(phosphino)alkylated phenanthridines via P-centered radicals, in the presence of a Ru photocatalyst.

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  5. Miscellaneous

  The N—O bond in acyl oximes can undergo cleavage via SER, yielding iminyl radicals and acyloxy anions [112–115]. This reactivity has been harnessed in recent advancements to enable visible-light-promoted C–N bond formation reactions, particularly for the synthesis of phenanthridines.

  In 2015, Yu's group published a visible-light-induced protocol for synthesizing phenanthridines from acyl oximes (Scheme 49) [116]. The authors examined a series of O-acyl oximes with different acyl groups, and found that electron-deficient benzoates with 4-CN, 4-F, and 4-CF₃ substituents were efficiently converted to phenanthridine 189a under visible light irradiation. This method exhibited excellent substrate compatibility, and p-trifluoromethylbenzoyl oximes with various substitution on the biphenyl moiety yielded phenanthridine derivatives in excellent yields.

  Scheme 49

  

  Scheme 49.  Visible-light-induced construction of phenanthridines from acyl oximes, in the presence of an Ir photocatalyst.

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  This method was also employed in the rapid total synthesis of the alkaloids noravicine 192 and nornitidine 193, known for their pharmacological properties, particularly antitumor activity. Specifically, treatment of the o-naphthyl vanillin derivative 190a with NH₂OH·HCl, followed by acylation with p-trifluoromethylbenzoyl chloride, provided the acyl oxime 191a in near-quantitative yield. Cyclization of 191a under the established conditions gave noravicine 192 in 93% yield. Similarly, nornitidine 193 was synthesized from the acyloxime 191b, achieving an overall yield of 90% over three steps.

  O-Acyl oximes are traditionally synthesized from their corresponding ketones or aldehydes through a two-step process involving oximation followed by acylation. To enhance the overall efficiency of this transformation, the same research group developed a one-pot procedure for the direct synthesis of azaarenes 196 from the aldehydes 194, using an O-acyl hydroxylamine, generated from p-cyano-benzamide 195, as a nitrogen source (Scheme 50) [117]. This streamlined process eliminates intermediate isolation, reducing the reaction steps and overall time.

  Scheme 50

  

  Scheme 50.  One-pot procedure for the synthesis of phenanthridines from aldehydes and O-acyl hydroxylamine, in the presence of an Ir photocatalyst.

  DownLoad: Full-Size Img PowerPoint

  A variety of o-aryl-benzaldehyde substrates were evaluated, all yielding corresponding phenanthridines in satisfactory yields, regardless of the substituents on the biphenyl moiety. However, biaryl ketones were found to be incompatible with these conditions and were fully recovered. To demonstrate the practicability of this one-pot transformation, the alkaloid trisphaeridine 196a, known for its excellent antitumor and antiretroviral activities, was synthesized in an 80% yield on a gram scale (1.43 g). This route is the shortest and most efficient synthesis of trisphaeridine reported to date.

  In 2016, Natarajan developed a visible-light-catalyzed method for synthesizing 6-arylphenanthridines 199 using aryl diazonium salts, which were generated in situ by reaction of N-(2-aminoaryl)benzoimines and tert–butyl nitrite (Scheme 51) [118]. This method demonstrated broad substrate compatibility, as substrates with electron-donating (such as Me- and MeO-) and electron-drawing (such as Cl-, NO₂-) substituents worked well, affording the corresponding products in 85%−94% yields.

  Scheme 51

  

  Scheme 51.  Visible-light-induced synthesis of 6-arylphenanthridines from N-(2-aminoaryl)benzoimines and tert–butyl nitrite acyl oximes, in the presence of a Ru photocatalyst.

  DownLoad: Full-Size Img PowerPoint

  The reaction began with the photoactivation of [Ru(bpy)₃]Cl₂ to the excited state [Ru(bpy)₃]Cl₂* which would transfer an electron to the diazonium salt 200 to afford radical 201 by extrusion of N₂ and release of [Ru(bpy)₃]³⁺. The former then provides a cyclohexadienyl-type radical 202, followed by oxidation by [Ru(bpy)₃]³⁺ to form the cationic derivative 203 with the regeneration of [Ru(bpy)₃]Cl₂ (path a), or collision with diazonium salts to produce radical 201 (path b). Ultimately, deprotonation of 203 by ^tBuO⁻ yields the desired 6-arylphenanthridine 199.

  Later, the same research group reported an efficient protocol for the preparation of phenanthridine-6-carboxylates from N-biarylglycine esters 204 under blue LED irradiation (Scheme 52) [119]. Substrates bearing electron-donating (e.g., Me- and MeO-) or electron-deficient groups (e.g., F-, Cl-, NO₂-, and CH₃COO-) at the aryl substituent provided the expected phenanthridine-6-carboxylates. Various ester groups, such as ethyl, n-propyl and phenyl, provided good yields in the desired products. To further demonstrate the practical utility of this methodology, a gram-scale reaction was conducted under optimized conditions, resulting in the target product in a 92% isolated yield, which demonstrates the efficacy of this protocol.

  Scheme 52

  

  Scheme 52.  One-pot procedure for the synthesis of phenanthridine-6-carboxylates from N-biarylglycine esters with rose bengal as photosensitizer.

  DownLoad: Full-Size Img PowerPoint

  Mechanistically, rose bengal (RB) irradiated by blue LEDs leads to its excited state RB*, which undergoes SET with glycine ester 204 to form the RB radical anion and the amine radical cation 206. RB radical anion is oxidized by O₂, leading to the ground state RB and a superoxide anion radical O₂^•−. A deprotonation reaction between 206 and O₂^•− afforded the biarylglycine ester radical 207 and hydroperoxyl radical HOO^•, followed by an intramolecular C–H aromatic coupling to form a new cyclohexadienyl radical 208. A hydrogen radical transfer from 208 to HOO^• gives methyl-5,6-dihydrophenanthridine-6-carboxylate 209. When irradiated under the optimized reaction conditions, 209a is transformed into the phenanthridine product 205a in a quantitative yield.

  Vinyl benzotriazoles, which are readily available and bench-stable, have emerged as efficient radical acceptors for the synthesis of phenanthridine derivatives. In a study conducted by Li et al., vinyl benzotriazoles 211 were used as alkyl radical precursors, reacting efficiently with alkyl bromides 212 under visible light irradiation to afford the desired products 213 in 30%–88% yields (Scheme 53) [120]. This method highlights the versatility of vinyl benzotriazoles as alternative substrates for phenanthridine synthesis, offering mild conditions and good efficiency.

  Scheme 53

  

  Scheme 53.  Photochemical synthesis of functionalized phenanthridines from vinyl benzotriazoles with alkyl bromides.

  DownLoad: Full-Size Img PowerPoint

  A possible reaction pathway is depicted in Scheme 53. Initially, homolysis of RBr under visible light irradiation generates alkyl radical R^• and bromine radical Br^•. The alkyl radical then undergoes intermolecular radical addition to vinyl benzotriazole, affording the radical intermediate 214, which subsequently undergoes ring opening by N₂ extrusion to generate the radical 215. Following this, radical 215 participates in an intramolecular radical cyclization, forming the cyclohexadienyl radical 216, which is ultimately trapped by bromine radical Br^• to produce 217. Finally, 217 is converted to the phenanthridine product 21 with the assistance of a base.

  6. Conclusion and outlook

  With the rapid advancements in visible light photoredox catalysis, the methodologies for the synthesis of phenanthridines have undergone remarkable growth over the past decade. This review highlights significant progress made between 2014 and 2024, focusing on cascade cyclizations involving 2-isocyanobiaryls, nitriles, vinyl azides, and vinyl benzotriazoles as radical acceptors, combined with a variety of radical precursors and intramolecular cyclization reactions. Photoredox catalysis allows these reactions to proceed efficiently under mild conditions and exhibit remarkable functional group tolerance. These achievement showcase the versatility of photoredox catalysis for constructing complex phenanthridine scaffolds.

  Despite these advances, there are key challenges that must be addressed to further expand the scope and utility of these methodologies.

  First, the scope of available radical precursors and radical acceptors is limited, which inevitably restricts the diversity of accessible products. Thus, there is a pressing need to expand the repertoire of heteroatom-centered radicals and to design safer, more atom-efficient radical precursors.

  Second, although significant progress has been made in forming tertiary carbon centers, stereoselective processes remain a key challenge. Developing stereo-controlled radical cyclization methods is particularly important for their applications in pharmaceutical synthesis, where enantioselectivity to chiral products is critical for biological activity.

  Third, while photoredox catalysis aligns well with green chemistry principles, future efforts should focus on the development of still more sustainable processes, such as those that minimize waste, utilize renewable energy sources, or use more environmentally friendly photocatalysts.

  Exploring new reaction mechanisms and cascade pathways, particularly those involving multi-component reactions or radical-polar crossover processes, could further enrich the synthetic diversity of phenanthridines and other heterocycles.

  We anticipate further significant progress in the photochemical synthesis of phenanthridines and other pharmaceutically relevant heterocycles. These advancements will undoubtedly broaden the applications of photoredox catalysis in drug discovery, materials science, and beyond, ensuring its place as a cornerstone of modern organic synthesis.

  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  CRediT authorship contribution statement

  Xia Mi: Writing – original draft. Chaoyang Wang: Writing – review & editing. Jingyu Zhang: Writing – review & editing. Remi Chauvin: Writing – review & editing. Xiuling Cui: Supervision.

  Acknowledgments

  This work was financially supported by the National Natural Science Foundation of China (No. 21602046), the Zhongjing Youth Talent Project from Henan University of Chinese Medicine (No. 03104150–2024–1–52), and the Foundation for University Key Teachers from the Education Department of Henan Province (No. 2020GGJS107).

  
  
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• 

  Figure 1  Examples of naturally occurring phenanthridine alkaloids.

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  Scheme 1  Reactions of 2-isocyanobiphenyl with AIBN, TTMSS, and DBP.

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  Scheme 2  Mechanism for the construction of 6-substituted tricyclic heteroaromatic frameworks by radical isocyanide insertions.

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  Scheme 3  Activated alkyl bromides as radical precursors for the synthesis of 6-alkylated phenanthridines.

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  Scheme 4  Synthesis of mono and difluoromethylated phenanthridines through radical alkylation and subsequent decarboxylation.

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  Scheme 5  Photocatalytic synthesis of 6-substituted phenanthridines with pendant trifluoromethyl and oxazoline groups by radical cascade reaction of trifluoromethylated tertiary bromides with 2-isocyanobiaryls.

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  Scheme 6  Photocatalytic alkylation of 2-isocyanobiaryls with bromoalkanes.

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  Scheme 7  Ethers as radical precursors for the synthesis of 6-alkylated phenanthridines.

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  Scheme 8  Katritzky salts as radical precursors for the synthesis of 6-α-keto-alkylated phenanthridines.

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  Scheme 9  Cyclopropanols as radical precursors for the synthesis of 6-β-keto-alkylated phenanthridines.

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  Scheme 10  Alkyl NHP esters as radical precursors for the synthesis of 6-alkylated phenanthridines.

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  Scheme 11  Xanthates as radical precursors for the synthesis of functional 6-alkylated phenanthridines.

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  Scheme 12  Decarboxylative cyclization/hydrogenation cascade reaction of α-oxocarboxylic acids and 2-isocyanobiaryls.

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  Scheme 13  Photoredox tri- and di-fluoromethylation of 2-isocyanobiaryls with different fluroalkyl reagents.

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  Scheme 14  Generation of CF₃ radical through diacetyl as the photooxidant for the synthesis of 6-trifluoromethylphenanthridines.

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  Scheme 15  Visible-light-induced Ir-photocatalyzed synthesis of 6-phosphonodifluoromethylated phenanthridines.

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  Scheme 16  Visible-light-induced Ir-photocatalyzed synthesis of difluoroalkylated phenanthridines.

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  Scheme 17  Sulfones and sulfonium salt as radical precursors for the photocatalytic synthesis of difluoroalkylated phenanthridines.

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  Scheme 18  Visible-light-induced photocatalyst-free synthesis of 6-perfluoroalkylated phenanthridines.

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  Scheme 19  Hydrazines as radical precursrs for the photochemical synthesis of 6-substituted phenanthridines.

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  Scheme 20  Visible-light-induced synthesis of 6-arylated phenanthridines from 2-isocyanobiaryls and different aryl radical precursors.

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  Scheme 21  C2-acyl benzothiazolines as radical precursors for the photo-synthesis of 6-acylated phenanthridines.

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  Scheme 22  Acyl chlorides as acyl radical precursors for the photo-synthesis of 6-carbonylated phenanthridines.

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  Scheme 23  Acyl fluorides as radical sources for the photo-synthesis of 6-arylacyl-phenanthridines.

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  Scheme 24  Synthesis of 6-phosphinoylated phenanthridines with Ir(ppy)₃ as a photocatalyst.

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  Scheme 25  Synthesis of 6-phosphinoyl-phenanthridines with 4CzIPN-^tBu as a photocatalyst.

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  Scheme 26  NH₄SCN as radical precursor for the Eosin Y-mediated photo-synthesis of 6-thiocyanatophenanthridines.

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  Scheme 27  Three-component reaction induced by an EDA complex for the photo-synthesis of 6-(vinylsulfonyl)phenanthridines.

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  Scheme 28  Visible-light-induced self-cyclization of 2-isocyanobiaryls to phenanthridines through a photoredox/PPh₃ catalytic system.

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  Scheme 29  The cyano group as a radical acceptor for the preparation of annelated phenanthridines.

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  Scheme 30  Alkyl carbazate as ester radical sources for the photo-synthesis of ester-functionalized pyrido[4,3,2-gh]phenanthridine derivatives in the presence of Eosin Y as photo-sensitizer.

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  Scheme 31  Visible-light-induced synthesis of alkylated pyrido[4,3,2-gh]phenanthridines via methylene radicals.

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  Scheme 32  Aliphatic carboxylic acids as radical precursors for the photo-synthesis of alkylated pyrido[4,3,2-gh]phenanthridines, in the presence of Eosin Y as photo-sensitizer.

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  Scheme 33  Visible-light-induced synthesis of trifluoroalkylated or difluoroalkylated pyrido[4,3,2-gh]phenanthridines.

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  Scheme 34  Difluoromethyl benzo[d]-thiazol-2-yl sulfone as radical precursor for the photo-synthesis of HCF₂-substituted pyrido[4,3,2-gh]phenanthridines, in the presence of an Ir photocatalyst.

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  Scheme 35  Visible-light-induced synthesis of ester-containing phenanthridines via alkoxycarbonyl radicals, in the presence of a photo-sensitizer.

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  Scheme 36  Cyclic oxime esters as radical precursors for the photo-synthesis of cyanoalkylpyrido[4,3,2-gh]phenanthridines, in the presence of an Ir photocatalyst.

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  Scheme 37  Visible-light-induced synthesis of keto-alkylated pyrido[4,3,2-gh]phenanthridines, in the presence of fluorescein.

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  Scheme 38  Cascade cyclization of 3–ethynyl-[1,1′-biphenyl]−2-carbonitriles with unsaturated α–bromocarbonyls, in the presence of a Ru photocatalyst.

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  Scheme 39  Photochemical cascade cyclization of N-(o-cyanobiaryl)acrylamides with benzyl-2-bromomalonates, in the presence of the Eosin Y sodium salt as photo-sensitizer.

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  Scheme 40  Three-component reaction for the photosynthesis of 4-sulfonated cyclopenta[gh]phenanthridine derivatives, in the presence of Eosin Y as photosensitizer.

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  Scheme 41  Reaction of biaryl vinyl azides with radicals.

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  Scheme 42  Visible-light-induced synthesis of 6-alkylated phenanthridines using biaryl vinyl azides, in the presence of an Ir photocatalyst.

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  Scheme 43  Visible-light-induced synthesis of alkylated phenanthridines using vinyl azides and NHP esters, in the presence of Eosin Y photosensitizer.

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  Scheme 44  β-Keto-α-diazos as radical precursors for the photo-synthesis of phenanthridines with o-aryl vinyl azides as radical acceptors, in the presence of Rh-6G.

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  Scheme 45  Visible-light-induced synthesis of 6-trifluoroethylated phenanthridines using different radical precursors.

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  Scheme 46  Synthesis of 6-(sulfonylmethyl)phenanthridines with (a) sulfonyl chlorides and (b) hydrazines as radical precursors, in the presence of a Ru photocatalyst.

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  Scheme 47  Three-component reaction for the synthesis of 6-alkylsulfonylmethylated phenanthridines using biaryl vinyl azide, DHPs and SO₂ surrogates, under thermal and photochemical conditions.

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  Scheme 48  Photochemical synthesis of 6-(phosphino)alkylated phenanthridines via P-centered radicals, in the presence of a Ru photocatalyst.

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  Scheme 49  Visible-light-induced construction of phenanthridines from acyl oximes, in the presence of an Ir photocatalyst.

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  Scheme 50  One-pot procedure for the synthesis of phenanthridines from aldehydes and O-acyl hydroxylamine, in the presence of an Ir photocatalyst.

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  Scheme 51  Visible-light-induced synthesis of 6-arylphenanthridines from N-(2-aminoaryl)benzoimines and tert–butyl nitrite acyl oximes, in the presence of a Ru photocatalyst.

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  Scheme 52  One-pot procedure for the synthesis of phenanthridine-6-carboxylates from N-biarylglycine esters with rose bengal as photosensitizer.

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  Scheme 53  Photochemical synthesis of functionalized phenanthridines from vinyl benzotriazoles with alkyl bromides.

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