CONCEPT

Hydroxylamine Derivatives as Nitrogen-Radical Precursors in Visible-Light PhotochemistryJacob Davies,[a]† Sara P. Morcillo,[a]† James J. Douglas[b] and Daniele Leonori*[a]

[a] Title(s), Initial(s), Surname(s) of Author(s) including Corresponding Author(s)DepartmentInstitutionAddress 1E-mail:

[b] Title(s), Initial(s), Surname(s) of Author(s)DepartmentInstitutionAddress 2

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CONCEPT

Abstract: In recent years hydroxylamines derivatives have been exploited as nitrogen-radical precursors in visible-light photochemistry. Their ability to serve as electrophores in redox chemistry has propelled the development of many novel transformations. The fundamental mechanistic aspects as well as the importance in the preparation of nitrogen-containing molecules will be highlighted.

Introduction

Nitrogen-containing molecules are fundamental to our society as they form the structural basis of almost all pharmaceuticals, agrochemicals, food additives and materials.[1] This ubiquity makes developing methods for C–N bond formation of great importance. Despite this relevance, their assembly remains a significant challenge, with increasing focus on greater efficiency, selectivity, and sustainability. General methods are based on ionic pathways and harness the natural nucleophilic polarity of the N atom, whereas an alternative strategy proceeds via a nitrogen-centered radical.[2]

These highly reactive species offer great opportunities for the assembly of C–N bonds with many complementary aspects to both ionic and transition metal-based protocols in terms of retrosynthetic bond-disconnection and reaction selectivity. Despite this relevance and potential, the development of nitrogen-radical chemistry has not experienced the same success as classical carbon-based radical methodologies. One contributing factor to this may lie in the limited access to these species, as proposed by an early pioneer of the field, Prof. Samir Z. Zard who identified “[A] dearth of convenient routes to generating these reactive species and a lack of awareness concerning their reactivity”.[2] The advent of visible-light-mediated photoredox catalysis has transformed the way chemists perform single electron transfer (SET) processes and access radical species.[3] As a result, over the last few years the chemistry of nitrogen radicals has witnessed a remarkable gain in interest, with the pioneering work from Minisci,[4] Forrester,[5] Zard,[2] Newcomb,[6] Walton,[7] Narasaka,[8] Suarez[9] and others fundamental to this renaissance.[10] In this Concept Article, we discuss the most notable developments in the use of hydroxylamines and their derivatives as nitrogen radical precursors, outlining how their

engagement in visible-light-mediated protocols has expanded the repertoire of possible transformations.

Nitrogen-Radicals: Classification and General Reactivity

Nitrogen-radicals can be broadly divided in four classes on the bases of N-hybridization and substituents (Scheme 1A). Iminyl radicals (A) contain an sp2-hybridised N atom, are -radicals, as demonstrated via EPR studies by Walton,[11] and have ambiphilic character. Amidyl radicals (B) also contains an sp2

N-atom but the single electron is accommodated in a p orbital, [12] hence -radicals, and they are electrophilic in nature. Aminyl radicals (C) and their protonated analogues aminium radicals (D), are also -radicals but they have opposite philicity: aminyls are very nucleophilic while the aminiums are one of the most electrophilic classes of radicals.[13] Other types of nitrogen-radicals exist but their reactivity can be exemplified using these four general classes (e.g. carbamoyl radicals and N-Ts radicals are consistent with the behavior of amidyl radicals). Nitrogen-radicals can undergo four main classes of reactions (Scheme 1B): (i) intramolecular cyclization onto alkenes (or alkynes) – classical exo-trig processes; (ii) intramolecular hydrogen-atom abstraction (i.e. 1,5-HAT; (iii) Norrish type-I fragmentation (although limited) and, (iv) intermolecular addition to -systems like olefins, alkynes and aromatics. It is important to note that these reaction modes are not shared by all classes of nitrogen-radicals as their philicity is responsible for the stabilization (or destabilization) of the respected transition states.

Scheme 1.

Hydroxylamines as Nitrogen-Radical Precursors

Hydroxylamines are excellent precursors for the generation of nitrogen-radicals owing to their weak N–O bond (BDE ≈ 50 kcal mol–1).[14] For use in photoredox catalysis, an electrophore needs to be installed on the O-atom (Scheme 2A). This functionality, depending on its nature, can undergo reductive or oxidative SET

[a] Jacob Davies, Dr. Sara P. Morcillo, Dr. Daniele LeonoriSchool of ChemistryUniversity of ManchesterOxford Road, M13 9PL, Manchester (UK)E-mail: daniele.leonori@manchester.ac.ukGroup website: https://leonoriresearchgroup.weebly.com

[b] Dr. James J. DouglasEarly Chemical Development, Pharmaceutical SciencesIMED Biotech Unit, AstraZenecaMacclesfield SK10 2NA (UK)

† These authors contributed equally to this work.

CONCEPT

with the photoexcited state (*) of various photocatalysts (PCs) and lead to the desired N–O bond homolysis. One of the main advantages of this strategy is that the electrophore redox properties can be tailored by simple structural modification and are typically independent of the substituents on the N atom.In general, there are three main classes of hydroxylamine derivatives used in the visible-light-mediated generation of nitrogen radicals (Scheme 2B). Electron poor O-acyl and O-aryl hydroxylamines (E and F respectively) share a common feature: they are (* + *) electrophores that upon SET reduction form stable radical anions [ketyl (e) and aryl (f) respectively], which lead to the bond homolysis. In contrast, -N-oxyacids (G) require SET oxidation of the carboxylate in order to trigger two - scissions (g), forming the radical. The identification of these simple classes of electrophores has provided a strong foundation for the development of many photochemical protocols based on different redox requirements.

Scheme 2.

Intramolecular Cyclizations

Some of the earliest work on visible-light-mediated generation of nitrogen-radicals focused on intramolecular endo- and exo-trig cyclizations giving access to N-heterocycles. The discussion of these processes will be divided on the basis of the initial SET taking place on the hydroxylamine precursors. Reductive SET of Hydoxylamine Precursors The generation of iminyl radicals from O-acyl and O-aryl oximes is possible under various reductive conditions as demonstrated in the seminal work of Zard, Narasaka and others.[2, 8] Zhang and Yu built on this knowledge and developed a photoredox protocol utilizing O-benzoyl oximes 1 (Scheme 3).[15] Introduction of a p-CF3 group on the benzoyl moiety (Ered

= –0.79 V vs SCE) facilitated SET reduction by *Ir(ppy)3 (E[*Ir(III)/Ir(IV)] =

–1.73 V vs SCE) and led to the iminyl radical which underwent intramolecular cyclizations to create quinolines (e.g. 2a), phenanthridines (e.g. 2b) and pyridines (e.g. 2c) in typically good yield. In general, the 6-endo cyclization to give pyridines necessitated the presence of an ester group at C-3, indicating the polarization required for efficient reactivity.

Scheme 3.

We began our research in the field of nitrogen-radicals via the use of electron poor O-aryl-oximes 3 in hydroimination reactions (Scheme 4A).[16] Following cyclic voltammetry studies on model precursors, we identified the highly activated 2,4-(NO2)2-C6H3

electrophore (Ered = –0.9 V vs SCE), enabling efficient reduction

by the photoexcited organic dye eosin Y (EY)[17] [E(EY•+/*EY) = – –1.08 V vs SCE]. This SET delivered the iminyl radical H that underwent 5-exo-trig cyclization onto the tethered olefin to form the carbon radical I. H-Atom transfer from 1,4-cyclohexadiene (1,4-CHD) gave the targeted pyrroline 4. 1,4-CHD serves a double role in our proposed mechanism, as both H-atom donor and reductant for the oxidised EY•+, ultimately leading to the formation of C6H6. This process displayed a broad scope with many functionalities tolerated, including electron rich and poor heterocycles (e.g. 4b), ester (e.g. 4c), free alcohol, alkyl chlorides, and N-Boc protected amines. While the cyclization onto disubstituted olefins was efficient (e.g. 4d), cyclization onto tri-substituted ones was more challenging and the corresponding products were obtained in lower yields (e.g. 4e). We propose that the increased stability of the tertiary carbon radical after iminyl cyclization led to slower H- abstraction and more competitive unwanted reactivity (e.g. direct oxidation to the tertiary carbocation which is more favoured for tertiary centres). Feng and Loh have recently extended this approach for iminyl radical generation and cyclization via the introduction of an additional C–C bond forming step (Scheme 4B).[18] By using silyl enolethers 6 to trap the initially formed carbon-radicals, keto pyrollines 7 were obtained in typically good yield. This approach is however limited to iminyl radicals with an -aromatic substituent and terminal aryl silyl enol ethers.

CONCEPT

During the exploration of this chemistry, we identified conditions for the direct photochemical activation of oximes 3 in the absence of EY, providing the pyrroline alcohols 8 (Scheme 5).[16]

Scheme 4.

This complementary mode is based on the use of Et3N as stoichiometric electron donor, with UV/Vis studies determining the formation of a supramolecular electron donor-acceptor (EDA)[19] complex J between Et3N and 3. As this EDA complex absorbs in the visible range (max ≈ 450 nm), irradiation with a 30 W CFL lamp triggered a SET delivering the radical ion pair K.

Scheme 5.

Following fragmentation and cyclization, the carbon radical I underwent unexpected oxidation. Control experiments suggested a mechanism via a rebound reaction, with the NO2 group serving as the oxidant via concurrent reduction to the nitroso. Consistent with the previous hydroaminaiton methodology this process displayed high functional group compatibility (e.g. 8b) and was used for the preparation of both secondary (e.g. 8c) and tertiary alcohols (e.g. 8d). We subsequently expanded the EY-mediated reductive approach to the generation of amidyl radicals from electron poor O-aryl-hydroxylamides 9 (Scheme 6).[20] These species underwent cyclizations onto tethered alkenes (5-exo-trig)[20a] and alkynes (5-exo-dig)[20b] providing access to lactams and cyclic (thio)carbamates 10 and 10’. As amidyl radicals are very electrophilic, the direct H-abstraction from 1,4-CHD has the potential to operate as an unwanted reaction pathway and can outcompete the intramolecular cyclization.[6a] Indeed, a trend between nitrogen radical electrophilicity and the barrier of direct H-abstraction was determined by computational studies.[20a] This withstanding, the method was successfully applied to the hydroamidation of N-Boc and N-Cbz protected derivatives (e.g. 10a), which display the highest electrophilicity and a low barrier for direct H-abstraction. Overall, this strategy enabled the preparation of a broad range of substrates including spirocyclic (e.g. 10b) and tricyclic (e.g. 10c) derivatives and was applied to the modification of drugs (e.g. mexiletine, 10d) and terpenes (e.g. (–)-linalool, 10e).

CONCEPT

Scheme 6.

The reductive generation of primary amidyl radicals from O-benzoyl hydroxyl-amides (11) was also demonstrated by Xie and Lu in the stereodivergent oxy-amination of olefins (Scheme 7). [21] In this process, the amidyl radical (L) undergoes 5-exo-trig cyclization followed by oxidation to give the bicyclic aziridine M. Depending on the basicity of the amine used as the stoichiometric electron donor and base, products of syn (12) or anti (13) addition were selectively obtained upon ring-opening by ArCO2

–.

Scheme 7.

Oxidative SET of Hydoxylamine Precursors The generation and cyclization of nitrogen radicals by SET oxidation of hydroxylamines is less explored and so far has been only applied to iminyl radicals. This has however enabled the development of divergent iminofunctionalization strategies that are elusive using previously discussed approaches. Taking inspiration from the work of Forester [5] and Zard,[22] our group, and independently the group of Studer have simultaneously applied -imino-oxy acids 14 (Eox ≈ +1.6V vs SCE for the Cs-carboxylate) in imino-functionalization reactions (Scheme 8).[23] Studer used Michael acceptors as radical traps to perform carboimination reactions (e.g. 15xi)[23a] and we developed a divergent strategy encompassing 14 different functionalizations.[23b] We found the strongly oxidizing organic dye mesityl acridinium (Fukuzumi’s catalyst, *Eox = +2.1 V vs

SCE)[24] proficient for these transformations rendering them transition metal-free.

Scheme 8.

By careful optimization of all reaction parameters we were able to achieve all imino-halogenations (15ii–v), as well as cascade reactions forming two C–N bonds across the olefin (15vi–viii). Iminoselenation (15ix) and thioetherifcation (15x) were also possible which streamlined the introduction of the SCF3 group. More importantly, the use of IBX-reagents delivered products of imino-cyanation (15xii), -olefination (15xiii) and -alkynylation (15xiv). This strategy enables the formation of molecules containing functionalized quaternary centres (e.g. 15A) and was also extended to the functionalization of primary (e.g. 15B) and secondary ones (e.g. 15C–C’). Furthermore, a number of these transformations could be applied to the late-stage modification of the morphane derivative thevinone (15a), despite the presence of a tertiary amine and the electron-rich aromatic core. The effectiveness of these oxidative manifolds with respect to the reductive ones (for example, see Scheme 4) in delivering the imino-functionalizations can be rationalized by looking at the electronic requirements necessary to render the overall process redox neutral (Scheme 9). In fact, independently from the mode for nitrogen-radical generation and cyclization, the carbon-radical I is a nucleophilic species that benefits from the reaction with polarized SOMOphiles having an electrophilic “X” group. This ensures efficient SH2 reaction, but thwarts mechanisms where a SET reduction of the photocatalyst is required to close the photoredox cycle. In fact, as the Y• species is an electron poor radical, its further SET oxidation is expected to be highly endoergonic. This redox mismatch renders strategies based on the reduction of hydroxylamine precursors reduction not suitable but is addressed by the implementation of oxidative pathways based on the use of -N-oxyacids.

CONCEPT

Scheme 9.

Intramolecular H-Abstractions – 1,5-HAT

The ability of nitrogen-radicals to undergo intramolecular transpositions via 1,5-HAT is advantageous for the functionalization of distal sp3

carbons.[25] This reactivity is of historical relevance as it is the key step in the name reaction developed by Hoffmann and Löffler, which also represents the first reported example of a radical transposition process.[26] This reactivity pattern has been exploited in photoredox catalysis where the nature of the redox cycles (reductive vs oxidative) can lead to divergent reaction profiles.Reductive SET of Hydoxylamine PrecursorsNevado used electron poor O-acyl aryl-oximes 16 to access, upon reductive SET, iminyl radicals (Scheme 10).[27] 1,5-HAT gave access to the corresponding -carbon radicals N, which cyclized onto the tethered aromatic ring (O). This reaction was facilitated by the presence of a Brönsted acid via protonation of the iminyl radical (M), enhancing its electrophilicity and lowering the enthalpic requirements for the HAT, as demonstrated by Forrester in related transformations.[28] This process enabled the preparation of bicyclic and tri-cyclic chromanones (e.g. 17a–d) with broad substitution patterns and in typically good yield.

Scheme 10.

The EDA generation of iminyl radicals from 2,4-(NO2)2-C6H3

oximes (18, see also Scheme 5) has been further expanded to the preparation of imidazoles (19) (Scheme 11).[29] In this case the iminyl radical undergoes an efficient 1,5-HAT and oxidation followed by intramolecular cyclization. The process allowed the synthesis of several bycyclic imidazoles and was expanded to the preparation of pyrrolidines (20). Utilizing the same mode of reactivity the group of Wu have accessed 5,6-dihydro[d][1,2] thiazine 2,2-dioxides (22) via DABSO trapping following 1,5-HAT on related oximes 21.[30] The subsequent ring closure by the imine provided cyclic sulfonimides in good yield.

Scheme 11.

Oxidative SET of Hydoxylamine PrecursorsThe generation of iminyl radicals by oxidation of -imino-oxy acids (23 and 24) has been recently demonstrated by our group and concurrently by the group of Studer (Scheme 12). [31] Following the same mechanistic analysis that lead to the development of the iminofunctionalization reactions (Scheme 9), we reasoned that a similar redox approach should result in an interrupted Hoffmann-Löffler cascade, ultimately providing access to -functionalized ketones. The process was realized by the use of Fukuzumi’s acridinium as the photocatalyst and NCS to afford -chlorination and expanded to fluorination by employing SelectFluor® and co-catalytic Ag2CO3 (Scheme 12A).[31a] In the case of the chlorination, the NH imine formed upon

CONCEPT

1,5-HAT reacted with the excess NCS providing the formation of the N-Cl imines (25), which were stable and could be purified by column chromatography. The process displayed high functional group compatibility (e.g. 25a–c) and was applied to the modification of a lithocholic derivative (26c). Studer developed cascade process leading to -C–C bond formation using Michael acceptors in the presence of an Ir-based photocatalyst, with CsF as the base to give a broad range of products (e.g. 27a–c) (Scheme 12B).[31b]

Scheme 12.

A current limitation of the 1,5-HAT methodologies is the requirement for tertiary centres to allow efficient functionalization. We have rationalized this by examining the BDEs of the C–H and N–H bonds involved in the transformation (Scheme 12C).[31a] The similarity in BDEs results in no significant enthalpic gain in the H-abstraction step, which is also slightly endothermic.

Fragmentations

Nitrogen-radicals can undergo fragmentation processes resembling the classical Norrish type-1 reactivity. However, this has so far only been exploited in the case of iminyl and aminium radical formation.[32] The application of hydroxylamines in related visible-light- mediated processes is a relatively new area of research and has so far only been applied to the ring opening of cyclic oximes.We have harnessed the ability of -imino-oxy acids to undergo oxidative fragmentation en route to iminyl radicals to develop a synthetic method to access distally functionalized nitriles (Scheme 13).[31a] The elementary steps of these cascade reactions resemble the iminofunctionalizations and the 1,5-HAT processes (Scheme 8, 9 and 12) and involve: (i) SET oxidation of the carboxylate, (ii) double -scissions to form the iminyl P, (iii) radical ring opening to deliver the nitrile and distal radical, (iv) SH2 functionalization with a SOMOphile and (v) final reduction.Using this approach we developed fluorination, chlorination, and azidation reactions following the ring opening of highly strained 4-membered rings (MRs) (e.g. 29a) as well as 5- (e.g. 29b and c), 6- (e.g. 29d) and even 7-MRs (e.g. 29e). Some limitations exist: in the case of the 5-MR the ring opening is possible at a quaternary or benzylic position while in the case of the more challenging 6- and 7-MRs this was possible only on -aryl substrates. This fragmentation strategy can also be used to access C-4 functionalization of 4-aryl-piperidines via the extrusion of CH3CN (e.g. 29f).

Scheme 13.

As an application, we benchmarked this method to the selective deconstruction and functionalization of several complex substrates like prasterone, estrone (29g), a precursor of drospirenone (29h) (birth control pill), and isosteviol, which gave access to complex natural product-like molecules. Reductive approaches for the generation of iminyl radicals have also been developed (Scheme 14). In particular, Zhou[33] and

CONCEPT

Xiao and Chen[34] have demonstrated the ring opening of 4-MR O-acyl oximes using Ir(ppy)3 as the photocatalyst and the following trap of the -nitrile radicals with an impressive range of -acceptors encompassing styrenes (e.g. 31a), alkynes, silyl enolethers (e.g. 31b) and isonitriles (e.g. 31c).

Scheme 14.

Addition to Olefins

The tendency of electrophilic amidyl radicals to react with electron rich -systems has been harnessed by MacMillan in the intramolecular -amination of aldehydes 32, which also represented the first reported enantioselective reaction of nitrogen-radicals (Scheme 15).[35] The chiral oxazolidinone 34 was used as an effective organocatalyst to generate the enamine S from 32. In this case the highly activated N-O-Bs carbamates 33 were used as precursors to the nitrogen radicals R. As the reaction does not require a photoredox catalyst, the authors proposed the direct photoexcitation of 33 as a likely pathway for initial N–O bond homolysis. Following this, a polarized and highly enantioenriched radical reaction between R and S provided access to -amino radical T. This species was proposed to undergo ground state SET with 33 as part of a radical chain propagation. This would regenerate R while forming iminium U, which, upon hydrolysis, delivered the product 35 regenerating the organocatalyst 34.Meggers and co-workers have applied their chiral-at-metal transition metal complexes to the highly enantioselective -amination of acylimidazoles 37 using precursors 33 (Scheme 15).[36]

Scheme 14.

Yields and enantioselectivity were very high for the functionalization of benzylic centres (e.g. 38a–c) but this reactivity could not be extended to fully aliphatic systems (e.g. 38d).

CONCEPT

Scheme 15.

Interestingly, improved results were obtained using a Rh-based catalyst instead of a more strongly redox active Ir-based. The source of induction has been rationalized based on a crystal structure between the 36 and 37, which clearly displayed facial differentiation in the nucleophilic enolate.The ability of electrophilic amidyl radicals to intercept styrenes has been demonstrated by Yu in the divergent assembly of poly-functionalised carbamates (Scheme 16).[37] Although the nature of the nitrogen-radical precursor 39 had to be tailored, several multicomponent reactions leading to -amino-ketones (40A), 1,2-diamines (40B) and 1,2-aminoalcohols (40C and 40D) were obtained. Critical for the success of this strategy was the choice of solvent, with DMSO utilized to achieve Kornblum oxidations leading to 40A and 40D.

Scheme 16.

Addition to Aromatics

The reaction of nitrogen-radicals with electron rich arenes has been exploited in several visible-light-mediated C–H aminations. Classical transition metal-based cross-couplings (e.g. [Pd]: Buchwald-Hartwig coupling; [Cu]: Chan-Lam and Ullmann couplings) require functionalized aromatics (e.g. aryl halides or aryl boronic acids), however processes going through nitrogen-radicals harness the natural nucleophilicity of arenes without the need for pre-functionalization (Scheme 17A).All the methods discussed in this section go through a similar mechanism centered on a photoredox cycle delivering the nitrogen radical (W) by SET reduction of the hydroxylamine precursor (V) (Scheme 17B). Following this, a polarized radical reaction with an electron rich aromatic creates the key C–N bond. This step gives a stable radical intermediate (X) that closes the photoredox cycle by SET with the oxidized PC. The corresponding Wheland intermediate (Y) yields the amination product (Z) by deprotonation. It should be noted that this reactivity is mostly restricted to amidyl and aminium radicals, with a limited number of iminyls and no current reports of aminyls. This difference arises because the key radical addition (X) is highly influenced by polar effects, with the best

combination between electron rich aromatics and electrophilic nitrogen radicals (se also Scheme 1).

Scheme 17.

Pioneering work on photoredox C–H aminations has been reported by the group of Sanford, which focused on the use of the phtalimidyl radical formed from 41 (Scheme 18).[38] Using Ir(ppy)3 as the photocatalyst, a broad range of aromatics were successfully engaged, with mono-substitued benzenes typically providing a mixture of ortho, meta and para amination products. Remarkably, the authors showed compatibility with highly functionalized substrates like caffeine (44a) and even deactivated arenes like poly-chlorinated benzenes and pyridines (e.g. 44b). In this case high selectivity for the meta-addition product was observed. Yu and co- workers have shown that 33 can effectively undergo coupling with highly electron rich 5-membered ring heterocycles like indoles (e.g. 45a), furans (e.g. 45b) and pyrroles.[39] We have developed a protocol for the arylation of amidyl radicals using EY as the photocatalyst and precursors 42 (Ar = 2,4-(NO2)2-C6H3).[20a] This process displayed a broad scope for both the N-substiuent and the aromatic coupling partner, such as indoles, furans, naphtols and azulene. The mild reaction conditions enabled the late-stage amidation of the complex ergot derivatives metergoline and nicergoline (46a). More recently, Tang has applied this reactivity in intramolecular settings and used it in the total synthesis of the pyrroloindoline alkaloid (±)-flustramide B.[40] Continuing this line of investigation, we have recently identified conditions for the preparation of aryl amines from electron poor O-aryl hydroxylamines (43, Ar = 2,4-(NO2)2-C6H3).[41] In this case

CONCEPT

the strong Bronsted acid HClO4 was required to access the highly electrophilic aminium radicals. In this way a broad range of hydroxylamines were selectively coupled with 5- and 6-membered ring (hetero)aromatics including several complex bioactive molecules like strychinine, nabumetone, fluoxetine and

gemfibrozil. The method was also used to produce a complex derivative containing two active blockbuster drugs (47a), donepezil (Alzheimer’s disease palliative) and indometacine (NSAID).

Scheme 18.

Conclusions

Significant progress has been made in the last few years in the development of methods for the generation of nitrogen-radicals from hydroxylamines. Many important challenges still remain, for example enantioselective variants of these reactions are especially needed as well as novel process based on the concept of dual catalysis. Although a significant challenge, methods that can overcome the current limitation of 1-5 HAT process to the functionalization of tertiary C-H bonds would open new substrate scope. Furthermore, while the use of oxidative or reductive electrophores allows the selective generation of nitrogen radicals, they often require multiple steps to introduce. The generation of new, more direct methods to access the active species would further increase the utility of current methodologies. This may also expand the use of these methods on larger, preparative scale where the in-situ generation of nitrogen radical precursor is a particularly attractive option.

Acknowledgements

D.L. thanks the European Union for a Career Integration Grant (PCIG13-GA-2013-631556), the Leverhulme Trust for a research grant (RPG-2016-131), EPSRC for a Fellowship (EP/P004997/1) and AstraZeneca and Eli Lilly for generous support.

Keywords: nitrogen-radicals • SET • visible-light • photoredox catalysis • hydroxylamine derivatives

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CONCEPT

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