C–C bond formation via photocatalytic direct functionalization of simple alkanes

9424 | Chem. Commun., 2023, 59, 9424–9444 This journal is © The Royal Society of Chemistry 2023 Cite this: Chem. Commun., 2023, 59, 9424 C–C bond formation via photocatalytic direct functionalization of simple alkanes A ´lvaro Velasco-Rubio, †Pol Martı ´nez-Balart, † Andre ´sM.A ´lvarez-Constantino †and Martı ´n Fan ˜ana ´s-Mastral * The direct functionalization of alkanes represents a very important challenge in the goal to develop more atom-efficient and clean C–C bond forming reactions. These processes, however, are hampered by the low reactivity of the aliphatic C–H bonds. Photocatalytic processes based on hydrogen atom transfer C–H bond activation strategies have become a useful tool to activate and functionalize these inert compounds. In this article, we summarize the main achievements in this field applied to the development of C–C bond forming reactions, and we discuss the key mechanistic features that enable these transformations. Introduction Carbon–carbon bond formation plays a central role in the synthesis of natural products, pharmaceuticals, agrochemicals, and organic materials. Thus, it lies at the heart of chemical sciences. Traditionally, C–C bond formation reactions have involved the coupling of organic electrophiles with pre-made organometallic reagents. 1 Despite their great utility, most of these transformations involve multistep procedures associated with the preparation and purification of the organometallic reagent prior to cross-coupling. Moreover, they are limited to the inherent reactivity and basicity of the organometallic reagent which can impose limitations with respect to the functional-group tolerance. In this context, the direct functionalization of C–H bonds offers a more atom-efficient and straightforward way to incorporate a carbon framework into readily available substrates. While the selective C–H functionalization of hydrocarbons has seen major advances in recent decades, 2 the direct functionalization of C(sp 3 )–H bonds in alkanes still represents one of the foremost challenges in synthetic chemistry. In contrast to unsaturated substrates, the lack of p-electrons and vacant p* molecular orbitals in alkanes makes them poor nucleophiles and hampers their coordination Centro Singular de Investigacio ´n en Quı ´mica Biolo ´xica e Materiais Moleculares (CiQUS), Universidade de Santiago de Compostela, 15705 Santiago de Compostela, Spain. E-mail: [email protected] A ´lvaro Velasco-Rubio A ´lvaro Velasco-Rubio, born in Salamanca (Spain), received his BSc in chemistry from the University of Salamanca, Spain, in 2015. He completed his MSc in 2016 and his PhD thesis in 2021 under the supervision of Prof. Carlos Saa ´and Jesu ´s A. Varela. He spent a predoctoral research stay at Caltech under the supervision of Prof. Brian M. Stoltz. In 2022, he joined the group of Prof. Martı ´n Fan ˜ana ´sMastral as a postdoctoral researcher. In 2023, he joined the group of Prof. Rube ´n Martı ´nas a Juan de la Cierva Researcher. Pol Martı ´nez-Balart Pol Martinez-Balart completed his BSc in Chemistry in 2019 at the University of Barcelona where he conducted research in asymmetric hydrogenations under the supervision of Prof. Antoni Riera at the IRB. After a stay at the company Enantia, Pol continued his MSc studies in Organic Chemistry at the University of Santiago de Compostela under the supervision of Prof. Jose ´Luı ´s Mascaren ˜as working on Rhcatalysed C–H activation of heterocycles. Currently, he is PhD candidate in the Fan ˜ana ´s-Mastral group at CiQUS working on bimetallic functionalization of light alkanes employing photocatalysis. †These authors contributed equally. Received 9th June 2023, Accepted 28th June 2023 DOI: 10.1039/d3cc02790b rsc.li/chemcomm ChemComm HIGHLIGHT Open Access Article. Published on 29 June 2023. Downloaded on 11/7/2023 1:38:27 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online View Journal | View Issue This journal is © The Royal Society of Chemistry 2023 Chem. Commun., 2023, 59, 9424–9444 | 9425 to metals, thus it is more difficult to activate and functionalize the alkane C–H bonds. Another important challenge in the functionalization of saturated hydrocarbons is selectivity. C–H bond dissociation energies increase in the order R 3 C–H o R 2 HC–H oRH 2 C–H oH 3 C–H in the range of approximately 95–104 kcal mol 1 . This difference in C–H BDEs makes cleavage of tertiary C–H bonds more facile, although terminal C–H bonds are generally more accessible. The presence of a heteroatom in the hydrocarbon structure can facilitate C–H activation since the hetero-functionality can serve to coordinate the substrate to the catalyst, and the functional group can activate the C–H bond towards cleavage. 3 However, activation and thus functionalization of simple alkanes lacking hetero-functionality represents a more substantial challenge. Nevertheless, different strategies have been reported for the selective C–H to C–C functionalization of alkanes. The electrophilic activation of alkanes represents an important strategy for the conversion of saturated hydrocarbons into acids or esters through carbonylation reactions, albeit they typically require high temperature and/or harsh acidic media. 4 Carbenes have also been applied in alkane functionalization with the formation of a C–C bond, mainly upon transition metalmediated carbene insertion into C–H bonds. 5 Besides alkane carbonylation and carbene insertion reactions, which have been thoroughly reviewed, 4,5 photocatalysis processes in which saturated hydrocarbons are activated either by single electron transfer (SET) or hydrogen atom transfer (HAT) have emerged as a very powerful tool for the direct functionalization of alkanes. The scope of this article is to cover the state-of-the-art techniques in the photocatalytic and photo-electrocatalytic functionalization of simple alkanes involving direct C–C bond formation, with the aim of highlighting the main achievements, their key mechanistic features, and the future challenges within the field. We have divided the review based on the nature of the species that is used to activate the aliphatic C–H bond. Photocatalytic reactions involving a halogen radical as the HAT reagent Chlorine radicals (Cl) have been broadly explored as HAT reagents in the formation of new C–C bonds (Scheme 1). The generation of Cl radicals is often based on a Ligand to Metal Charge Transfer (LMCT) process in a 3d transition metal complex (i.e. Ni, Cu, Fe, Ce or Ti). 6 The general mechanism of this transformation often relies on the formation of a 3d transition metal–chloride complex which after irradiation generates an active Clin the reaction media through a photoinduced homolytic M–Cl cleavage via LMCT. The generated Cl radical can abstract a hydrogen atom from alkanes to form a carbon centred radical which then reacts with the corresponding electrophile to form the new C–C bonds. Additionally, the Clcan be suitably generated upon reaction of a nickel– chloride complex with an excited photocatalyst (mainly iridium complexes) and subsequent LMCT on the oxidized nickel complex. 7 Another useful strategy to generate Cl radicals is based on photoredox catalysis. In this case the photocatalyst oxidizes a chloride anion (Cl  )toCl via an outer-sphere electron transfer mechanism. Photocatalytic generation of halogen radicals from HX via SET In 2018 the group of Wu reported the functionalization of alkanes using HCl as a HAT catalyst precursor. 8 In this reaction Scheme 1 General mechanisms for the generation of Cl radicals. Andre ´sM.A ´lvarezConstantino Andre ´sM.A ´lvarez-Constantino obtained his BSc in Chemistry (2019) and MSc in Chemistry at the Interface with Biology and Materials Science (2021) from the University of Santiago de Compostela, where he worked in Rh-catalysed C–H activation and DFT mechanistic studies under the supervision of Prof. Jesu ´sA. Varela and Prof. Carlos Saa ´at CiQUS. After that, he joined the Fan ˜ana ´s-Mastral group, and he is currently a PhD candidate (Xunta de Galicia predoctoral fellowship) working on the functionalization of light hydrocarbons by means of organometallic photocatalysis as well as in computational mechanisms elucidation. Martı ´n Fan ˜ana ´s-Mastral Martı ´n Fan ˜ana ´s-Mastral obtained his PhD from the University of Oviedo (Spain) in 2007. During that time, he carried out a short stay at the group of Prof. Steven Ley at the University of Cambridge (UK). In 2009 he joined the group of Prof. Ben L. Feringa at the University of Groningen (The Netherlands) as a postdoctoral researcher. In 2014 he moved to CiQUS (University of Santiago de Compostela, Spain), where he leads the ‘‘Sustainable Catalysis and Asymmetric Synthesis’’ group. His current research interests focus on the development of synthetic methods towards the stereoselective carboboration of hydrocarbons and the direct functionalization of alkanes. Highlight ChemComm Open Access Article. Published on 29 June 2023. Downloaded on 11/7/2023 1:38:27 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online 9426 | Chem. Commun., 2023, 59, 9424–9444 This journal is © The Royal Society of Chemistry 2023 the generation of new C–C bonds was demonstrated by a Giesetype reaction with Michael acceptors and by allylation with allylic sulfones using a stop-flow microtubing reactor (Scheme 2). Clis generated after the reaction of Cl  with the photoexcited Mes– Acr photocatalyst. Hydrogen atom abstraction produces a carbon centred radical which adds to a Michael acceptor generating a new carbon radical which undergoes SET with the reduced photocatalyst to regenerate the active species. Final protonation with HCl delivers the desired product and releases the chloride anion. For allylic sulfones, S H 20-addition of the carbon radical produces a benzene sulfinyl radical which reacts with the reduced photocatalyst in a similar manner. Both reactions showed a broad alkane scope, including ethane, which led to the corresponding products in very good yields. Regarding the electrophile, the scope was limited to activated Michael acceptors and activated allylic sulfones. Later, the same group developed a similar protocol based on bromine radical photo-HAT processes, instead of chlorine (Scheme 3). 9 It was shown that bromine radicals display excellent reactivity and selectivity for tertiary C–H bonds, whereas chlorine radicals showed almost no selectivity. Thus, alkanes such as methyl-cyclopentane or 2,3-dimethyl-butane could be alkylated in excellent yields and regioselectivities under these new bromine radical-based conditions. In the same year, the group of Barriault reported hydroalkylation of Michael acceptors that exploits the use of Clas the HAT reagent in combination with Ir photocatalysis (Scheme 4). 10 In this case, after excitation of the iridium catalyst with blue light, a SET process takes place between the excited iridium complex (*Ir III ) with its counter anion (Cl  ) to form the electrophilic Clwhich may be stabilized by coordination of the pyridine base, or benzene, attenuating its high reactivity in order to promote a more selective process. Generation of the carbon radical via HAT with the alkane, followed by addition to the corresponding Michael acceptor via Giese type reaction and subsequent SET process with the reduced form of the Ir catalysts, restarting the Ir catalytic cycle and producing the carbanion which gets protonated with HCl. The reaction was limited to activated diester Michael acceptors and to the use of cycloalkanes such as cyclopentane, cyclohexane and cyclooctane that provided the corresponding products in good to excellent yields. Besides the use of a Michael acceptor in Giese-type reactions, Li reported the first Minisci-type reaction with alkanes through a cooperative catalysis merging the photoredox generation of chlorine radical and a cobaloxime catalyst, which enables hydrogen evolution for catalytic turnover (Scheme 5). 11 This Minisci-type alkylation is limited to cyclic alkanes and promotes a cross-dehydrogenative C(sp 3 )–H heteroarylation on position 4 of the 2-phenylquinoline under far UV-C irradiation, in chloroform as solvent in the presence of TFA. This strong acid was shown to be indispensable for the reaction since Scheme 2 Hydro-alkylation/allylation driven by HCl as the HAT catalyst. Scheme 3 Hydro-alkylation of Michael acceptors using Bras the HAT reagent. ChemComm Highlight Open Access Article. Published on 29 June 2023. Downloaded on 11/7/2023 1:38:27 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online This journal is © The Royal Society of Chemistry 2023 Chem. Commun., 2023, 59, 9424–9444 | 9427 mechanistic studies revealed that protonation of the heteroarene and subsequent excitation is required for the oxidation of the Cl anion (that comes from the Bu 4 NCl) via the SET process. The chlorine radical promotes the HAT step regenerating the Cl  and the new alkyl radical. Ris added over the position 2, or 4, of the heteroarene leading to the N-centred radical-cation. This species will lastly undergo oxidation with the Co II complex, promoting the hydrogen evolution process, and leading to the final product. LMCT: Ni/Ir catalysis In 2016 the group of Doyle reported a new methodology for direct C(sp 3 )–H cross-coupling enabled by catalytic formation of Clfrom L n Ni(III)(CO 2 R)Cl intermediates. This methodology was mainly applied to the direct arylation of ethers but one example on the use of cyclohexane was reported. 12 Two years later, this group expanded the methodology to the direct esterification of simple alkanes with chloroformates (Scheme 6). 13 The proposed mechanism for this transformation starts with the oxidative addition of Ni(0) to chloroformate to generate a Ni(II)(Cl)(CO 2 R) complex. Concomitantly, the Ir(III)complexis photoexcited to the active triplet Ir(III)* which undergoes a SET with the Ni(II) complex to produce a Ni(III)(Cl)(CO 2 R) species. The photolysis of this intermediate delivers Cland L n Ni(II)(CO 2 R). The Clabstracts a hydrogen from the alkane to generate an alkyl radical which recombines with Ni(II)(CO 2 R) species to form aNi( III) intermediate that releases the desired product after reductive elimination. Finally, a SET process takes places between the resulting Ni(I)speciesandIr(II) to restart both catalytic cycles. Cyclic and acyclic alkanes worked in good to excellent yields. Regarding selectivity, it was compromised with linear and branched alkanes, showing a site preference according to the stability of the formed carbon radical (31421411). LMCT: Fe catalysis In 2021, the group of Jin and Duan reported the iron-catalysed functionalization of alkanes using Michael acceptors and/or diazocarboxylates as coupling partners via Clgeneration through LMCT from FeCl 3 (Scheme 7). 14 The reaction shows a broad scope of cyclic and linear alkanes including ethane and propane, with low regioselectivity for linear alkanes. In fact, regioselectivity on linear systems depends on the stability of the corresponding generated carbon radicals (31421411) and the number of available hydrogen atoms with the same chemical environment. Moreover, branched alkanes were also tested in the reaction conditions, but no selectivity was achieved over primary/tertiary hydrogens. In the cases of ethane and propane, due to the low solubility in MeCN at ambient temperature and pressure, catalyst loading was required to be increased and the reaction was diluted to increase the relative concentration of the gaseous alkane. In 2022, the same group extended this methodology to the use of methane. 15 The use of the simplest alkane requires higher catalyst loadings, as well as higher pressure and higher dilution to increase the relative concentration of the gas. Mechanistically, this transformation Scheme 4 Hydro-alkylation of Michael acceptors enabled by the generation of Clvia photoredox catalysis. Scheme 5 Minisci-type alkylation through dual cobalt/Clcatalysis. Highlight ChemComm Open Access Article. Published on 29 June 2023. Downloaded on 11/7/2023 1:38:27 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online 9428 | Chem. Commun., 2023, 59, 9424–9444 This journal is © The Royal Society of Chemistry 2023 starts with the photoexcitation of the Fe(III)–Cl complex to [Fe(III)–Cl]* under UV-A irradiation. Then, homolysis of the Fe–Cl bond provides Clwhich reacts with the corresponding alkane to obtain the alkyl radical. This radical undergoes a Giese type reaction to obtain a new carbon centred radical that after a SET process provides the carbanion and regenerates the Fe–Cl active species. Finally, protonolysis gives rise to the desired product. The group of Jin and Duan also reported in the same year iron-catalysed direct alkynylation of methane and other light alkanes using ethynyl phenyl sulfones (Scheme 8). 16 This methodology can be applied to cyclic, linear and branched alkanes. In this last case, in sterically hindered systems, excellent selectivity towards the functionalization of primary hydrogens was observed. Mechanistically, the alkyl radical generated by Clpromoted alkane hydrogen atom abstraction reaction with the alkyne via a-addition followed by a sulphonyl radical elimination to release the desired alkynylated product. The sulphonyl radical reacts via a SET process with Fe(II) species to restart the iron catalytic cycle. This mechanism was supported by experimental studies and DFT calculations. LMCT: Cu catalysis In 2021, the group of Rovis reported the copper(II)-catalysed coupling of alkanes with Michael acceptors (Scheme 9). 17 The method is based on the use of a mixture of CuCl 2 and LiCl that provides chlorocuprate species [Cu II Cl 3 ]  which undergoes LMCT to generate the Cland [Cu I Cl 2 ]  upon irradiation with Scheme 6 Ni-catalysed esterification of alkanes. Scheme 7 Iron-catalysed functionalization of alkanes enabled by LCMT Clgeneration. Scheme 8 Iron-catalysed alkynylation of alkanes enabled by LCMT Cl generation. ChemComm Highlight Open Access Article. Published on 29 June 2023. Downloaded on 11/7/2023 1:38:27 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online This journal is © The Royal Society of Chemistry 2023 Chem. Commun., 2023, 59, 9424–9444 | 9429 UV-A light. The Clabstracts the hydrogen to generate the carbon centred radical which undergoes a Giese-type reaction to obtain a more stable a-radical ester which recombines with [Cu I Cl 2 ]  to form a Cu II -enolate that after proto-demetallation with HCl releases the desired product and restarts the catalytic cycle. The transformation features a broad scope of C–H donors. Among them, different simple alkanes were proven to be efficient partners for this reaction, albeit low regioselectivity was observed when a linear substrate such as pentane was used. Remarkably, activated endocyclic alkenes, such as acid anhydrides, furnish the corresponding products with high diastereoselectivity. This stereocontrol is proposed to be modulated by the formation of the Cu II -enolate which undergoes stereoselective protonation to regenerate the oxidized copper catalyst. LMCT: Ti catalysis One year later, the group of Mitsunuma and Kanai reported the Ti-catalysed functionalization of cyclic alkanes using ketones or Michael acceptors as coupling partners (Scheme 10). 18 The proposed mechanism starts with the excitation of TiCl 4 which after a LMCT provides Cland TiCl 3 . When Michael acceptors are used as the electrophile, a typical Giese type reaction takes place. However, when ketones are used as the electrophile the generated TiCl 3 acts as Lewis acid, enhancing the electrophilicity of the ketone. Therefore, after the addition of the alkyl radical a titanium alkoxide is obtained, which after proto-demetallation with HCl or TMSCl releases the desired product, and the catalytic cycle is restarted. Simultaneously to the work of Mitsunuma and Kanai, Schelter and co-workers reported the reactivity of dianionic species Ti(IV)Cl 62 in C(sp 3 )–H bond functionalization of light alkanes, including methane and ethane (Scheme 11). 19 [PPh 4 ] 2 TiCl 6 was found to be significantly more air and moisture stable than TiCl 4 . The use of methane required an alternative catalytic system involving a combination of TiCl 4 (MeCN) 2 (10 mol%) and pyridine hydrochloride (PyrHCl, 20 mol%) as the source of the Ti(IV)Cl 62 anion. Mechanistic studies indicated that photoexcitation into the LMCT band of Ti(IV)Cl 62 leads to the excited complex. Upon vibrational relaxation, the formation of Cl together with Ti(III)Cl 52 takes place. Clpromotes the HAT and after alkyl radical addition to the electron-poor olefin, the resulting organoradical undergoes SET with Ti(III)Cl 52 , leading to Ti(IV)Cl 5  and the corresponding carbanion. This gets protonated with in situ formed HCl to yield the product and photoactive Ti(IV)Cl 62 catalyst regeneration. LMCT: Ce catalysis In 2021, Zhang and Liu developed a Minisci-type reaction with alkanes by using CeCl 3 as the photocatalyst (Scheme 12). 20 Compared to the methodology previously reported by Li based on cooperative photoredox/cobaloxime catalysis (see Scheme 5), 11 this protocol allows the reaction to be carried out under milder conditions with visible light (405 nm) irradiation. Beyond cyclic alkanes, a linear alkane such as n-hexane also proved to be compatible, albeit with poor regioselectivity. The catalytic cycle begins with the oxidation of Ce(III)Cl n1 with O 2 to generate Ce(IV)Cl n and a superoxide radical anion (O 2   ). Ce(IV)Cl n undergoes a photoinduced LMCT that generates the Cland the Ce(III)Cl n1 species. The alkyl radical R,formedbyCl - mediated hydrogen abstraction, adds to the protonated heteroarene at the 2-position leading to a N-centred radical-cation, Scheme 9 Cu-catalysed functionalization of alkanes. Scheme 10 TiCl 4 -catalysed functionalization of alkanes. Highlight ChemComm Open Access Article. Published on 29 June 2023. Downloaded on 11/7/2023 1:38:27 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online 9430 | Chem. Commun., 2023, 59, 9424–9444 This journal is © The Royal Society of Chemistry 2023 which undergoes a subsequent rearomatization with the formed oxygen radical-anion yielding the desired product along H 2 O 2 . TheroleofO 2 was analysed and discussed, leading to the conclusion that singlet oxygen ( 1 O 2 ) is not involved in the reaction mechanism. Other methods involving Clas the HAT reagent In 2022, the Guin group reported an alternative methodology to the direct coupling of alkanes and nitrogen heterocycles by iridium photocatalysis which involves a non-traditional generation of Clunder aerobic conditions (Scheme 13). 21 This transformation involves oxygen reduction to the superoxide radical anion (O 2   ) by the photoexcited Ir(III) complex. This superoxide species provides the chloride anion (Cl  ) from DCE, via nucleophilic substitution or an electron-transfer pathway. Oxidation of the Cl  with the photoexcited heteroarene via SET provides the Clwhich abstracts a hydrogen atom from the alkane to generate the key alkyl radical. Addition to the protonated nitrogen heterocycle provides a radical cation species which upon O 2 -mediated aromatization, furnishes the alkylated heterocycle along with hydroperoxide radical (HOO). The in situ generated HOOwas proposed to propagate a radical chain pathway via HAT from the alkane. This methodology presented a relevant improvement in terms of regioselectivity, leading to better regioisomeric ratios in linear alkanes. Furthermore, branched alkanes are also tolerated although they furnish the corresponding product in poor regioisomeric ratios. Scheme 11 [PPh 4 ] 2 TiCl 6 -catalysed functionalization of alkanes. Scheme 12 Minisci-type alkylation through dual cerium/Clcatalysis. Scheme 13 Minisci-type alkylation through dual iridium/Clcatalysis. ChemComm Highlight Open Access Article. Published on 29 June 2023. Downloaded on 11/7/2023 1:38:27 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online This journal is © The Royal Society of Chemistry 2023 Chem. Commun., 2023, 59, 9424–9444 | 9431 Interestingly, the reaction with this type of alkanes exhibits certain diastereoselectivity. Very recently, the groups of Bach, Riedle and Hauer reported BCl 3 -promoted alkylation of aldehydes using alkanes as C–H donors (Scheme 14). 22 Experimental and computational studies revealed that the process involves a radical chain mechanism. DFT calculations showed that upon irradiation, the boron– aldehyde complex generates Clwhich undergoes HAT with the alkane to afford the alkyl radical. Afterwards, a radical addition to the BCl 3 –aldehyde complex furnishes a stabilized radical carbocation where homolytic B–Cl dissociation leads to the boron alkoxide product and restarts the Clcatalytic cycle. In contrast to other methodologies where the key step is the LMCT for generating the Cl, no redox–active transition metal is required here. Instead, an electron is transferred from the bounded chlorine to the aromatic p-system of the aldehyde, weakening the B–Cl bond. The reaction worked in good to excellent yields with a variety of alkanes (including ethane and propane with good regioselectivity) and several benzaldehyde derivatives. Photocatalytic reactions mediated by an oxygen-centred radical Oxygen-centred radicals have been thoroughly studied and applied in several classic radical chemical transformations by using stoichiometric amounts of peroxide oxidants, such as peroxides or molecular oxygen. 23 Over the last decade, advances in photoredox chemistry have allowed the catalytic generation and use of this reactive species as HAT agents in selective C(sp 3 )–H functionalization. The generation of this O-centred radical relies on two different processes: LMCT or SET. LMCT processes involve a Ce–alkoxide complex that undergoes photoinduced homolytic Ce–OR cleavage releasing catalytic amounts of RO. On the other hand, SET methodology provides different O-centred radicals after single electron reduction, or oxidation, of selected HAT agents –such as hypervalent iodine compounds, H 2 O 2 or N-oxides –in combination with excited organic or metal-based photocatalysts. LMCT: Ce catalysis with free alcohols In 2018, Zuo demonstrated how the use of CeCl 3 catalysis in combination with alcohols could be efficiently applied to the functionalization of light alkanes mediated by alkoxy radicals (Scheme 15). 24 The reaction was shown to be effective for alkylation and heteroarylation of the gaseous alkanes using Michael acceptors and isoquinolines, respectively. The proposed mechanism, which has been recently supported by extensive mechanistic studies, 25 involves the formation of a Ce(IV)–alkoxide complex ([Ce(OMe)Cl 5 ] 2 ) that undergoes photoinduced LMCT leading to the selective formation of alkoxy radical that is responsible for the rate-limiting alkane hydrogen abstraction. Subsequent radical addition to the Michael acceptor forms a new carbon centred radical which reacts with the Ce(III)intermediate through a SET process furnishing the product with concomitant regeneration of the active Ce(IV) catalyst. In 2020, the same group extended this concept to the functionalization of higher linear and cyclic alkanes by means Scheme 14 BCl 3 -promoted alkylation of aldehydes. Scheme 15 Ce-catalysed functionalization of methane and ethane using alcohols as HAT agents. Highlight ChemComm Open Access Article. Published on 29 June 2023. Downloaded on 11/7/2023 1:38:27 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online 9432 | Chem. Commun., 2023, 59, 9424–9444 This journal is © The Royal Society of Chemistry 2023 of a Ce-catalysed C–H amination using DBAD. In the case of C–H alkylation, cyclohexane was the only alkane tested with various electron-poor olefins as electrophilic coupling partners (Scheme 16). 26 In this work, the role of the alcohol as the HAT reagent was evaluated. It was found that MeOH is selective towards the functionalization of 31C–H bonds, while the use of bulkier alcohols such as tBuOH decreases the regioselectivity. Alcohols bearing electron-withdrawing substituents like 2,2,2-trichloroethanol (TCE) proved to be efficient although they led to almost equimolar 31:21ratios when lineal alkanes were used. The effect of additives in the regeneration of the catalytic species Ce IV L n was also studied. It was observed that reaction requires catalytic amounts of TBACl for maintaining the high turnover efficiency, probably due to the necessity of an external chloride which would act as the supporting ligand in the formation of [Ce(OR)Cl n ] species, rather than the insoluble Ce(OR) 4 . Additionally, it was observed that the use of 9,10-diphenylanthracene (DPA) in the C– H alkylation reaction promoted an acceleration on the reaction likely because of a photoinduced electron transfer to close the cerium catalytic cycle. SET: Ru catalysis with hypervalent iodine(III) reagents Chen and colleagues reported a strategy to produce benzoyloxy radicals from hydroxyl benziodoxole species PFBI-OH to achieve Minisci-type alkane heteroarylation processes (Scheme 17). 27 PFBI-OH displayed a significant degree of steric sensitivity for alkane hydrogen abstraction, being more selective towards the more sterically accessible 21C–H bonds over the weaker 31ones. A large variety of cyclic and acyclic alkanes were shown to undergo this transformation with excellent yields. The proposed mechanism for the reaction starts with the oxidation of PFBI-OH upon the photoexcitation of the Ru(II) complex followed by a SET process, generating PFBIradical and Ru(III)species;PFBI  promotes HAT over the alkane to generate the alkyl radical and generates a carboxylic acid as a side product. The alkyl radical adds to the N-protonated heteroaryl ring forming an intermediate that evolves to the final product by a SET mediated rearomatization process. An alternative ionic pathway involving reoxidation of Ru(II) with the alkyl radical and generation of a tertiary carbocation followed by nucleophilic trapping was also considered but seems to be less feasible. SET: 4CzIPN catalysis with H 2 O 2 as the oxidant and HAT reagent Duan and co-workers reported a visible light-induced metalfree synthesis of substituted phenanthridines by the reaction of simple alkanes with 2-isocyanobiaryls using aqueous H 2 O 2 as Scheme 16 Ce-catalysed functionalization of alkanes. Scheme 17 Photoredox-mediated Minisci-type alkylation of Nheteroarenes with alkanes. ChemComm Highlight Open Access Article. Published on 29 June 2023. Downloaded on 11/7/2023 1:38:27 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online This journal is © The Royal Society of Chemistry 2023 Chem. Commun., 2023, 59, 9424–9444 | 9439 The same group reported the use of 5,7,12,14-pentacenetetrone (PT) as a HAT photocatalyst for the C–H allylation of cyclic alkanes with activated allyl sulfones as in (Scheme 36). 54 The use of this arylketone as the HAT photocatalyst allowed the reaction to be efficiently carried out both under UV-A (365 nm) and even visible light (425 nm) irradiation. In 2019, the group of Gong reported the first asymmetric C–C bond formation in the field of photocatalytic direct alkane functionalization. This was achieved by merging HAT photocatalytic activation and chiral copper catalysis in the enantioselective alkylation of cyclic sulfonimines (Scheme 37). 55 In this transformation, PT is used as the HAT photocatalyst for the generation of the alkyl radical under visible light irradiation, while a chiral bisoxazoline/Cu complex acting as a Lewis acid Scheme 33 TBADT/Cu-catalysed direct C–H allylation of unactivated alkanes. Scheme 34 General mechanism of aryl ketones as HAT catalysts. Scheme 35 Arylketone-catalysed Michael addition of cycloalkanes to 1,1-bis(phenylsulfonyl)ethylene. Scheme 36 Arylketone-catalysed radical C–H allylation of cyclic alkanes. Scheme 37 Enantioselective Cu-(BOX)/PT-catalysed functionalization of alkanes. Highlight ChemComm Open Access Article. Published on 29 June 2023. Downloaded on 11/7/2023 1:38:27 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online 9440 | Chem. Commun., 2023, 59, 9424–9444 This journal is © The Royal Society of Chemistry 2023 catalyst. It was proposed that the coordinated Cu-imine species undergoes SET with the ketyl radical intermediate restarting the photocatalytic cycle and generating a metal-stabilized carbon radical that evolves through intermolecular radical–radical coupling in which the regioand stereoselectivity are sterically governed by the chiral ligand-transition metal moiety. Beyond functionalization of benzylic and allylic substrates, this methodology could also be efficiently applied to unactivated simple cyclic and acyclic alkanes with moderate to excellent enantioselectivity and very good selectivity towards the functionalization of the more substituted carbons. The high regioselectivity observed in compounds with tertiary C(sp 3 )–H bonds was attributed not only to the different formation rates of primary, secondary and tertiary carbon radicals, but also to the steric recognition by the HAT photocatalyst and transition-metal catalyst. In 2021, Wang and co-workers reported a Pd-catalysed allylic alkylation involving a transient radical nucleophile (Scheme 38). 56 The combination of 5,7,12,14-pentacenetetrone (PT) as a HAT photocatalyst with a Pd(0) catalyst promoted the three-component coupling between an alkane, a Michael acceptor and an allylic carbonate. Mechanistically, the alkyl radical generated via PTmediated HAT adds to the Michael acceptor generating a new carbon-centred radical which undergoes SET with the ketyl radical leading to a carbanion which acts as the nucleophile in the Pdcatalysed allylic alkylation of the carbonate. This methodology was showntobeeffectiveforcyclicalkanes and branched acyclic ones, displaying high levels of site selectivity for tertiary carbons. The utility of this protocol was highlighted by the concise synthesis of ()-Mesembrine. In 2018, Martin and co-workers demonstrated how the merging of a diarylketone photocalyst and a Ni catalyst resulted as an efficient system for alkane C(sp 3 )–H arylation and alkylation with organic bromides (Scheme 39). 57 In this strategy, the triplet photoexcited diarylketone enables the homolytic cleavage of the C(sp 3 )–H bond to generate a carbon-centred radical that combines with a Ni(II)Ar intermediate, generated from oxidative addition of the organic bromide to the Ni(0) catalyst, to form a Ni(III) intermediate. This intermediate undergoes reductive elimination to give rise to the product. A final SET process releases both the catalytically active arylketone and the Ni(0) species. In 2022, Maruoka and co-workers described a new cationic DABCO derivative as a HAT catalyst for radical Michael addition of alkanes to trisubstituted electron deficient olefins (Scheme 40). 58 The proposed mechanism, supported by experimental studies, starts with the oxidation of the cationic DABCObased catalyst by [Mes–Acr + *]. The single electron oxidation occurs at the naphthyl pendant group. Then, the nitrogen transfers intramolecularly an electron to the naphthyl group to obtain the active radical species which undergoes HAT over the alkane. Subsequently, a Michael addition step takes place to generate a carbon-centred radical which undergoes a SET from the reduced [Mes–Acr] to release the product. Direct C–C bond formation in alkanes through (photo)electrocatalysis Electrochemical reactions in which redox transformations are achieved with traceless electricity, instead of oxidants or reductants, have gained considerable attention in the past few years due to its inherent sustainability and tunability. 59 In fact, electroand photocatalysis are powerful methodologies in organic synthesis. Both share essential aspects since the same open–shell intermediates are generated upon one electron Scheme 38 Pd-catalysed allylic alkylation through photocatalytic generation of the nucleophile. Scheme 39 Ni/ketone-catalysed C(sp 3 )–H arylation and alkylation of alkanes. ChemComm Highlight Open Access Article. Published on 29 June 2023. Downloaded on 11/7/2023 1:38:27 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online This journal is © The Royal Society of Chemistry 2023 Chem. Commun., 2023, 59, 9424–9444 | 9441 exchange between the organic molecule and the photocatalyst, or electrode. However, each field presents some drawbacks like the energy limitation for photoredox transformations (constrained by the used wavelength) or the overoxidation of the generated radical species under electrochemical conditions. 60 Very recently, the combination of both has received attention as it was shown to be capable of generating new synthetic pathways, enabling milder conditions and better functional group tolerance and chemoselectivity in several examples. 60 Within the context of simple alkane functionalization through C–C bond forming reactions, new Minisci-type transformations have been developed using (photo)electrocatalysis. The merging of both techniques not only allows the replacement of terminal oxidants with electrochemistry, but also allows us to obviate the required Iror Co-based co-catalyst for closing catalytic cycles, that can interfere with the reduction and elimination of alkyl radicals, limiting the scope of the photochemical methods. In 2020, Xu and co-workers were able to merge both photoand electrocatalysis, reporting the first photoelectrochemical method that achieves dehydrogenative cross-coupling between a range of heteroarenes with cyclopentane and cyclohexane in good to excellent yields (Scheme 41). 61 Regarding the reaction setup, they conducted the reaction in an undivided electrolytic cell using a reticulated vitreous carbon (RVC) anode and a Pt cathode. Mechanistically anodic oxidation of Cl  and subsequent homoleptic rupture under light irradiation, leads to a tow unit of Cl. The radical performs the HAT over the alkane leading to the alkyl radical (R) that adds to the heteroarene, yielding an N-centred radical–cation intermediate. Subsequent HAT between the second Cland the heteroarene leads to the final product. One year later, the group of Zeng reported the photoelectrocatalytic heteroarylation of alkanes through Ce catalysis (Scheme 42). 62 Reaction setup was also based on an undivided electrolytic cell, albeit the choice of electrode differed from the work of Xu, and comprised a carbon felt (C felt) anode and a nickel foam (Ni foam) cathode. The reaction resembles some mechanistic features of the Ce-catalysed alkane functionalization reported by Zuo. 24–26 Anodic oxidation of Ce(III) in the presence of nBu 4 NCl leads to the Ce(IV) photoactive species. The alkoxy radical generated by photoinduced LMCT promotes the HAT over the alkane, and the alkyl radical is added over the activated heteroarene. Anodic oxidation and deprotonation yield the desired product as well as the required H + for cathodic hydrogen evolution. Regarding the alkane scope, the reaction tolerates a variety of cycloalkanes and linear ones such as n-pentane and n-hexane, the heteroarylation at the C-2 position being the preferred regioselectivity. The group of Qi simultaneously reported the electrocatalytic radical alkylation of heteroarenes, using sulfonamides as HAT reagents (Scheme 43). 63 Similar to previous examples, an undivided electrolytic cell comprising a carbon-based anode Scheme 40 Cationic DABCO-based HAT photocatalyst for the conjugate addition of alkanes. Scheme 41 Photoelectrochemical alkylation of heteroarenes promoted by the formation of Clradical. Highlight ChemComm Open Access Article. Published on 29 June 2023. Downloaded on 11/7/2023 1:38:27 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online 9442 | Chem. Commun., 2023, 59, 9424–9444 This journal is © The Royal Society of Chemistry 2023 and a metal-based cathode was used. Opposite to the methodologies of Xu and Qui, light is not required for this reaction since anodic oxidation of sulfonamide, assisted by the base, leads to the corresponding N-centred radical responsible for the HAT process. The resulting alkyl radical adds to the 2-position of the activated heteroarene yielding a new N-centred radical. Second deprotonation and anodic oxidation releases the final product. Finally, HFIP undergoes a cathodic reduction thus promoting the hydrogen evolution process. Kinetics studies suggested that the generation of the N-centred radical was likely to be the rate-determining step, therefore a stoichiometric amount of the sulfonamide was used for increasing reaction rates. This methodology allows the use of both cyclic and linear alkanes, displaying good regioselectivity for the latter. However, sterically bulky branched alkanes, such as 2,3-dimethyl-butane, proved not to be efficient for this transformation. Also in 2021, Ravelli reported the C–H alkylation of benzothiazoles with cyclic alkanes via the combination of TBADTphotocatalysis under UV-A irradiation and electrochemistry (Scheme 44). 64 Reaction setup differs from previous examples since an undivided cell did not work properly for this transformation. Therefore, a standard H-type electrochemical cell (Nafions N-117 polymeric membrane) equipped with a threeelectrode system was used instead. Anolyte was composed of a LiNTf 2 [0.05 M] MeCN/H 2 O (10 : 1) solution along with the starting materials and TBADT, separated into the catholyte by the polymeric membrane, which was composed of a LiNTf 2 [0.05 M] water solution. The N-117 membrane preserves both different chemical environments around each electrode and only allows the proton exchange from anode to cathode for the cathodic H 2 evolution process. The proposed reaction mechanism relies on the three-fold role of the decatungstate anion: HAT photocatalyst, photoredox catalyst and electrocatalyst. The reaction starts with a first HAT process catalysed by TBADT and subsequent alkyl radical addition over the benzothiazole. The resulting N-centred radical intermediate was proposed to evolve through two possible routes: a back-HAT (b-Hat) or a spincentre shift (SCS). The first alternative involves a b-HAT from Scheme 42 Cerium-catalysed photoelectrochemical alkylation of nitrogen heterocycles. Scheme 43 Electrochemical alkylation of nitrogen heterocycles using an N-alkyl sulfonamide as the HAT reagent. ChemComm Highlight Open Access Article. Published on 29 June 2023. Downloaded on 11/7/2023 1:38:27 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online This journal is © The Royal Society of Chemistry 2023 Chem. Commun., 2023, 59, 9424–9444 | 9443 the reduced form of the decatungstate anion H [W 10 O 32 ] 5 to give neutral benzothiazoline Vwith regeneration of the [W 10 O 32 ] 4 species. Then, intermediate Vwould undergo a photoelectrochemical sequence, where TBADT acts as photoredox catalyst promoting the oxidative SET and later regeneration after cathodic reduction; to deliver radical species VI. The alternative SCS pathway would involve proton-mediated formation of intermediate VI.Thelast step from VIrelies on the role of decatungstate anion as an electrocatalyst to oxidize the radical and yield the final product. Conclusions The area of photocatalytic alkane C–H functionalization has grown significantly in recent years. Several groups have reported different catalytic strategies, mainly based on a hydrogen atom transfer C(sp 3 )–H activation event, for the development of atom-efficient C–C bond forming reactions. In this article, we have outlined these transformations that are enabled either by halogen or oxygen-centred radicals, photoexcited species or electrocatalysis. Moreover, we have also emphasized their key mechanistic features. Despite these great advances, several challenges still need to be met. This field is largely dominated by Gieseand Miniscitype reactions. Future efforts should be directed towards the development of catalytic strategies that allow the use of different radical trapping reagents that could expand the chemical space of these transformations. Another important issue to be solved is the regioselectivity of the HAT step, especially when linear alkanes are used. The design of new HAT agents that offer the possibility to tune site selectivity upon modification of steric or electronic properties offers exciting opportunities. Finally, the enantioselective direct C–H functionalization of alkanes represents an almost uncharted territory. New synthetic tools to achieve this goal across several transformations will have tremendous impact in the important field of asymmetric C–C bond forming reactions. Author contributions All the authors conceptualized and discussed the concept of this article. A. V.-R., P. M.-B. and A. M. A.-C. performed the literature research and wrote the article (equal contributions). The manuscript was co-written and corrected by M. F.-M. Conflicts of interest There are no conflicts to declare. Acknowledgements Financial support from the European Research Council (ERC-CoG 863914-BECAME), AEI (PID2020-118237RB-I00), Xunta de Galicia (ED431C 2022/27; Centro singular de investigacio ´n de Galicia accreditation 2019–2022, ED431G 2019/03) and the European Regional Development Fund (ERDF) is gratefully acknowledged. A. M. A.-C. thanks Xunta de Galiciaforapredoctoralfellowship. Notes and references 1(a) E. Negishi, Angew. Chem., Int. Ed., 2011, 50, 6738–6764; (b) C. C. C. Johansson Seechurn, M. O. Kitching, T. J. Colacot and V. Snieckus, Angew. Chem., Int. Ed., 2012, 51, 5062–5085; (c) A. H. Cherney, N. T. Kadunce and S. E. Reisman, Chem. Rev., 2015, 115, 9587–9652. 2(a) X. Chen, K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew. Chem., Int. Ed., 2009, 48, 5094–5115; (b) J. Wencel-Delord, T. Dro ¨ge, F. Liu and F. Glorius, Chem. Soc. Rev., 2011, 40, 4740–4761; (c) L. Ackermann, Acc. Chem. Res., 2014, 47, 281–295; (d) N. Y. S. Lam, K. Wu and J.-Q. Yu, Angew. Chem., Int. Ed., 2021, 133, 15901–15924. 3 C. Sambiagio, D. Scho ¨nbauer, R. Blieck, T. Dao-Huy, G. Pototschnig, P. Schaaf, T. Wiesinger, M. F. Zia, J. Wencel-Delord, T. Besset, B. U. W. Maes and M. Schnu ¨rch, Chem. Soc. Rev., 2018, 47, 6603–6743. 4(a) G. A. Olah, Acc. Chem. Res., 1987, 20, 422–428; (b) A. E. Shilov and G. B. Shul’pin, Chem. Rev., 1997, 97, 2879–2932; (c) N. J. Gunsalus, A. Koppaka, S. H. Park, S. M. Bischof, B. G. Hashiguchi and R. A. Periana, Chem. Rev., 2017, 117, 8521–8573; (d) A. J. L. Pombeiro, in Alkane Functionalization, ed. A. J. L. Pombeiro and M. F. C. Guedes da Silva, Wiley, Oxford, 2019, ch. 1, pp.1– 15. 5(a) H. M. L. Davies and J. R. Manning, Nature, 2008, 451, 417–424; (b)P.J.Pe ´rez, Alkane CH Activation by Single-Site Metal Catalysis, Scheme 44 TBADT-catalysed photoelectrochemical alkylation of benzothiazoles. Highlight ChemComm Open Access Article. Published on 29 June 2023. Downloaded on 11/7/2023 1:38:27 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online 9444 | Chem. Commun., 2023, 59, 9424–9444 This journal is © The Royal Society of Chemistry 2023 2012; (c) M. P. Doyle, R. Duffy, M. Ratnikov and L. Zhou, Chem. Rev., 2010, 110, 704–724. 6 F. Julia ´,ChemCatChem, 2022, 14, e202200916. 7 L. Capaldo and D. Ravelli, Eur. J. Org. Chem., 2017, 2056–2071. 8 H.-P. Deng, Q. Zhou and J. Wu, Angew. Chem., Int. Ed., 2018, 57, 12661–12665. 9 P. Jia, Q. Li, W. C. Poh, H. Jiang, H. Liu, H. Deng and J. Wu, Chem, 2020, 6, 1766–1776. 10 S. Rohe, A. O. Morris, T. McCallum and L. Barriault, Angew. Chem., Int. Ed., 2018, 57, 15664–15669. 11 C.-Y. Huang, J. Li and C.-J. Li, Nat. Commun., 2021, 12, 4010. 12 B. J. Shields and A. G. Doyle, J. Am. Chem. Soc., 2016, 138, 12719–12722. 13 L. K. G. Ackerman, J. I. Martinez Alvarado and A. G. Doyle, J. Am. Chem. Soc., 2018, 140, 14059–14063. 14 Y. Jin, Q. Zhang, L. Wang, X. Wang, C. Meng and C. Duan, Green Chem., 2021, 23, 6984–6989. 15 Q. Zhang, S. Liu, J. Lei, Y. Zhang, C. Meng, C. Duan and Y. Jin, Org. Lett., 2022, 24, 1901–1906. 16 Y. Jin, L. Wang, Q. Zhang, Y. Zhang, Q. Liao and C. Duan, Green Chem., 2021, 23, 9406–9411. 17 S. M. Treacy and T. Rovis, J. Am. Chem. Soc., 2021, 143, 2729–2735. 18 M. Yamane, Y. Kanzaki, H. Mitsunuma and M. Kanai, Org. Lett., 2022, 24, 1486–1490. 19 G. B. Panetti, Q. Yang, M. R. Gau, P. J. Carroll, P. J. Walsh and E. J. Schelter, Chem. Catal., 2022, 2, 853–866. 20 J. Xu, H. Cai, J. Shen, C. Shen, J. Wu, P. Zhang and X. Liu, J. Org. Chem., 2021, 86, 17816–17832. 21 M. Bhakat, B. Khatua and J. Guin, Org. Lett., 2022, 24, 5276–5280. 22 D. P. Schwinger, M. T. Peschel, T. Rigotti, P. Kabacin ´ski, T. Knoll, E. Thyrhaug, G. Cerullo, J. Hauer, R. de Vivie-Riedle and T. Bach, J. Am. Chem. Soc., 2022, 144, 18927–18937. 23 L. Chang, Q. An, L. Duan, K. Feng and Z. Zuo, Chem. Rev., 2022, 122, 2429–2486. 24 A. Hu, J.-J. Guo, H. Pan and Z. Zuo, Science, 2018, 361, 668–672. 25 Q. An, Z. Wang, Y. Chen, X. Wang, K. Zhang, H. Pan, W. Liu and Z. Zuo, J. Am. Chem. Soc., 2023, 145, 359–376. 26 Q. An, Z. Wang, Y. Chen, X. Wang, K. Zhang, H. Pan, W. Liu and Z. Zuo, J. Am. Chem. Soc., 2020, 142, 6216–6226. 27 G.-X. Li, X. Hu, G. He and G. Chen, ACS Catal., 2018, 8, 11847–11853. 28 Y. Zhang, Y. Jin, L. Wang, Q. Zhang, C. Meng and C. Duan, Green Chem., 2021, 23, 6926–6930. 29 B. Wang, C. A. Pettenuzzo, J. Singh, G. E. Mccabe, L. Clark, R. Young, J. Pu and Y. Deng, ACS Catal., 2022, 12, 10441–10448. 30 M. Schlegel, S. Qian and D. A. Nicewicz, ACS Catal., 2022, 12, 10499–10505. 31 (a) M. D. Tzirakis, I. N. Lykakis and M. Orfanopoulos, Chem. Soc. Rev., 2009, 38, 2609–2621; (b) V. D. Waele, O. Poizat, M. Fagnoni, A. Bagno and D. Ravelli, ACS Catal., 2016, 6, 7174–7182; (c) D. Ravelli, M. Fagnoni, T. Fukuyama, T. Nishikawa and I. Ryu, ACS Catal., 2018, 8, 701–713. 32 D. C. Duncan, T. L. Netzel and C. L. Hill, Inorg. Chem., 1995, 34, 4640–4646. 33 C. Tanielian, Coord. Chem. Rev., 1998, 178–180, 1165–1181. 34 S. Bonciolini, T. Noe ¨l and L. Capaldo, Eur. J. Org. Chem., 2022, e202200417. 35 D. Dondi, M. Fagnoni and A. Albini, Eur. J. Chem., 2006, 12, 4153–4163. 36 S. Protti, D. Ravelli, M. Fagnoni and A. Albini, Chem. Commun., 2009, 7351–7353. 37 Z. Wen, A. Maheshwari, C. Sambiagio, Y. Deng, G. Laudadio, K. Van Aken, Y. Sun, H. P. L. Gemoets and T. Noe ¨l, Org. Process Res. Dev., 2020, 24, 2356–2361. 38 G. Laudadio, Y. Deng, K. van der Wal, D. Ravelli, M. Nun ˜o, M. Fagnoni, D. Guthrie, Y. Sun and T. Noe ¨l, Science, 2020, 369, 92–96. 39 (a) I. Ryu, A. Tani, T. Fukuyama, D. Ravelli, M. Fagnoni and A. Albini, Angew. Chem., Int. Ed., 2011, 50, 1869–1872; (b) I. Ryu, A. Tani, T. Fukuyama, D. Ravelli, S. Montanaro and M. Fagnoni, Org. Lett., 2013, 15, 2554–2557. 40 M. Bergami, S. Protti, D. Ravelli and M. Fagnoni, Adv. Synth. Catal., 2015, 357, 3687–3695. 41 K. Kim, S. Lee and S. H. Hong, Org. Lett., 2021, 23, 5501–5505. 42 M. C. Quattrini, S. Fujii, K. Yamada, T. Fukuyama, D. Ravelli, M. Fagnonia and I. Ryu, Chem. Commun., 2017, 53, 2335–2338. 43 X. Wang, M. Yu, H. Song, Y. Liu and Q. Wang, Org. Lett., 2021, 23, 8353–8358. 44 X.-Y. Yuan, Y.-F. Si, X. Li, S.-J. Wu, F.-L. Zeng, Q.-Y. Lv and B. Yu, Org. Chem. Front., 2022, 9, 2728–2733. 45 L. Capaldo, S. Bonciolini, A. Pulcinella, M. Nun ˜o and T. Noe ¨l, Chem. Sci., 2022, 13, 7325–7331. 46 I. B. Perry, T. F. Brewer, P. J. Sarver, D. M. Schultz, D. A. DiRocco and D. W. C. MacMillan, Nature, 2018, 560, 70–75. 47 D. Mazzarella, A. Pulcinella, L. Bovy, R. Broersma and T. Noe ¨l, Angew. Chem., Int. Ed., 2021, 60, 21277–21282. 48 W. Liu, Y. Ke, C. Liu and W. Kong, Chem. Commun., 2022, 58, 11937–11940. 49 H. Cao, Y. Kuang, X. Shi, K. L. Wong, B. B. Tan, J. M. C. Kwan, X. Liu and J. Wu, Nat. Commun., 2020, 11, 1956. 50 Y. Jin, E. W. H. Ng, T. Fan, H. Hirao and L.-Z. Gong, ACS Catal., 2022, 12,10039–10046. 51 P. Martı ´nez-Balart, B. L. To ´th, A ´. Velasco-Rubio and M. Fan ˜ana ´sMastral, Org. Lett., 2022, 24, 6874–6879. 52 (a) I. Loeff, A. Treinin and H. Linschitz, J. Phys. Chem., 1983, 87, 2536–2544; (b) S. A. Carlson and D. M. Hercules, Photochem. Photobiol., 1973, 17, 123–131; (c) Y. Hou, L. A. Hucka and P. Wan, Photochem. Photobiol. Sci., 2009, 8, 1408–1415. 53 S. Kamijo, G. Takao, K. Kamijo, T. Tsuno, K. Ishiguro and T. Murafuji, Org. Lett., 2016, 18, 4912–4915. 54 S. Kamijo, K. Kamijo, K. Maruoka and T. Murafuji, Org. Lett., 2016, 18, 6516–6519. 55 Y. Li, M. Lei and L. Gong, Nat. Catal., 2019, 2, 1016–1026. 56 Y. Shen, Z.-Y. Dai, C. Zhang and P.-S. Wang, ACS Catal., 2021, 11, 6757–6762. 57 Y. Shen, Y. Gu and R. Martin, J. Am. Chem. Soc., 2018, 140, 12200–12209. 58 A. Matsumoto, M. Yamamoto and K. Maruoka, ACS Catal., 2022, 12, 2045–2051. 59 (a) M. Yan, Y. Kawamata and P. S. Baran, Chem. Rev., 2017, 117, 13230–13319; (b) J. E. Nutting, M. Rafiee and S. S. Stahl, Chem. Rev., 2018, 118, 4834–4885; (c) T. H. Meyer, L. H. Finger, P. Gandeepan and L. Ackermann, Trends Chem., 2019, 1, 63–76. 60 (a) L. Capaldo, L. L. Quadri and D. Ravelli, Angew. Chem., Int. Ed., 2019, 58,17508–17510; (b) J. P. Barham and B. Ko ¨nig, Angew. Chem., Int. Ed., 2020, 59, 11732–11747; (c) Y. Yu, P. Guo, J.-S. Zhong, Y. Yuan and K.-Y. Ye, Org. Chem. Front., 2020, 7, 131–135. 61 P. Xu, P.-Y. Chen and H.-C. Xu, Angew. Chem., Int. Ed., 2020, 59, 14275–14280. 62 Z. Tan, X. He, K. Xu and C. Zeng, ChemSusChem, 2022, 15, e202102360. 63 Y. Liu, B. Shi, Z. Liu, R. Gao, C. Huang, H. Alhumade, S. Wang, X. Qi and A. Lei, J. Am. Chem. Soc., 2021, 143, 20863–20872. 64 L. Capaldo, L. L. Quadri, D. Merli and D. Ravelli, Chem. Commun., 2021, 57, 4424–4427. ChemComm Highlight Open Access Article. Published on 29 June 2023. Downloaded on 11/7/2023 1:38:27 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online