Mohammed Latrache

Norbert Hoffmann
email: norbert.hoffmann@univ-reims.fr

Photochemical Radical Cyclization Reactions with Imines, Hydrazones, Oximes and Related Compounds

Photochemical reactions are a key method to generate radical intermediates. Often under these conditions no toxic reagents are necessary. During recent years, photo-redox catalytic reactions considerably push this research domain. These reaction conditions are particularly mild and safe which enables the transformation of poly-functional substrates into complex products. The synthesis of heterocyclic compounds is particularly important since they play an important role in the research of biologically active products. In this review, photochemical radical cyclization reactions of imines and related compounds such as oximes, hydrazones and chloroimines are presented. Reaction mechanisms are discussed and the structural diversity and complexity of the products are presented. Radical intermediates are mainly generated in two ways: (1) Electronic excitation is achieved by light absorption of the substrates. (2) The application of photoredox catalysis is now systematical studied for these reactions. Recently, also excitation of charge transfer complexes have been studied in this context with many perspectives.

Introduction

Radical reactions are an interesting tool of synthetic organic chemistry and offer numerous alternatives to polar reactions. Thus, they contribute to extend the molecular diversity as it is highly appreciated, for instance, in the domain of pharmaceutical or agro chemistry. Due to the increased reactivity of intermediates, stable chemical bonds are formed in a convenient way. [START_REF] Parsons | An introduction to free radical chemistry[END_REF] Although, polar effects play an important role in radical chemistry 2 , these reactions are carried out with a large variety of substrates. In the past, toxic reagents or activating groups have often been used to perform radical reactions in a selective way. [START_REF] Baguley | Flight form the Tyranny of Tin: The Quest for Practical Radical Sources Free from Metal Encumbrances[END_REF] For example, many of these transformations are carried out with tin reagents or selenium substituents on the starting molecules. Continuous efforts have been made to avoid the utilization of such reagents and to perform these reactions in a more sustainable way. [START_REF] Perchyonok | Streamlining Free Radical Green Chemistry[END_REF] The application of photochemical reaction conditions is a general method to generate radical species. In this context the photon is considered as a clean and traceless reagent. [START_REF] Bonfield | Photons as a 21st century reagent[END_REF] Since more than 10 years, photochemical reactions are again widely applied to organic synthesis. [START_REF] Hoffmann | Photochemical reactions as key steps in organic synthesis[END_REF] To a large extent, the recent renaissance of this research domain is based on works on photo-redox catalytic reactions and their application to organic chemistry. [START_REF] König | Chemical Photocatalysis[END_REF] Meanwhile, a large variety of photoredox catalysts with different redox potentials for almost each functional group are described.

A lot of intramolecular radical reactions, especially cyclizations have been studied. [START_REF] Studer | Catalysis of Radical Reactions: A Radical Chemistry Perspective[END_REF] They are of particular interest since a high degree of molecular complexity is generated in this way. The synthesis of heterocycles is an important topic in domains like pharmaceutical chemistry or material science. The photochemically induced radical cyclizations and cyccloadditions play an important role. To a large extent, they contribute to heterocyclic chemistry. [START_REF] Lefebvre | Photochemical rearrangements in heterocyclic chemistry[END_REF][START_REF] Dénès | Heteroatom-Centered Radicals for the Synthesis of Heterocyclic Compounds[END_REF] Imines possess a C=N double bond which may be easily functionalized or incorporated in heterocyclic compounds via cyclization reactions. [START_REF] Layer | The Chemistry of Imines[END_REF][START_REF] Tomaszewski | Free-Radical Chemistry of Imines[END_REF] Imines may be in chemical or more precisely in tautomeric equilibrium with enamines when mobile hydrogen atoms are located in the α position. [START_REF] Jie | Differentiation between enamines and tautomerizable imines in the oxidation reaction with TEMPO[END_REF] Substitution of the nitrogen atom by a second nitrogen (hydrazones) or by an oxygen (oxime derivatives) reduces or inhibits tautomerization. Photochemical reactions of these derivatives have also been reported. [START_REF] Wettermark | Photochemistry of the carbon-nitrogen double bond[END_REF] In this regard, they may be compared to corresponding carbonyl compounds. [START_REF] Uraguchi | Unveiling Latent Photoreactivity of Imines[END_REF] One of the privileged photochemical processes is the fragmentation of the N-N or the N-O bond. Thus a variety of N-centered radicals are generated.

Imines

Generation of radical intermediates by electronic excitation of the substrates

Radical cyclisation reactions with electronically excited imines have been much less studied when compared to their carbonyl analogues. UV irradiation of imine functions provides an efficient way to access N-centered radical species which can initiate radical cyclization chemistry. [START_REF] Padwa | Photochemistry of the carbon-nitrogen double bond[END_REF][START_REF] Kandappa | Taming the excited state reactivity of imines -from non-radiative decay to aza Paterno-Büchi reaction[END_REF] Recently, Stephenson et al. reported a masked N-centered radical strategy designed to supply 1aminonorbornanes 3 from the Schiff bases of aminocyclopropanes 1 by initiating a multi-step radical fragmentation/ cyclization sequence forming two new C-C bonds (Scheme 1). [START_REF] Staveness | Exploiting imine photochemistry for masked N-centered radical reactivity[END_REF] The treatment of cyclopropylimine such as 1 with violet light (390 nm) results in the formation of the S1(n, 𝜋*) excited state diyl 4. The strain driven ring opening of the cyclopropane is induced by the N-centered radical. In the resulting diradical intermediate 5, a 6-exo-trig cyclization at the alkene moiety followed by a 5-exotrig cyclization radical combination process (6) occur leading to the final product 2. It should be pointed out that the imine function is regenerated in this step. In this synthesis, the imine is both introduced (1) and removed (3) via simple and mild transformations. Scheme 1: Photochemically generated masked N-centered radicals for the synthesis of 1aminonorbornanes and the proposed mechanism.

A variety of cyclopropylimines with fused aryl and heteroaryl rings has been used to access to the corresponding Schiff base-protected 1-aminonorbornanes in good yields. In this reaction, the photochemical rearrangement of N-cyclopropylimines to 1-pyrrolines could be achieved. [START_REF] Campos | N-cyclopropylimine-1-pyrroline rearrangement. A novel photochemical reaction[END_REF][START_REF] Sampedro | Mechanism of the Ncyclopropylimine-1-pyrroline photorearrangement[END_REF] However, this reaction was not observed. In almost all cases, these transformations yield 1-aminonorbornanes 2. Notably, it is also found that the role of the nitro motif was necessary. For example, a 3,5bis(trifluoromethyl)benzimine system was unable to give the corresponding product upon irradiation at 390 nm or at shorter wavelengths.

The same strategy has been studied in intermolecular version via a formal [3+2] cycloaddition (Scheme 2). [START_REF] Sowden | A one pot photochemical method for the generation of functionalized aminocyclopentanes[END_REF] In this case, cyclopropylimines 8 and substituted alkenes 9 have been used to generate highly functionalized cyclopentylamines 11. It should be pointed out that in this transformation a [3+2] cycloaddition, hydrolysis of the imine 10 and N-functionalization (11) are all carried out in a one-pot procedure.

Scheme 2: Photochemically generated masked N-centered radical strategy for the synthesis of cyclopentylamines.

The ring opening of the cyclobutane was also observed under similar conditions (Scheme 3). [START_REF] Harmata | Bridged bicyclic building block upgrading: Photochemical synthesis of bicyclo[3.1.1]heptan-1-amines[END_REF] Irradiation of the bicyclo [1.1.1] pentan-1-amine derived imine 12 generates the N-centered radical species 16, which initiates cyclobutane ring cleavage generating the primary radical intermediate 17. This nucleophilic radical reacts then with an alkene to give an inert bicyclo [3.1.1] heptan-1-imine 14. The reaction has been performed with a variety of styrenes 13. The imine products are easily hydrolyzed to give primary amine building blocks. Scheme 3: Photochemical synthesis of bicyclo[3.1.1]heptan-1-amines.

The photochemical cyclopropylimine-pyrroline rearrangement has been reported for the first time in 2001. [START_REF] Campos | N-cyclopropylimine-1-pyrroline rearrangement. A novel photochemical reaction[END_REF] In 2005, a thorough study of the mechanism, regiochemistry and stereochemistry of the reaction has been published. It was found that electronically excited nonequilibrated diradicals are involved in the mechanism as transients. Their decay leads to pyrrolines and cyclopropylimine isomers. The regiochemistry of the reaction is related to the ability of different groups to stabilize the radical formed during the reaction. The stereochemistry of reaction depends on the irradiation time and the substitution of the imine. Simple and complex substitution pattern of the cyclopropane ring and in the iminic position of the N-cyclopropylimine structure have been used to synthesize the corresponding 1pyrrolines (Scheme 4). [START_REF] Sampedro | Mechanism of the Ncyclopropylimine-1-pyrroline photorearrangement[END_REF] Scheme 4: The N-Cyclopropylimine-1-pyrroline photorearrangement.

In 2015, Kutateladze et al. reported an imine-based photoassisted intramolecular cycloaddition to synthesize complex nitrogen poly-heterocycles (Scheme 5). Irradiation of imines containing o-amido groups 21 produces reactive amino azaxylylenes intermediates 22. They are photogenerated via excited state intramolecular proton transfer (ESIPT), which undergo intramolecular [4 + 2] (24) and [4 + 4] (23) cycloadditions to yield complex N,O-heterocycles with a spiro-connected nitrogen heterocyclic moiety. 23 A variety of cyclic imines containing o-amido groups with tethered furan and pyrrole-based unsaturated pendants have been used to access the corresponding [4 + 2] and [4 + 4] formal cycloadditions products in good yields. Scheme 5: Photogeneration of amino azaxylylenes and their intramolecular photocyclizations.

The mechanism of such reactions has previously been experimentally and computationally studied with azaxylylenes photogenerated by ESIPT in aromatic o-amido ketones and aldehydes bearing unsaturated functionalities (Scheme 6). [START_REF] Mukhina | Intramolecular cycloadditions of photogenerated azaxylylenes: An experimental and theoretical study[END_REF] Amides of aromatic o-ketones and aldehydes 25 undergo fast and efficient ESIPT leading to their tautomeric form, azaxylylene 26S. Intersystem crossing yields the triplet azaxylylene diradicaloid species 26T. In a first step, the nitrogen centered radial adds to a double bond to form the diradical intermediate 27. Radical combination leads to both 28 and 29. Scheme 6: The proposed mechanism of the intramolecular [4 + 2] and [4 + 4] formal cycloadditions.

Hydrogen atom transfer, induced by light absorption, generates high energy radical species that can rearrange or react with other species to form complex structures. Hoffmann et al. reported a photochemically induced intramolecular hydrogen atom transfer in cyclic imines followed by a cyclization leading to two compound families resulting either from the formation of a C-C bond or a C-N bond (Scheme 7). 25 A mechanism supported by a computational study is suggested. After electronic excitation of imine function 30 which generates the triplet excited state diyl 34, an intramolecular hydrogen atom transfer occurs from the acetal moiety to the imine nitrogen atom in one-step process (the proton and the electron are simultaneously transferred). Single electron transfer from acetal functions is very difficult [START_REF] Mella | Electron Transfer Photoinduced Cleavage of Acetals. A Mild Preparation of Alkyl Radicals[END_REF] which excludes a two-step HAT process (the electron is transferred first, and the proton follows). [START_REF] Hoffmann | Electron and hydrogen transfer in organic photochemical reactions[END_REF] The hydrogen abstraction at the carbon atom of the imine function is energetically less favored. The resulting diradical 35 undergoes intersystem crossing to give singlet state intermediate 36 or 36'. C-C Coupling reaction yields the bicyclo[3.2.1]-octane derivative 32 and the N-C coupling produces the bicyclo[3.3.0]octane derivative 31. Similar reactions have been carried out with α,βunsaturated furanones. [START_REF] Jahjah | Stereoselective Triplet-Sensitized Radical Reactions of Furanone Derivatives[END_REF] Scheme 7: Photoinduced intramolecular radical cyclisation via 1,5-HAT with imines.

Generation of radical intermediates by photoredox catalysis.

Numerous reports of radical additions to imines under visible light photocatalysis for the synthesis of saturated N-heterocycles have been reported. In 2016, Bode's group described a photocatalytic synthesis of piperazines from silicon amine protocol (SLAP) reagents with an imine moiety using [Ir(ppy)2dtbbpy]PF6 as the catalyst (Scheme 8). [START_REF] Hsieh | Silicon amine reagents for the photocatalytic synthesis of piperazines from aldehydes and ketones[END_REF] Single-electron oxidation of the α-silyl amine 38 by photoexcited Ir(III)* complex and desilylation generate the Ir(II) species and the nitrogen stabilized carbon-centered radical 40. This latter species adds to iminic carbon giving the cyclized N-centered radical 41. A single-electron-transfer reduction followed by protonation affords the piperazine product 39 and regenerates the Ir(III) catalyst. This reaction tolerates a wide range of heteroaromatic, aromatic, and aliphatic SLAP reagents. Scheme 8: Photoredox catalytic synthesis of piperazines using SLAP reagents and the proposed mechanism.

The synthesis of substituted morpholines, oxazepanes, thiomorpholines, and thiazepanes (43) has also been reported (Scheme 9). [START_REF] Hsieh | Lewis acid induced toggle from Ir(II) to Ir(IV) pathways in photocatalytic reactions: synthesis of thiomorpholines and thiazepanes from aldehydes and SLAP reagents[END_REF] The key point in this transformation is the use of a Lewis acid to activate the imine 42 which induces an alternative photocatalytic cycle with an initial Lewis acid-assisted singleelectron reduction of the imine. Scheme 9: Photoredox catalytic synthesis of saturated N-heterocycles using SLAP reagents. Shortly thereafter, Romanov-Michailidis et al. also developed an efficient approach for the synthesis of saturated nitrogen containing heterocycles using a dual-catalyst system composed of an iridium photocatalyst and a lithium phosphate base (Scheme 10).31 Condensation of complex aminodihydropyridine (DHP) reagents 44 with heteroaromatic, aromatic, and aliphatic aldehydes 45 give imino-tethered DHP intermediates 46 that undergo photoredox catalytic cyclization with visible light irradiation to afford corresponding cyclization products 47 in high yields (54-86%) and with excellent levels of diastereocontrol (up to >14 : 1 dr). The mechanism begins with a proton coupled electron transfer (PCET) quenching of the photoexcited Ir(III)* species by imino-DHP 46 with help from the Brønsted-basic phosphate anion (X-)32 to give radical-cationic intermediate 48 which then undergoes βcleavage to affords α-heteroatom stabilized C-centered radical 49. The latter adds to the iminic carbon via 6-endo-trig cyclization to give N-centered radical 50. Single-electron-transfer reduction followed by proton transfer leads to the product and regenerates Ir(III) photocatalyst.

Scheme 10: Synthesis of saturated N-heterocycles by photoredox cyclization of imino-tethered dihydropyridines and the proposed mechanism.

Radical alkylation and subsequent cyclization in photoredox-mediated radical/polar crossover (RPC) process leading to saturated N-heterocycles has been reported (Scheme 11). [START_REF] Pantaine | Photoredox radical/polar crossover enables construction of saturated nitrogen heterocycles[END_REF] Under visible light irradiation conditions, alkyl radicals possessing pendant leaving groups (e.g. bromide) generated from corresponding alkyl silicates leads to C-C bond formation with imines. Subsequent reduction of the resulting nitrogen-centered radical 54 furnishes an amide anion 55 that engage the leaving group in an intramolecular nucleophilic substitution. The substituted pyrrolidines, piperidines, and azepanes were obtained in yields up to 84%. Further examples of radical reactions with silicates have been published. [START_REF] Corcé | Silicates as Latent Alkyl Radical Precursors: Visible-Light Photocatalytic Oxidation of Hypervalent Bis-Catecholato Silicon Compounds[END_REF] Scheme 11: Photoredox-mediated radical/polar crossover (RPC) process for the synthesis of saturated N-heterocycles.

In 2014, the group of Wu and Liu developed a visible-light supported method for aerobic catalytic oxidative cyclization of phenol-2-imines 56 (Scheme 12). [START_REF] Wang | Synthesis of 2-substituted pyrimidines and benzoxazoles via a visible-light-driven organocatalytic aerobic oxidation: enhancement of the reaction rate and selectivity by a base[END_REF] By combining bis(tetrabutylammonium salt) (TBA)-eosin Y and molecular oxygen as oxidant in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base, 39 examples of phenol-2-imines (56) were readily transformed with excellent yield into 2-substituted benzoxazoles 57. The suggested photocatalytic aerobic dehydrogenation mechanism is depicted in Scheme 12. [START_REF] Chen | Efficient Aerobic Oxidative Synthesis of 2-Substituted Benzoxazoles, Benzothiazoles, and Benzimidazoles Catalyzed by 4-Methoxy-TEMPO[END_REF] The phenol moiety can be easily deprotonated to the corresponding phenolate anion 58, a much stronger electron donor, in the presence of DBU. The efficient electron transfer from phenolate anion to the excited TBA-eosin Y generates the phenoxyl radical 59. The photocatalyst is regenerated by oxidation of the TBA-eosin Y radical ion by molecular oxygen. The phenoxyl radical 59 undergoes intramolecular 5-endo cycloaddition to the imine carbon atom to form the corresponding aminyl radical 60 which can react with the photocatalyst or superoxide radical anions to afford the dehydrogenated product 57 selectively. Scheme 12: Visible-light supported aerobic catalytic oxidative cyclization of 2-substituted phenolic imines and the proposed mechanism.

The photocycloaddition reaction of 2H-azirines, known for a long time, is an extremely versatile and important process for the synthesis of aza-heterocycles. Remarkable achievements have been made toward understanding the factors which determine the photochemical behavior in a given system. [START_REF] Padwa | Azirine photochemistry[END_REF] In 1991, Müller and Mattay reported the synthesis of imidazolophanes 62 and pyrrolophanes 63 by means of photoinduced electron transfer (PET) using 1, 4-naphthalenedicarbonitrile (DCN) as the photocatalyst (Scheme 13). [START_REF] Müller | A new synthesis for imidazolo-and pyrrolophanes by [3+2] cycloaddition with azaallenyl radical cations[END_REF] Under these conditions, the electron acceptor is excited by irradiation with light at λ=350 nm in the presence of azirine 61, leading to the DCN radical anion and a reactive azirine radical cation. This latter species opens to the linear 2-azaallenyl radical cation 64. In a two-step process, radical addition of 64 to activated alkynes or imine double bond leads to intermediates 65, 66 which subsequently undergo a reduction/cyclization sequence (67, 68) followed by aromatization to give corresponding imidazolophanes 62 and pyrrolophanes 63. Further studies of consecutive radical addition cyclization reactions leading to N-polyheterocyclic compounds have been reported. In 2018, Dixon's group described a visible light photocatalyzed polarity reversed Povarov reaction of aryl imines 77 and electron deficient alkenes. Using [Ir{dF(CF3)ppy}2(dtbpy)]PF6 as photocatalyst and the commercial Hantzsch ester as a stoichiometric reductant, a range of substituted tetrahydroquinoline 79 were obtained in high yields and with typically good to excellent diastereoselectivity in favor of the trans diastereoisomer (Scheme 15). [START_REF] Leitch | Photocatalytic reverse polarity Povarov reaction[END_REF] A proton coupled electron transfer (PCET) based mechanism is proposed. After photochemical excitation of the photo-catalyst, electron transfer occurs from the Hantzsch ester (HE) derivative to the catalyst yields the Ir(II) species. Electron transfer from this Ir(II) species coupled to a proton transfer from the Hantzsch ester radical cation to the imine function leads to the α-amino radical 81 which then reacts with the phenyl vinyl sulfone in a step-wise radical cyclization to give the stabilized Povarov radical intermediate 82. In a base assisted homolytic aromatic substitution-type mechanism, this intermediate 82 loses a proton to form strongly reducing radical anion intermediate 83 which can reduce fresh imine substrate 80 with concomitant protonation to lead to the product 84 and regenerates the key α-amino radical in a radical chain process. Another consecutive radical addition cyclization reaction leading to various isoquinolines and related polyaromatics has been reported (Scheme 16). [START_REF] Tian | Visible-light photoredox-catalyzed iminyl radical formation by N-H cleavage with hydrogen release and its application in synthesis of isoquinolines[END_REF] In a photoredox catalytic process, an iminyl radical intermediate 88 is generated by N-H cleavage. The latter initiates a cascade C-N/C-C bonds formation in the presence of alkynes to give the cyclization products 87 in good yields up to 92%. It should be noted that the photocatalyst is regenerated in a cobalt co-catalytic cycle. In these steps the intermediate 90 is transformed into the final product 87 (rearomatization) via electron and proton transfer to the Co(II) species.

Using a dual photoredox/cobaloxime catalytic system, oxidative [4+2] annulation of NH imines and alkenes for the synthesis of multisubstituted 3,4-dihydroisoquinolines has been described. [START_REF] Hu | Selective Oxidative [4+2] Imine/Alkene Annulation with H2 Liberation Induced by Photo-Oxidation[END_REF] Scheme 16: Visible-light synthesis of isoquinolines and related polyaromatics.

imidoyl chlorides

Activation of C-heteroatom bond on the imine carbon is useful for the generation of imidoyl radicals by photoredox catalysis. This attractive intermediate has been used as key intermediate in the synthesis of various nitrogen-containing heterocycles. Intra-and intermolecular additions of imidoyl radicals to triple carbon-carbon and carbon-nitrogen bonds, as well as cyclizations onto aromatic rings under visible-light irradiation were reported. [START_REF] Minozzi | Imidoyl radicals in organic synthesis[END_REF] In 2013, Zhou et al. reported a visible-light-mediated radical addition cyclization of trifluoroacetimidoyl chlorides 91 with alkynes 92 for the synthesis of 2-trifluoromethyl quinolines 93 using imidoyl radicals as a key intermediate (Scheme 17). [START_REF] Dong | Visible-light-induced radical cyclization of trifluoroacetimidoyl chlorides with alkynes: catalytic synthesis of 2-trifluoromethyl quinolines[END_REF] Various functional groups including methoxy, ester, and ketone present in alkyne, and a variety of para, meta, ortho-substituted phenylacetylenes all worked well to afford the 2-trifluoromethyl quinolines in good yields. Scheme 17: The synthesis of 2-trifluoromethyl quinolines and the proposed mechanism.

Under similar conditions, the intramolecular cyclization version was also described. In this case, N-[2-(alkynyl)phenyl]trifluoroacetimidoyl chlorides 98 were used to synthesize 2-trifluoromethyl indoles 99 carrying acyl groups in position 3 (Scheme 18a). A large variety of functional groups can tolerate these mild reaction conditions. [START_REF] Dong | Synthesis of 2-trifluoromethyl indoles via visiblelight induced intramolecular radical cyclization[END_REF] A similar reaction was carried out by Fu et al. for the synthesis of 6-trifluoromethyl phenanthridines 101 through photoredox-catalyzed intramolecular radical cyclization of trifluoroacetimidoyl chlorides 100 (Scheme 18b). [START_REF] Fu | An approach to 6-trifluoromethyl-phenanthridines through visible-light-mediated intramolecular radical cyclization of trifluoroacetimidoyl chlorides[END_REF] Scheme 18: Light-promoted imidoyl radical cyclization.

Oximes

Generation of radical intermediates by electronic excitation of the substrates

In photochemical or microwave induced reactions, oximes are suitable precursors for nitrogen centered radicals. [START_REF] Walton | Functionalised Oximes: Emergent Precursors for Carbon-, Nitrogen-and Oxygen-Centered Radicals[END_REF] A variety of nitrogen containing heterocycles are obtained in this way. A typical example is depicted in Scheme 19. Irradiation of the oxime derivative 102 leads to homolytic fragmentation of the N-O bond (103). [START_REF] Sakuragi | Homolytic Aromatic Substitution by Iminyl Radicals. Photolysis of Aromatic Ketone O-Acyloximes in Aromatic Solvents[END_REF] Concomitantly formed acyloxyl radicals or phenyl radicals (resulting from decarboxylation) preferentially react with the solvent. Cyclization of intermediate 103 yields the phenanthridine 104. This reaction is frequently observed. For example, it plays a key role in the photochemical stability of pesticides containing this functional group. [START_REF] Fréneau | Phototransformation of tetrazoline oxime ethers: photoisomerization vs. photodegradation[END_REF] In this context, a profound theoretical investigation has been carried out on the competition between the bond fragmentation and E/Z isomerization of the oxime function. A series of phenanthridine have been synthesized using sensitization with dicyanoanthracene. [START_REF] Hofstra | Catalytic Oxidative Cyclization of 2-Arylbenzaldehyde Oxime Ethers under Photoinduced Electron Transfer Conditions[END_REF] In this case mechanistic studies based on the Hammett plots were carried out. Scheme 19. Photochemically induced radical cyclization via formation of nitrogen centered radical leading to phenanthridine.

The same reaction was carried out with benzofuran 105a and benzothiophene derivatives 105b (Scheme 20). [START_REF] Mcburney | Interplay of ortho-with spiro-cyclisation during iminyl radical closures onto arenes and heteroarenes[END_REF] In this case, the oxime was used with a carbonate protecting group. The iminyl radical intermediate 106 was generated by UV irradiation. EPR spectroscopy has been carried out. DFT calculations revealed that spirocyclization (107) is kinetically favored, especially at low temperatures, while ortho cyclisation (108) is thermodynamically favored. The corresponding phenanthridines 109a,b have been isolated in good yields. The synthesis strategy can be further extended in heterocyclic chemistry, for example to the preparation of corresponding pyrrolizidine derivatives. [START_REF] Alonso | Photochemistry of acyloximes: synthesis of heterocycles and natural products[END_REF] Scheme 20. Synthesis of phenanthridines with benzofuran and benzothiophene substituted oxime derivatives.

Addition cyclization reactions were carried out. In such an example, a nitrogen centered radical intermediate 111 is generated from a corresponding oxime 110 (Scheme 21). [START_REF] Alonso | New Light-Induced Iminyl Radical Cyclization Reactions of Acyloximes to Isoquinolines[END_REF] After addition of an alkyne 114, a vinyl radical 112 is formed. The final isoquinoline derivative 113 is then obtained in a cyclization step. Scheme 21. Radical addition cyclization applied to the synthesis of isoquinoline derivatives.

Generation of radical intermediates by irradiation of charge transfer complexes

Excitation of a ground state charge transfer complex is now applied to the formation of radical intermediates. Such a reaction was carried out with visible light irradiation (Scheme 22). [START_REF] Han | Photocatalist-Free Visible-Light Photoredox Dearomatization of Phenol Derivatives Containing Ketoximes: An Easy Access to Spiropyrrolines[END_REF] In this case, the oxime function in 115 carries a dinitrophenyl substituent as leaving group. The intramolecular radical addition takes place on a phenol substituent. The resulting spiropyrroline derivatives 116 were obtained in yields up to 93%. In the present paper 27 examples have been published. It is a typical example of a dearomtization reaction. Such transformations are often used to increase structural complexity. Visible light irradiation is also recommended since the dienone moiety in 116 undergoes photochemical rearrangements under UV irradiation. Furthermore, the reaction has been carried out in the presence of DBU. It has been shown that DBU deprotonates the phenol moiety and generate a charge transfer complex with dinitrophenyl substituent on the oxime function (117). Both the phenolate and the charge transfer complex significantly increase the light absorption in the visible domain (450 -600 nm). After photochemical excitation, electron transfer takes place in the charge transfer moiety leading to a radical ion pair 118. [START_REF] Davis | Visible-Light-Mediated Synthesis of Amidyl Radicals: Transition-Metal-Free Hydroamination and N-Arylation Reactions[END_REF][START_REF] Crisenza | Synthetic Methods Driven by the Photoactivity of Electron Donor-Acceptor Complexes[END_REF] The cleavage of the N-O bond of the oxime and the release of dinitrophenolate 119 yields the nitrogen centered radical intermediate 120. The latter undergoes cyclization (121) and after transfer of an electron to the radical cation of DBU, the final product 116 is formed. Scheme 22. Synthesis of spiropyrrolines. The cleavage of the N-O bond is induced by visible light absorption of a charge transfer complex 117.

A similar reaction with an intramolecular charge transfer interaction between tertiary amines and the 2,4-dinitrophenyl protecting group has also been reported. A typical example is presented in Scheme 23. [START_REF] Li | Visible Light as a Sole Requirement for the Intramolecular C(sp 3 )-H Imination[END_REF] After light absorption of the charge transfer complex 122, an intramolecular electron transfer takes place leading to the intramolecular radical ion pair 123. N-O Bond fragmentation occurs and 2,4dinitrophenolate 119 is released. In the resulting iminyl radical intermediate 124, an intramolecular hydrogen transfer leads to imine iminium species 125. Nucleophilic addition and deprotonation yield the dihydroimidazole 126. Under the reaction conditions, oxidation takes place and the imidazole 127 is isolated in good yield. This convenient imidazole synthesis was carried out with 27 substrates leading to the corresponding imidazole derivatives with yields up to 85%. If a corresponding pyrrolidine substrate was used instead of a piperidine, no oxidation in the final step was observed. The resulting dihydroimidazoles were isolated in good yields. Scheme 23. Synthesis of imidazoles using excitation of an intramolecular charge transfer complex of a tertiary amine and a dinitrophenyl moiety.

Using the above-mentioned activation by light absorption of an intermolecular charge transfer complex with a dinitrophenyl substituted oxime function (128), the radical intermediate 129 is generated by the release of dinitrophenolate (Scheme 24). [START_REF] Mao | N-Radical-Initiated Cyclization through Insertion of Sulfur Dioxide under Photoinduced Catalyst-Free Conditions[END_REF] Cyclization yields the intermediate 130. This intermediate is trapped by SO2 and various silyl enol ethers 131 leading to the final product 132. A variety of aromatic substrates have been successfully transformed. Also, heteroaromatic compounds (Ar 1 = 2-furyl) can be obtained. In the present report, 20 different derivatives have been transformed with yields up to 92%. Scheme 24. Synthesis of pyrrolines using radical trapping with SO2 and silyl enol ethers.

Generation of radical intermediates by photoredox catalysis.

Using photoredox catalysis with an iridium complex, a one pot procedure for the synthesis of phenanthridines has been realized (Scheme 25). [START_REF] An | Visible-Light-Promoted and One-Pot Synthesis of Phenanthridines and Quinolines form Aldehydes and O-Acyl Hydroxylamine[END_REF] In the first acid catalyzed step, the oxime derivative 135 is formed by condensation of 133 and 134. In the photochemical step, the nitrogen centered radical 136 is generated. Cyclization leads to the final product 137. Under these mild reaction conditions, also benzonaphtyridines such as 138, 139 or 140 have been synthesized. Starting from corresponding precursors, a variety of quinoline derivatives such as 141 and 142 are accessible. In the present report, the preparation of 28 derivatives with yields up to 89% has been described. The reaction sequence was also applied to the synthesis of benzophenanthridine alkaloids and pyridines. [START_REF] Jiang | Visible-Light-Promoted Iminyl-Radical Formation form Acyl Oximes: A Unified Approach to Pyridines, Quinolines, and Phenanthridines[END_REF] Scheme 25. Photoredox catalytic synthesis of phenanthridines and quinoline derivatives.

The oxime function can also be protected with phenyl substituents. In this case, the cleavage of the N-O bond is accompanied with the release of phenol or phenolate. In the photochemical transformation of 143 in the presence of 1,5-dimethoxynaphthalene (DMN), a photochemical electron transfer from this donor molecule to 143 is involved (Scheme 26). [START_REF] Mikami | Photochemcial Transformation of γ,δ-Unsaturated Ketone O-(p-Cyanophenyl)oximes to 3,4-Dihydro-2H-Pyrrole Derivatives[END_REF] The nitrogen centered radical 144 is thus generated. Cyclization leads to the bicyclic radical 145. After hydrogen abstraction from 1,4-cyclohexadiene, the final products 146 are obtained. Recently, similar reactions have been carried out using photoredox catalysis with visible light. [START_REF] Davis | Visible-Light-Mediated Synthesis of Amidyl Radicals: Transition-Metal-Free Hydroamination and N-Arylation Reactions[END_REF] In this case also simple ketones such as chloroanthraquinone can be used as sensitizer or photocatalyst. [START_REF] Usami | Visible-Light-Mediated iminyl Radical Generation from Benzyl Oxime Ether: Synthesis of Pyrroline via Hydroimination Cyclization[END_REF] Detailed theoretical and physicochemical studies of such reactions have been carried out. [START_REF] Alonso | Photocyclization of Iminyl Radicals: Theoretical Study and Photochemcial Aspects[END_REF] Scheme 26. Photoredox catalyzed synthesis of hexahydrocyclopenta[b]pyrroles and hexahydroindoles.

Radical species which result from a cyclization step can be trapped by various reagents. This leads to a further increase of molecular complexity and diversity. A large variety of pyrrolines have been synthesized starting from 147 in which the oxime group is O-alklylated by lactic acid (Scheme 27). [START_REF] Jiang | Iminyl-Radicals by oxidation of α-Imino-oxy Acids: Photoredox-Neutral Alkene Carboimination for the Syntheisis of Pyrrolines[END_REF] During the reaction, pyrroline radical intermediates 148 are formed. Several electron deficient alkenes 149 are added which leads to the final products 150. More than 30 compounds 150 have been reported in the present investigation. The products were isolated with yields up to 91%. Various carboxylic acid derivatives haven been used as leaving groups such as oxalic acid [START_REF] Portela-Cubillo | Dioxime oxalates; new iminyl radical precursors for syntheses of N-heterocycles[END_REF] or groups enabling Barton decarboxylation. [START_REF] Boivin | Iminyl Radicals: Part III. Further Synthetically Useful Sources of Iminyl Radicals[END_REF] Scheme 27. Synthesis of a large variety of pyrrolines starting form oximes. Photoredox catalysis is involved.

The following photoredox catalysis mechanism has been suggested (Scheme 28). After photochemical excitation of the Ir(III) complex, the carboxylate function in 151 is oxidized. An Ir(II) species is formed. The resulting neutral radical 152 immediately undergoes fragmentation; carbon dioxide and acetaldehyde are released. Cyclization of the resulting iminyl radical 153 yields the alkyl radical 154. Addition of the electron deficient alkene leads to the electrophilic radical 155. The latter is reduced by the Ir(II) species. In this step, the photoredox catalyst is regenerated. Protonation of the anion intermediate 156 yields the final product 157. Scheme 28. Proposed mechanism for formation of pyrrolines in the photo-redoxcatalytic transformation of oximes with electron-deficient alkenes.

Very similar reactions have been carried out with silyenolethers as trapping reagent. In such an investigation, also a large variety of pyrrolines have been synthesized. [START_REF] Cai | Visible-Light-Promoted Carboimination of Unactivated Alkenes for the Synthesis of Densely Functionalized Pyroline Derivatives[END_REF] About 35 examples are reported. The products are obtained with yields up to 83%. Also, styryl borates have been successfully used as trapping reagent. [START_REF] Shen | Diastereoselective and Stereodivergent Synthesis of 2-Cinnamylpyrrolidines Enabled by Photoredox-Catalyzed Iminoalkenylation of alkenes[END_REF] Various trapping reagents enables the introduction of a large number of functional groups. A selection of pyrroline derivatives from one particular investigation is depicted in Figure 1. [START_REF] Davies | Photoredox Imino Functionalization of Olefines[END_REF] The reactions have been carried out using photo redox catalysis with N-methyl mesitylacridinium perchlorate. The usefulness of this synthetic approach is also demonstrated in the modification of natural products (Scheme 29). [START_REF] Hoffmann | Combining Photoredox and Metal Catalysis[END_REF] The morphine derivative 158 was readily transformed into the corresponding dihydropyrroline compounds 160, 161 and 162. The nitrogen centered radical 159 is the key intermediate in these reactions. Photoredox catalysis is often combined with organometallic catalysis. [START_REF] Hoffmann | Combining Photoredox and Metal Catalysis[END_REF] In such a reaction, oximes like 163 have been transformed into dihydropyrroles 164 (Scheme 30). [START_REF] Tu | Radical Aza-Cyclization of α-Imino-oxy Acids for Synthesis of Alkene-Containing N-Heterocycles via Dual Cobaloxime and Photoredox Catalysis[END_REF] As previously discussed, a dihydropyrrole radical intermediate 165 is generated in a photoredox catalytic process. It is trapped by a cobalt complex (166) and elimination of a cobalt species ([Co]H) leads to the final product 164. Under similar conditions and in the presence of alkenes the latter are added leading to corresponding radicals 167 which are then trapped by a cobalt complex (168). Elimination of a cobalt species leads to the final products 169. Around 60 examples are reported in the present study. The products have been isolated in yields up to 95% for simple cyclizations and yields up to 77% for cyclization with subsequent addition to alkenes. Scheme 30. Photoredox-organometallic dual catalysis applied to the synthesis of dihydropyrrols from oxime derivatives.

Radical addition may also occur at the carbon atom of the oxime function. In a photoredox catalytic reaction, styrene derivatives 170 have been added to oximes from α-keto or glyoxylic acid 171 yielding butyrolacton compounds 172 (Scheme 31). [START_REF] Cavanaugh | Synthesis of α-Benzyloxyamino-γ-butyrolactones via Polar Radical Crossover Cycloaddition Reaction[END_REF] In the present report 21 different butyrolactones been synthesized with yields up to 88%. The products can easily be reduced to the corresponding α-amino lactones. The reaction starts with the excitation of the acridinium photo catalyst PC. At the excited state, it is capable of oxidizing the alkene 170 and radical cation 173 is generated. The latter reacts with the glyoxylic acid oxime 171 leading to the intermediate 174. Deprotonation by an amine base and radical cyclization yields intermediate 175. Hydrogen from thiophenolate is transferred and the final product 172 is obtained. The concomitantly generated phenylthiyl radical 176 oxidizes the reduced species 177 of the acridinium photocatalyst which is thus regenerated. Phenylthiyl radicals 176 are also generated by photochemical fragmentation of diphenyl disulfide. Thiyl radicals play a key role as mediators in many radical reactions. [START_REF] Dénès | Thiyl Radicals in Organic Synthesis[END_REF] Scheme 31. Photo redox catalytic synthesis of butyrolactones form alkenes and glyoxylic acid oximes.

Chloroimino derivatives

Generation of radical intermediates by electronic excitation of the substrates

The acyl substituents of the oxime function can be replaced by other leaving groups such as halogens. For example, chloroimino derivatives like 178 undergo photochemically induced radical cyclization leading to quinoxalinones 179 (Scheme 32). [START_REF] Li | Visible Light-Induced Radical Cyclization of Ethyl 2-(N-Arylcarbamoyl)-2-Chloroiminioacetates: Synthesis of Quinoxalin-2(1H)-ones[END_REF] The reaction was carried out with visible light in the presence or the absence of a ruthenium base photoredox catalyst. Depending on the substitution pattern either the first or the second variant was more efficient. The reaction has been carried out with 20 different substrates. The quinoxalinones 179 have been isolated with yields up to 97%. As previously explained, the iminyl radicals 180 are generated. Radical cyclization may occur either in the ipso position (181) or the ortho position (182) of the aromatic ring. The first reaction mode is kinetically favored but reversible. Furthermore, a rearrangement of 181 into 182 was discussed. Thus generally, the final products 179 result from ortho cyclization. Scheme 32. Synthesis of quinoxalinones using radical cyclization with chloroimino derivatives.

Generation of radical intermediates by photoredox catalysis.

An interesting observation was made for the transformation of compound 183 (Scheme 33). [START_REF] Friestad | Addition of carbon-centered radicals to imines and related compounds[END_REF] When the reaction was carried out in the presence of the photoredox catalyst Ru(phen)3Cl2, mainly compounds 184 and 185 resulting from spiro cyclization at the p-methoxyphenyl substituent were isolated. Addition of the electrophilic nitrogen centered radical 186 with the electron richer aryl substituent is indeed favored since polar effects have an influence on radical reactions. 2

Hydrazones

In the case of hydrazone derivatives, radical reactions can be carried out at the carbon atom or at the nitrogen atoms, which provide numerous perspectives for applications to the synthesis of heterocycles. [START_REF] Friestad | Addition of carbon-centered radicals to imines and related compounds[END_REF] A remarkable radical cyclization has been reported for the keto hydrazone 191 (Scheme 34). [START_REF] Rono | Enantioselective Photoredox Catalysis Enabled by Proton-Coupled Electron Transfer: Development of an Asymmetric Aza-Pinacol Cyclization[END_REF] The reaction is carried out in the presence of the chiral phosphoric acid derivative 193 involving photoredox catalysis with the iridium complex 194. The Hantzsch ester 195 is used as hydrogen donor. The hydroxyl hydrazine product 192 was obtained in high yield and almost complete enantioselectivity. Scheme 34. Enantioselective photopinacolization like reaction of a ketohydrazone.

The following mechanism has been discussed. After Photochemical excitation of the photo-catalyst, electron transfer occurs from the Hantzsch ester derivative to the catalyst leading to the [Ir] 0 species (Scheme 35). This step initiates the catalytic cycle. Electron transfer from the [Ir] 0 species to the ketone function leads to the intermediate 196. It must be pointed out that this transfer is coupled to a proton transfer from the phosphoric acid derivative 194. Aside many chemical processes, such proton coupled electron transfer (PCET) processes are now widely reported in photoredox catalytic reactions. [START_REF] Miller | Proton-Coupled Electron Transfer in Organic Synthesis: Fundamentals, Applications, and Opportunities[END_REF] In the present case, this step is exergonic by 5.2 kcal/mol as it was determined by calculations. C-C bond formation leads to the intermediate 197 with a tertiary alcohol function and a nitrogen centered radical. During this step, the phosphoric acid derivative 193 remain complexed to the intermediates in the way that efficient chiral induction occurs. The final product 192 is formed by hydrogen atom transfer from the Hantzsch ester 195. In an additional photochemical process, involving electron and proton transfer steps, the pyridine derivative 200 is formed via intermediates 198 and 199 and the catalytically active species [Ir] 0 is generated. Scheme 35. Suggested mechanism of the enantioselective photo-redox catalytic mixed pinacolization analogue cyclization (Scheme 34).

Consecutive radical addition cyclization reactions lead to complex polycyclic compounds. In a photoredox catalytic reaction, the hydrazone derivative 201 carrying an alkyne substituent was transformed with the malonic ester derivative 202 (Scheme 36). [START_REF] Zhou | Synthesis of cyclohexylidenehydrazinefuced polycyclics via photocatalytic radical cascade reaction of 2-ethynylaldehyd hydrazones[END_REF] Two rings are formed in this reaction (203). The products were obtained in yields up to 92%. The synthesis of 20 different products by this method has been reported. The reaction has been carried out on gram scale. It can also be used for the preparation of polycyclic pyridine derivatives. The reaction starts with the excitation of the iridium photocatalyst which is now capable of reducing the malonic ester bromide 202. The radical intermediate 204 is generated by release of bromide. Addition of this radical to the alkyne function (205) and double cyclization yields the nitrogen centered radical 206. Oxidation of the latter leads to the corresponding cation 207. After deprotonation, the final product 203 is obtained. Scheme 36. Radical addition cyclization reaction leading to cyclohexylidenehydrazine-fused polycycles. Cyclization reactions are also observed at the amine nitrogen of a hydrazone function. [START_REF] Yu | When Light Meets Nitrogen-Centered Radicals: From Reagents to Catalysts[END_REF] Hydrazone derivatives such as 208a,b or 210 (Scheme 37) undergo radical cyclization leading to dihydropyrazoles such as 209a,b or to dihydropyridazine such as 211 or tetrahydropyrazines 212. [START_REF] Hu | Photocatalytic Generation of N-Centered Hydrazonyl Radicals: A Strategy for Hydroamination of β,γ-Unsaturated Hydroazones[END_REF] Photoredox catalysis with Ru(bpy)3Cl2 was applied to generate the nitrogen centered radicals 214 from the 213. In the case of 208a,b, only exocyclization was observed leading to the radical intermediates 215 and the final products 209a,b were isolated. In the case of 210, both exo and endo cyclization were observed. Thus products 211, 212 and 216 are formed. It should be pointed out that 216 is formed by trapping of the primary radical 215 by a dichloromethyl radical. Calculations revealed that exo cyclization is kinetically favored and thermodynamically disfavored in the case of 208a,b. The reaction conditions have further been optimized. In the presence of TEMPO, radical intermediates 215 are trapped. Elimination of TEMPO-H then yields dihydropyrazoles. [START_REF] Hu | Oranophotocatalytic Generation of N-and O-Centred Radicals Enables Aerobic Oxyamination and Dioxygenation of Alkenes[END_REF] Various trapping reagents favors the formation of corresponding dihydropyrazoles or tetrahydropyrazoles. [START_REF] Zhao | Photocatalytic Hydrazonyl Radical-Mediated Radical Cyclization/Allylation Canscade: Synthesis of Dhydropyrazoles and Tetrahydropuridazines[END_REF] Scheme 37. Formation of dihydropyrazoles, dihydropyridazines or tetrahydropyridazines from hydrazones.

In similar reactions carried out in a basic medium, aromatic compounds 218 carrying an alkyne function and a hydrazinyl aryl sulfone group are transformed into phthalazines 219 (Scheme 38). [START_REF] Brachet | Visible light amination/Smiles cascade: access to phthalazine derivatives[END_REF] In the present paper, 25 derivatives have been successfully transformed and the products have been isolated with yields up to 83%. This compound family is interesting due to their pharmaceutical properties such as bactericidal or antitumor activities. Scheme 38. Photoredox catalytic synthesis of phthalazines.

Again, a nitrogen centered radical 221 is generated by oxidation of the corresponding anion 220 using photoredox catalysis with Ru(bpy)3Cl2 (Scheme 39). In a first cyclization, the racial intermediate 222 is generated. In a Smiles rearrangement, SO2 is eliminated, and a second cyclization takes place which leads to the radical 223 or 223'. The latter intermediate is reduced by electron transfer from the Ru(I) species generated in the photoredox catalytic cycle (224). Protonation occurs in the diarylmethyl position of 224 and not at the nitrogen atom of the phthalazine ring. Deuterium labeling experiences showed that a proton or a deuterium is transferred from the solvent. Similar reactions have been recently reported. [START_REF] Huynh | Spotlight on Photoinduced Aryl Migration Reactions[END_REF] Scheme 39. Mechanism of Photoredox catalytic synthesis of phthalazines involving a Smiles rearrangement.

Conclusion

Imines and related compounds with a C=N double bond such as oximes or hydrazones play a key role in the synthesis of numerous heterocycles. The synthesis methodology is considerably enriched by radical reactions. It is well established that photochemical reactions give access to a large variety of radical intermediates. Thus toxic reagents, typically used in many ground state radical reactions are avoided. In this way, radical chemistry becomes more and more sustainable. Since about 15 years in academic research and for some years now in chemical industry, photochemical reactions experience a renaissance in the field of organic synthesis. This impact originates mainly from numerous research activities in the domain of photoredox catalysis, especially with visible light. More recently, systematic studies on the excitation of charge transfer complexes to generate reactive intermediates have been carried out. These developments also push radical chemistry so that it will significantly gain importance in organic synthesis.

Scheme 13 :

 13 Scheme 13: The synthesis of imidazolophanes and pyrrolophanes.

Scheme 15 :

 15 Scheme 15: The photocatalytic polarity reversed Povarov reaction and the postulated mechanism.

  The reaction is initiated by photochemical excitation of [Ru(bpy)3] 2+ . Single-electron-transfer from electron donor (n-Bu)3N to excited [Ru(bpy)3] 2+* generates [Ru(bpy)3] + and the radical cation of tributylamine. The imidoyl chloride is reduced and a chloride ion is released. The resulting radical intermediate 94 undergoes radical addition (95) cyclization with the alkyne 92. The bicyclic radical intermediate 96 is oxidized by either the photoexcited [Ru(bpy)3] 2+* catalyst or the radical cation (n-Bu)3N •+ yielding the cation intermediate 97. After deprotonation (rearomatization), the final product 93 is obtained.

Figure 1 .

 1 Figure 1. Structural diversity in a pyrroline family is generated by variation of the trapping reagent.

  Scheme 33. Competitive formation of sprio cyclic products 184 and 185 in the radical cyclization with chloroimino derivatives.

Acknowledgements

Our current research in the field of imine photochemistry is supported by the Agence Nationale de Recherche (ANR, Project IMPHOCHEM).

Notes and references

Conflicts of interest

There are no conflicts to declare.