Photochemical Generation of Nitrogen-Centered Amidyl, Hydrazonyl

Perspective pubs.acs.org/acscatalysis

Photochemical Generation of Nitrogen-Centered Amidyl, Hydrazonyl, and Imidyl Radicals: Methodology Developments and Catalytic Applications Markus D. Kar̈ kas̈ * Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden ABSTRACT: During the past decade, visible light photocatalysis has become a powerful synthetic platform for promoting challenging bond constructions under mild reaction conditions. These photocatalytic systems rely on harnessing visible light energy for synthetic purposes through the generation of reactive but controllable free radical species. Recent progress in the area of visible light photocatalysis has established it as an enabling catalytic strategy for the mild and selective generation of nitrogen-centered radicals. The application of visible light for photocatalytic activation of amides, hydrazones, and imides represents a valuable approach for facilitating the formation of nitrogen-centered radicals. Within the span of only a couple of years, significant progress has been made for expediting the generation of amidyl, hydrazonyl, and imidyl radicals from a variety of precursors. This Perspective highlights the recent advances in visible light-mediated generation of these radicals. A particular emphasis is placed on the unique ability of visible light photocatalysis in accessing elusive reaction manifolds for the construction of diversely functionalized nitrogen-containing motifs and as a platform for nontraditional bond disconnections in contemporary synthetic chemistry. KEYWORDS: amidyl radicals, C−H amidation, C−N bond formation, nitrogen-centered radicals, photochemistry, visible light

1. INTRODUCTION

and has enabled an array of nontraditional bond constructions in synthetic chemistry. 1.1. Visible Light Photoredox Catalysis: A Versatile Catalytic Platform for Promoting Chemical Reactivity. Chemists have long recognized that sunlight is an inexhaustible source of energy and that novel patterns of reactivity can be accessed via photochemical activation.5 However, a majority of elementary organic compounds only absorb UV light, thereby limiting the use of visible light that makes up most of the solar spectrum. Organic photochemistry has traditionally employed ultraviolet (UV) light, which requires the use of specialized UV light photoreactors. Furthermore, UV photons are relatively high in energy and can facilitate considerable decomposition reactions, especially when weak bonds or sensitive functional groups are present in the starting or target compounds.6 Over the past decade, there has been a renaissance in synthetic photochemistry. This originates from the recognition that the transition metal-based polypyridyl chromophores (Figure 1) that have been extensively exploited in solar energy conversion technologies, such as water splitting7 and carbon dioxide reduction,8 can also be employed to harness visible light energy for synthetic purposes. The metal-based photocatalysts operate by absorbing light in the visible region, resulting in the formation of a long-lived redox-active excited state, which can act as both a

Nitrogen-containing compounds are important motifs and have a widespread presence in natural products, pharmaceuticals, agrochemicals, and material science. Therefore, the development of selective carbon−nitrogen (C−N) bond formation strategies under mild reaction conditions has attracted considerable attention from synthetic chemists. Traditional methods for C− N bond formation rely on Cu-mediated Ullman and Goldberg couplings1 or Pd-catalyzed Buchwald−Hartwig amination/ amidation.2 However, these methods typically suffer from the disadvantage of elevated temperatures and prefunctionalized substrates. Free radicals are ubiquitous intermediates in biological systems and can be leveraged to drive reactions that would otherwise be difficult to achieve with typical ionic transformations. The perception that radical reactions are nonselective and cannot be controlled has often discouraged scientists from using radicals in synthetic settings. However, this viewpoint is gradually shifting, and radical reactions are now frequently being considered and incorporated in contemporary organic syntheses as the advantages of radical chemistry becomes more widely understood. These advances have been made feasible because of the increasing insight into the principal factors that govern radical processes, such as bond dissociation energies (BDEs), radical polarity, and radical propagation.3,4 In this context, visible light-mediated catalysis has recently emerged as a mild and sustainable alternative for the generation of free radicals © 2017 American Chemical Society

Received: April 28, 2017 Revised: June 14, 2017 Published: June 19, 2017 4999

DOI: 10.1021/acscatal.7b01385 ACS Catal. 2017, 7, 4999−5022

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ACS Catalysis

Figure 1. Examples of typical photoredox catalysts.

Figure 2. Redox cycle of [Ru(bpy)3]2+.

Scheme 1. Hofmann−Löffler−Freytag Reaction

altering the metal center or tuning the electronic properties of the ligand backbone, provides a versatile synthetic platform for mediating challenging bond constructions in an intuitive and logical manner.10 1.2. Nitrogen-Centered Radicals: A Historical Perspective. Compared to carbon-centered radicals, nitrogen-centered radicals have been relatively underutilized from a synthetic perspective. This originated from a lack of convenient methods for producing these radical species, which limited their broad applicability in academic and industrial settings. 11 The quintessential strategy for generating nitrogen-centered radicals revolved around the photochemical or thermal homolysis of nitrogen−halogen (N−X) bonds (with X being chloro, bromo or iodo) in acidic media, in the Hofmann−Löffler−Freytag reaction (Scheme 1).12 Here, the generated nitrogen-centered ammo-

stronger oxidant and/or a stronger reductant than the ground state of the photocatalyst.9 The excited state can engage in singleelectron transfer (SET) events with the accompanying substrate, reagent, or a secondary catalyst to access productive reactivity that is unattainable under thermal control (Figure 2). This type of redox-activation offers several benefits over traditional chemical methods for promoting free radical chemistry, including the replacement of hazardous and toxic reagents that have traditionally been employed in stoichiometric quantities, such as tin hydrides, azobis(isobutyronitrile) (AIBN), and Et3B. The exceptionally mild reaction conditions by which these openshell intermediates can be accessed using visible light photoredox catalysis provides high functional group compatibility. This feature, in combination with the straightforward modulation of the inherent properties of the metal-based photocatalysts, by 5000


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ACS Catalysis

promote various conceptually challenging synthetic transformations, such as directed carbon−hydrogen (C−H) bond functionalization.11 The purpose of this Perspective is therefore to illustrate the recent advances that have been accomplished in the field of visible light-mediated generation of amidyl, hydrazonyl, and imidyl radicals, with a particular emphasis on the unique features of visible light photocatalysis in accessing elusive catalytic platforms and as a foundation for mediating challenging bond disconnections.

nium radical 7 is presumed to undergo intramolecular 1,5hydrogen atom transfer13,14 (HAT) to yield a carbon-centered radical (8). Trapping of this carbon radical with a chlorine atom produces the γ-halogenated amine 9, which undergoes ionic cyclization upon treatment with a base, ultimately providing the desired heterocycle 6. Alternatively, if there are no favorably disposed or activated hydrogen atoms present, the nitrogencentered radical can undergo addition to unsaturated hydrocarbons, such as alkenes, alkynes, and dienes.15,16 Recent developments in the field of visible light photocatalysis have established it as an enabling catalytic platform for the mild and selective generation of nitrogen-centered radicals. This allows the creation of nitrogen radical species in a controlled fashion, thereby providing new and elaborate reaction manifolds for the construction of diversely functionalized nitrogencontaining motifs.17 The application of visible light for photocatalytic activation of amides represents a valuable strategy for facilitating the formation of nitrogen-centered amidyl radicals (Figure 3). These amidyl radicals have been demonstrated to

2. PHTHALIMIDES AS NITROGEN-CENTERED RADICAL PRECURSORS Initial efforts in applying visible light photoredox catalysis for the intermolecular C−H amination of arenes and heteroarenes were described by Sanford and co-workers.18 The approach was inspired by the work of Skell and co-workers who disclosed that homolysis of the N−Br bond in N-bromophthalimide is facilitated by UV light. The generated PhthN• and Br• radicals subsequently react with benzene to produce the amination and bromination products, respectively.19 Sanford and co-workers realized that avoiding the formation of Br• could potentially augment the yield of the desired amination product. Using Ntrifluoromethylacyloxyphthalimide (10) as the aminating reagent in the presence of the highly reducing photocatalyst fac-[Ir(ppy)3] (2) showed that it could be employed as a convenient source of the PhtN• radical (14). After establishing a suitable aminating reagent, a variety of (hetero)arenes (11) were subjected to the optimal reaction conditions (Scheme 2). Mono-, di-, and trisubstituted arenes could be utilized in the transformation, affording the C−H imidated products 12 in modest to very good yields. Arenes containing electron-donating groups generally provided higher yields and high levels of ortho/para selectivity, while substrates bearing electron-withdrawing substituents gave lower yields and modest meta selectivity. A variety of heterocycles were also compatible with the C−H amination protocol, with electron-rich heteroarenes displaying C2 selectivity and pyridine derivatives affording the meta-substituted products. The proposed mechanism for the transformation

Figure 3. Strategies for the visible light-mediated formation of amidyl radicals.

Scheme 2. Visible Light-Mediated C−H Imidation Using N-Trifluoromethylacyloxyphthalimide (10) as the Nitrogen Radical Precursora

a

Major isomers are shown. 5001


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ACS Catalysis commences with photoexcitation of fac-[Ir(ppy)3] (2) to produce [Ir(ppy)3]* (2*), which is a strongly reducing species (E1/2{IrIV/IrIII*} = −1.73 V vs SCE). SET from the excited state photocatalyst to N-trifluoromethylacyloxyphthalimide (10) produces the trifluoroacetate anion 13 and the nitrogen-centered imidyl radical PhtN• (14). Radical addition of PhtN• to the arene 11 results in radical intermediate 15, which is subsequently oxidized by the oxidized photocatalyst ([Ir(ppy)3]+) to regenerate fac-[Ir(ppy)3] (2). Finally, deprotonation of the cationic Wheland intermediate20 16 provides the imidated product 12 (Scheme 2).18 Lee and co-workers demonstrated that the nitrogen-centered imidyl radical PhtN• (14) could be generated from Nchlorophthalimide (17) via reductive scission of the N−Cl bond. Employing the fluorinated iridium-based photoredox catalyst fac-[Ir(dFppy)3] (18) in combination with K2CO3 (3 equiv) and acetic acid (0.2 equiv) proved to be optimal when using a 20 W household compact fluorescent light (CFL) bulb as the source of visible light. An assortment of substrates possessing different electronic and steric properties was amenable to the reaction, and a range of mono-, di-, and trisubstituted arenes as well as pyridines were tolerated. A gram scale, one-pot Nchlorination/C−H imidation/deprotection sequence using commercially available reagents was also applied to mesitylene (11b), thus illustrating the potential utility of the developed method (Scheme 3). The reaction was proposed to proceed through a similar mechanism as the one depicted in Scheme 2.21

Cleavage of N−N bonds represents a complementary approach for the generation of nitrogen-centered radicals.22 Studer and co-workers previously disclosed that N-aminated dihydropyridines could be used efficiently as nitrogen-radical precursors in hydroamination of alkenes.23 Encouraged by these results, Studer and co-workers reasoned that the nitrogencentered imidyl radical PhtN• (14) could also be generated upon single-electron reduction from the corresponding pyridinium salt 19. The N-aminopyridinium salt, which can be stored for several months, is readily accessible in one step by reacting the commercially available pyrylium salt with an N-aminophthalimide, thus providing the pyridinium reagent 19 in excellent yield. Cyclic voltammetry of N-aminopyridinium salt 19 showed an irreversible reduction at −0.80 V vs SCE, suggesting that the excited state of the [Ru(bpy)3]2+ photocatalyst (E1/2{RuIII/ RuII*} = −0.81 V vs SCE) would be sufficient to induce the SET process. Employing 5 mol % [Ru(bpy)3]2+ (1) and blue LEDs at 40 °C, a variety of (hetero)arenes were imidated in good to excellent yields using N-aminopyridinium salt 19 as the nitrogenradical precursor (Scheme 4). Electron-rich arenes consistently provided higher yields, and as expected, monosubstituted substrates afforded a mixture of regioisomers. The suggested mechanism is shown in Scheme 4 and is believed to involve oxidative quenching of [Ru(bpy)3]2+*. Subsequent N−N bond cleavage of the singly reduced pyridinium salt 19 produces PhtN• (14), which adds to the (hetero)arene 11. SET from the produced radical intermediate 15 to [Ru(bpy)3]3+ and subsequent deprotonation of carbocation 16 delivers the imidated product 12 and regenerates [Ru(bpy)3]2+, thereby closing the catalytic cycle.24

Scheme 3. Visible Light-Induced Imidation of (Hetero)arenes with N-Chlorophthalimide (17)

3. NITROGEN-CENTERED RADICALS DERIVED FROM SULFONYL COMPOUNDS 3.1. C−H Amidation of Heteroarenes and Hydrazones. In connection to Studer and co-workers’ work on N−N bond cleavage employing N-aminopyridinium salt 19, a related strategy was also demonstrated in which the sulfonyl-based pyridinium salt 21 could be leveraged as a nitrogen-radical precursor for addition to various indole derivatives.24 The developed protocol using reagent 21 as a source of sulfonamidyl radicals tolerated an assortment of substituents at the 5-position of the indole core. Substituents at the 6- and 7-position, as well as 3-substituted N-methylindoles were also amenable to the catalytic strategy. Furthermore, the free N−H indole and its alkyl and aryl derivatives also afforded the α-amidated products in good yields (Scheme 5). However, N-protected indoles bearing electron-deficient groups, such as acetyl- or Bocprotecting groups, were not suitable substrates. Yu and Qin have also utilized hydroxylamine derivatives as nitrogen-centered sulfonamidyl radical precursors.25 The authors settled on using fac-[Ir(ppy)3] (2) as photocatalyst for affecting the direct C−H amidation of heteroarenes because of its strongly reducing nature in the excited state (E1/2{IrIV/IrIII*} = −1.73 V vs SCE). Using indole 22a as a model substrate and NaHCO3 as a base, a range of different nitrogen-centered radical precursors were evaluated. It was established that hydroxylamine derivative 25b was the most efficient precursor for facilitating direct amidation. The scope of the heteroarene coupling partners was subsequently investigated, and it was established that the protocol tolerated a variety of indole derivatives, pyrroles, and (benzo)furans (Scheme 6). The proposed mechanism involves initial photoexcitation of the iridium-based photocatalyst, which undergoes SET with hydroxylamine derivative 25b, thus 5002


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ACS Catalysis Scheme 4. Imidation of (Hetero)arenes via N−N Bond Cleavage of N-Aminopyridinium Salt 19

Scheme 5. Amidation of Indoles Using N-Aminopyridinium Salt 21

affording the 2-amidated products in high yields. C3-substituted indoles as well as the more biologically relevant tryptamine (22d) and melatonin derivatives (22l), and indole propanoic acid (22m) all underwent the transformation smoothly. Other heteroarenes, such as 7-azaindole, pyrrole, and benzofuran derivatives, were also compatible and gave the desired amidated products 23n−p as single regioisomers in moderate to high yields. The scope of the sulfonamide coupling partner 32 was subsequently established (Scheme 7, right). The photocatalytic conditions were shown to accommodate a variety of coupling partners, including aliphatic, styryl, and heterocyclic sulfonamides. Furthermore, different functionalized N-alkyl moieties, such as alkyne, carbamate, ester, and olefin, were tolerated. The catalytic protocol also allowed for the construction of heterocycle-fused 2-amidated indole derivatives in moderate to good yields via intramolecular C2-amidative cyclization.26 Hydrazones are privileged structural motifs in synthetic chemistry and versatile reagents as the CN bond is susceptible to both oxidative and reductive cleavage, and the N−N bond is amenable to reductive cleavage to produce primary amines.29 A SET strategy for accessing hydrazonamides 35 from the corresponding hydrazones 34 was recently disclosed by Yu and Zhu (Scheme 8).30 The developed protocol showed excellent chemoselectivity, good functional group compatibility with none of the corresponding amidated arenes as a side product. Mechanistic experiments revealed that addition of the radical trapping agent 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) to the reaction inhibited the amidation, indicating that a SET radical pathway is operative. On the basis of these observations, a mechanism involving SET from the excited state of the photocatalyst (2) to 25b furnishes the nitrogen-centered radical 28. Subsequent radical addition to the hydrazone CN bond produces a hydrazyl radical intermediate (36), which can be oxidized by the IrIV photocatalyst. Finally, deprotonation of the generated diazenium cation 37 delivers the amidated hydrazone 35. 3.2. Intermolecular Functionalization of Olefins. The design of economic and environmentally friendly catalytic systems for direct functionalization of alkenes has been of long-standing interest in synthetic chemistry.31 In this context, the Yu laboratory reported an efficient, regioselective visible light-promoted method for chloroamination of olefins (38)

promoting reductive scission of the N−O bond. Addition of the generated nitrogen-centered sulfonamidyl radical 28 to the heteroarene 22 is followed by oxidation by the IrIV photocatalyst to regenerate the IrIII photocatalyst and furnishes the amidated product 26 upon rearomatization (Scheme 6). Subsequent work by the groups of Zhang and Yu exploited the reactivity of nonactivated sulfonamides for the direct oxidative C−H amidation of heteroarenes using visible light photoredox catalysis.26−28 Initial observations revealed that N-methyl-paratoluenesulfonamide (31) in combination with bleach (aqueous NaClO solution) as the oxidant and [Ir(ppy)2(dtbbpy)]+ (3) as photocatalyst was the most efficient catalytic system for delivering the amidated products 23. The scope of the visible light-mediated direct C−H amidation reaction was explored using numerous heteroarenes (Scheme 7, left). In general, it was found that indoles substituted at the C4−C7 were tolerated, 5003


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ACS Catalysis Scheme 6. Redox-Neutral C−H Amidation of Heteroarenes with Hydroxylamine Derivativesa

a

2 equivs of sulfonamide 24 or 25 were used in all reactions unless otherwise noted. b4 equivs of 25b were used.

Scheme 7. Direct Oxidative C−H Amidation of Heteroarenes Enabled by Visible Light Photoredox Catalysisa

a

[Ir] = [Ir(ppy)2(dtbbpy)]+ (3). 2 equivs of sulfonamide 31 or 32 were used in all reactions unless otherwise noted. b2 equivs of 31 were used for 4 h. c2 equivs of NaClO were used.

photocatalyst [Ir(ppy)2(dtbbpy)]+ (3) in DCE proved to be optimal for affecting the chloroamination. Different protecting

where N-chlorosulfonamide 24e served as both the nitrogen and chlorine source.32 Irradiation with white LEDs in the presence of 5004


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ACS Catalysis Scheme 8. C−H Amidation of Hydrazones via Visible Light Photoredox Catalysis

groups on the nitrogen atom were initially examined, and it was shown that the electron-rich p-MeO-C6H4−SO2 group and its electron-neutral counterparts Ph-SO2 and p-Me-C6H4−SO2 (Ts) provided the chloroaminated products 39 in similar yields (70−73%). However, employing the electron-deficient benzenesulfonamide p-NO2−C6H4−SO2 led to diminished yield (50%), while using tert-butyl chloro(methyl)carbamate proved to be ineffective under the developed conditions, giving full recovery of the starting materials (not shown). A variety of styrene derivatives were subsequently explored, and all evaluated substrates afforded the corresponding products in 50−83% yield. Electron-neutral aliphatic olefins were also suitable substrates, delivering the chloroamination products as single regioisomers in slightly lower yields than their aromatic counterparts (Scheme 9). For substrate 38c, the transformation was also carried out on gram scale using as little as 0.5 mol % loading of the photocatalyst to provide product 39c in 74% isolated yield, highlighting the scalability of the catalytic protocol. A plausible mechanism for the chloroamination is shown in Scheme 9 and involves oxidative quenching of IrIII* by N-chlorosulfonamide 24e. The generated nitrogen-centered radical 40 then adds to olefin 38 and subsequent oxidation of the produced benzylic radical 41 by IrIV regenerates the IrIII photocatalyst. Finally, trapping of the resulting benzylic cation 42 by a chloride anion furnishes the chloroaminated product 39. An alternative and competitive pathway involves a radical chain mechanism33 where chlorine atom abstraction from 24e by the produced benzylic radical 41 would give product 39 and another equivalent of the nitrogencentered radical 40. Visible light-mediated N−N bond scission has also been exploited for the functionalization of alkenes. The group of Koike and Akita harnessed this reactivity in the development of a protocol for regioselective intermolecular aminohydroxylation of olefins.34−37 Various N-protected 1-aminopyridium salts were prepared and examined as potential nitrogen-centered precursors. Optimization studies revealed that the N-Ts-protected 1-aminopyridinium salt 44 in combination with fac-[Ir(ppy)3] (2) as photocatalyst delivered the aminohydroxylated product 45a in excellent yield as a single regioisomer. The scope of the

Scheme 9. Visible Light-Promoted Chloroamination of Olefinsa

a

[Ir] = [Ir(ppy)2(dtbbpy)]+ (3). 1.2 equiv of N-chlorosulfonamide 24e was used in all reactions.

photocatalytic aminohydroxylation was explored, and it was established that various styrene derivatives (43) were tolerated, furnishing the vicinal aminoalcohol products 45 in good to excellent yields (Scheme 10). The use of α-methylstyrene (43h) and α-pyridylstyrene (43i) as substrates was also compatible with 5005


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ACS Catalysis Scheme 10. Intermolecular Aminohydroxylation Using Photoredox Catalysis

a

[Ir(ppy)2(dtbbpy)]PF6 (2 mol %) was used as photocatalyst. b1.8 equiv of aminopyridinium salt 44 was used.

Scheme 11. Photoinduced Synthesis of Substituted Imidazolines and Oxazolidinesa

a

[Ir] = [Ir(ppy)2(dtbbpy)]+ (3).

strongly oxidizing IrIV species to produce a β-aminocarbocationic intermediate (49) and regeneration of the IrIII photocatalyst 2. The carbocationic intermediate 49 is then intercepted by H2O to give the desired 1,2-aminoalcohol derivative 45.34 The application of aminopyridinium salt 44 in photoredox catalysis was recently extended by Xu and co-workers to enable the direct synthesis of substituted imidazolines (51) and oxazolidines (52).38 Here, fac-[Ir(ppy)3] (2) was also shown to be the optimal photocatalyst in the presence of a nitrile source, such as acetonitrile, for affecting the synthesis of imidazolines. The protocol proceeded smoothly using a variety of substituted

the developed protocol, providing products 45h and 45i that contain tertiary alcohol moieties. When employing internal alkenes, the reactions also proceeded in a regiospecific manner; however, the products (see 45k and 45l) were isolated as mixtures of two diastereomers. The proposed mechanism for the intermolecular aminohydroxylation is outlined in Scheme 10 and is believed to involve SET from the excited photocatalyst IrIII* to the aminopyridinium salt 44. This facilitates N−N bond scission to yield the nitrogen-centered sulfonamidyl radical 47, which adds to the alkene 43 in a regiospecific manner. The generated carbon-centered radical 48 is subsequently oxidized by the 5006


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ACS Catalysis Scheme 12. Radical Smiles Rearrangement

Scheme 13. Visible Light-Mediated Radical Amination/Smiles Rearrangement for Synthesis of Phthalazine Derivatives

operationally simple, and rely on easily accessible starting materials and reagents. 3.3. Intramolecular Functionalization of Alkynes and Hydrazones. The Smiles rearrangement41 involves the intramolecular nucleophilic substitution at the ipso-position on an activated aromatic system. This is followed by migration of the activated aromatic ring to the more nucleophilic heteroatom. In the Truce−Smiles variant, the nucleophile is typically a carbanion, allowing for carbon−carbon (C−C) bond formation. Radical versions of the Smiles rearrangement are also known and are triggered by attack of free radicals at the ipso-position, and can proceed without the presence of additional activating groups. Subsequent SO2 extrusion and hydrogen atom abstraction gives the rearranged product (Scheme 12).42,43 Belmont and co-workers recently demonstrated that phthalazine derivatives could be accessed via a radical amination/Smiles rearrangement sequence using visible light photoredox catalysis.44 Here, nitrogen-centered hydrazonyl radicals 60 were generated oxidatively using [Ru(bpy)3]2+ as a photocatalyst in the presence of 1.5 equiv NaOH under blue light irradiation to deliver phthalazines 59. The impact of the alkyne substitution was initially studied, and it was shown that both electron-

styrene derivatives 50 to afford the corresponding substituted imidazolines (51) in good to excellent yields. In addition to acetonitrile, other nitriles, such as propiononitrile, cyclopropanecarbonitrile, and benzonitrile, were also amenable to the catalytic conditions (Scheme 11, left). The authors noted that switching to the photocatalyst [Ir(ppy)2(dtbbpy)]+ (3) and conducting the reactions in acetone allowed for the preparation of substituted oxazolidines (52). The direct three-component cyclization of the nitrogen-centered radical and acetone permitted the use of a range of unactivated olefins as well as both electron-withdrawing and electron-donating substituents on the aromatic ring (Scheme 11, right). The mechanism for these transformations is presumed to be analogous to the one depicted in Scheme 10 except that interception of the generated carbocationic intermediate 49 occurs by nitrile or acetone.39 Subsequent cyclization of the cationic nitrile- or acetone-derived intermediates delivers the substituted imidazolines and oxazolidines, respectively. These visible light-mediated strategies for the synthesis of imidazoline and oxazolidine derivatives through a radical addition and formal [3 + 2] annulation pathway represent attractive complements to previously developed methods40 as they can be conducted at mild reaction conditions, are 5007


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ACS Catalysis Scheme 14. Photocatalytic Hydro- and Oxyamination of β,γ-Unsaturated Hydrazones

through copper catalysis46 or using stoichiometric amounts of oxidants,47 such as TEMPO+. The Xiao and Chen laboratories recently expanded the activation mode when it was demonstrated that visible light-mediated generation of nitrogencentered hydrazonyl radicals from β,γ-unsaturated hydrazones can be harnessed to accomplish hydroamination48 or cascade reactions.49,50 Initial work by the groups was devoted to the application of visible light photoredox catalysis to develop a protocol for the intramolecular hydroamination of β,γunsaturated hydrazones.48 It was envisioned that generation of nitrogen-centered hydrazonyl radicals could be accomplished via direct activation of the N−H bond of hydrazones (64), which would subsequently engage in cyclization with the pendant olefin to ultimately furnish the corresponding 4,5-dihydropyrazoles (65). Similar to the work by Belmont and co-workers,44 a combination of [Ru(bpy)3]2+ (1, 2 mol %) and NaOH (1.5 equiv) proved to be effective conditions for the hydroamination. Both aliphatic and phenyl substituted β,γ-unsaturated hydrazones were tolerated and provided the desired 4,5-dihydropyrazoles 65a−p in moderate to good yields (Scheme 14). For the aromatic hydrazones (64a−j), the electronic properties and substitution pattern on the phenyl ring did not have any noticeable effect on the reaction outcome. The mechanism for the intramolecular hydroamination is believed to proceed through reductive quenching of the excited state of the photocatalyst (RuII*) by hydrazone 64. This produces the reduced RuI photocatalyst and the nitrogen-centered hydrazonyl radical 67, which undergoes a 5-exo-trig cyclization to furnish a carbon-centered radical (68). A presumed HAT event from CHCl3 to radical 68 delivers the 4,5-dihydropyrazole 65 along with a trichloromethyl radical, which can regenerate the RuII photocatalyst through a SET event (Scheme 14). Alternatively, the carbon-centered radical 68 can also be intercepted with TEMPO to generate oxyamination products 66 if the reaction is

donating and electron-withdrawing substituted aryl moieties were tolerated, furnishing the desired phthalazines 59a−f in moderate to good yields. The aliphatic pentyne and cyclohexenyl derivatives 58g and 58h could also be converted to the cyclized products in 55% and 66% yield, respectively. Differently substituted sulfonylhydrazones were subsequently examined, and the para-substituted derivatives 58i−k provided the corresponding phthalazines in good yields (Scheme 13). However, the more sterically encumbered xylene substrate 58l only gave 30% of product 59l, while the 1-naphthalene substituted derivative led to almost full recovery of the starting material. The catalytic protocol was also amenable to heteroarene-derived sulfonylhydrazones, giving the thiophene and pyridine heterocyclic compounds 59m and 59p in 71% and 64% yield, respectively. The method was also applied in a onepot two-step procedure in which in situ preparation of sulfonylhydrazones 58 from the corresponding sulfonylhydrazides and aldehydes, followed by radical Smiles rearrangement provided phthalazines 59 in yields similar to that of the two-step process. A proposed mechanism for the radical hydroamination/ radical Smiles rearrangement is depicted in Scheme 13 and is believed to involve base-promoted oxidation of 58 by RuII* to give the nitrogen-centered hydrazonyl radical 60 and RuI. Subsequent intramolecular 6-exo-dig cyclization produces a vinylic radical (61), which readily undergoes the radical Smiles rearrangement via attack at the ipso-position and results in extrusion of SO2. Finally, reduction of the generated nitrogen- or carbon-centered phthalazine radical 62 by RuI regenerates the RuII photocatalyst and subsequent protonation of 63 delivers the target compound 59 (Scheme 13). Intramolecular alkene hydroamination strategies have been demonstrated to be versatile methods for the synthesis of structurally diverse nitrogen-based heterocycles.45 Radical hydroamination involving the direct generation of nitrogencentered radicals via N−H bond cleavage can be accomplished 5008


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ACS Catalysis Scheme 15. Dual Photoredox/Cobalt Catalysis for the Synthesis of Dihydropyrazole-Fused Benzosultams

makes use of photoredox and a cobalt activation mode, highlights the unique features of photoredox catalysis for turnover of the interdependent catalytic cycles, allowing oxidant-free systems to be realized. A third catalytic activation mode was also designed by the Chen laboratory for accessing 1,6-dihydropyridazines using a visible light photocatalytic/TEMPO-mediation strategy.50 Under the previously developed photocatalytic conditions, β,γunsaturated hydrazones 64 underwent 5-exo-trig cyclization to afford the 4,5-dihydropyrazole scaffold 66 when the reactions were conducted in the presence of TEMPO (see Scheme 14). However, switching to β,γ-unsaturated hydrazones 76 resulted in products 77 containing the 1,6-dihydropyridazine scaffold, indicating that hydrazones such as 76 favor the 6-endo-trig cyclization mode (Scheme 16). Here, TEMPO does not function as a radical trap,54 but instead, facilitates abstraction of the azaallylic hydrogen atom through a HAT process, thereby serving as a hydrogen atom acceptor.55,56 The generality of the transformation was subsequently evaluated, and it was established that the catalytic protocol tolerated a wide range of aromatic β,γunsaturated hydrazones bearing electron-neutral, electron-poor, or electron-rich substituents at the ortho-, meta-, or para-position of the aromatic moiety. The heterocyclic systems 76g and 76h did not have any major detrimental effect on the reaction and delivered the corresponding 2-thiophenyl and 3-indolyl containing products 77g and 77h in 59% and 53% yield, respectively. Furthermore, the catalytic protocol could also successfully be extended to aliphatic β,γ-unsaturated hydrazones (76i−m). A proposed mechanism for the radical cascade reaction is depicted in Scheme 16 and is assumed to proceed through base-triggered oxidative quenching of the excited photocatalyst ([Ru(bpy)3]2+*) by hydrazone 76. This produces a nitrogen-centered hydrazonyl radical (78), which engages in 6-

carried out in the presence of stoichiometric amounts of TEMPO.48 Subsequent work by the Xiao and Chen laboratories involved the development of an external oxidant-free nitrogen-radical 5exo cyclization/addition/aromatization cascade of β,γ-unsaturated hydrazones (69) to produce dihydropyrazole-fused benzosultams (70) through the merger of photoredox and cobalt catalysis.49 Inspired by the recent reports by Lei51 and Wu52 on photoredox-mediated dehydrogenative cross-couplings,53 Xiao and Chen reasoned that combining a photocatalyst and a hydrogen-evolving cobalt catalyst would facilitate the generation of an oxidant-free catalytic system with liberation of molecular hydrogen (H2) being the only byproduct. After screening several different cobalt catalysts, the authors found that a dual catalytic system consisting of [Co(dmgH)2ClPy] (71, dmgH2 = dimethylglyoxime) and [Ru(bpy)3]2+ (1) was the most efficient combination for the desired cascade transformation. A variety of substituted aromatic and aliphatic β,γ-unsaturated hydrazones reacted smoothly under the catalytic conditions, providing the benzosultam products 70 in moderate to good yields (Scheme 15). Luminescence quenching experiments revealed that efficient quenching of the excited photocatalyst (RuII*) by hydrazones 69 only occurred in the presence of K2CO3, suggesting a base-triggered quenching mechanism being operative. The generated nitrogen-centered hydrazonyl radical 72 subsequently undergoes 5-exo-trig radical cyclization/ addition sequence to produce an arenium radical intermediate (74). Oxidation of this intermediate by the CoII catalyst, which is generated through SET from the reduced photocatalyst (RuI) to the CoIII complex 71, followed by deprotonation furnishes product 70. Protonation of the CoI species gives a CoIII−H species that liberates H2 upon reaction with another proton (Scheme 15).49 The designed dual catalytic platform, which 5009


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ACS Catalysis

sequently explored, and the method was amenable to the preparation of 2-substituted pyrrolidines (81a−e) in good to excellent yields. The catalytic protocol also allowed the formation of the optically active isoleucine-derived 2,3disubstituted pyrrolidines 81h and 81i in 85% and 56% yields, respectively. Additionally, substrates not accessible under classic HLF conditions, such as the acid-labile oxazolidines 81j and 81k, could also be constructed with the established visible lightpromoted method. The reaction outcome could also be tuned by simply omitting NaOH to furnish the δ-chlorinated products 82 in good to excellent yields (Scheme 17). Furthermore, regioselective late-stage functionalization of the biologically relevant (−)-cis-myrtanylamine-derived N-chlorosulfonamide 80l and (+)-dehydroabietylamine-derived N-chlorosulfonamide 80m was also feasible under the standard C(sp 3 )−H functionalization conditions. Mechanistically, the generation of the vital nitrogen-centered sulfonamidyl radical 83 is achieved through oxidative quenching by the photoexcited catalyst (IrIII*). Subsequent intramolecular 1,5-HAT generates a carboncentered radical (84), which can be oxidized by the IrIV photocatalyst to produce a carbocation (85) and regeneration of the IrIII photocatalyst. Trapping of the resulting carbocation by chloride gives the chlorinated product 82, which can undergo NaOH-promoted cyclization to deliver pyrrolidine 81.

Scheme 16. Synthesis of 1,6-Dihydropyridazines through the Merger of Visible Light Photocatalysis and TEMPOMediation

4. CATALYTIC AMIDYL RADICAL GENERATION FROM AMIDES VIA PROTON-COUPLED ELECTRON TRANSFER The Knowles group has been particularly successful in designing several recognizable catalytic transformations through the merger of photoredox and Brønsted base catalysis.60,61 These systems rely on proton-coupled electron transfer (PCET) for affecting homolytic N−H bond activation in which a proton and an electron are transferred in a concerted fashion from a single donor to two independent acceptors: a Brønsted base and a oneelectron oxidant. Compared to the stepwise process, the energetic features of PCET events are distinct and may allow one to access pathways that would otherwise be inaccessible.62 Initial work by the Knowles group demonstrated that hydroamination of olefins could be leveraged using a PCET activation strategy.60 After having identified thiophenol as the optimal hydrogen atom donor, the authors showed that the combination of thiophenol, a weak phosphate base (Bu4NOP(O)(OBu)2) and the excited state of [Ir(dF{CF3}ppy)2(bpy)]+ (88) efficiently enabled the intramolecular hydroamination of unactivated olefins (Scheme 18). The catalytic protocol accommodated a variety of di-, tri-, and tetrasubstituted olefins, as well as styrenyl acceptors. Bicyclic motifs could also be accessed in high yield and high diastereoselectivity. The developed method was subsequently applied to different natural product derivatives, such as gibberellic acid (86k) and progesterone (86l), and delivered the corresponding hydroamination products 87k and 87l in high yields and excellent diastereoselectivities. However, the authors noted that the catalytic strategy did not allow for intermolecular couplings or the formation of larger rings with high efficiency, presumably due to the fact that back-electron transfer from the generated amidyl radical and the reduced photocatalyst is kinetically favored over productive C−N bond formation. Luminescence quenching experiments supported a PCET activation pathway as efficient quenching of the photocatalyst was only observed in solutions containing both amide and the phosphate base. On the basis of these studies, amide activation is proposed to occur via PCET,

endo-trig radical cyclization to generate benzylic radical 79. Finally, a TEMPO-mediated HAT process delivers the 1,6dihydropyridazine 77, and regeneration of [Ru(bpy)3]2+ is achieved through SET to CHCl3 or another oxidant, thereby closing the catalytic cycle.50,57 3.4. Remote C(sp3)-H Functionalization. The direct functionalization of nonactivated C−H bonds represents an attractive catalytic platform for accessing complex organic compounds in a straightforward and economical fashion.58 The synthetic importance of methods for remote C(sp3)−H functionalization enticed Yu and Qin to devise a visible lightmediated strategy for remote C(sp3)−H amidation and chlorination of N-chlorosulfonamides.59 It was established that simply irradiating a CH3CN solution containing the Nchlorosulfonamides 80 in the presence of the photocatalyst [Ir(ppy)2(dtbbpy)]+ (3) and Na2HPO4 at room temperature followed by treatment with NaOH afforded the corresponding pyrrolidines 81 (Scheme 17). The substrate scope of the visible light-mediated intramolecular C(sp3)−H amidation was sub5010


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ACS Catalysis Scheme 17. Visible Light-Mediated Remote C(sp3)−H Amidation and Chlorination of N-Chlorosulfonamides

resulting in N−H bond homolysis and the generation of amidyl radical 89. Radical addition to the pendant olefin produces a nascent carbon-centered radical (90) that is subsequently reduced by the hydrogen atom donor catalyst to deliver product 87. Next, SET from the reduced iridium photocatalyst (IrII) to the oxidized HAT catalyst regenerates thiophenol and the photocatalyst and closes the catalytic cycles (Scheme 18). The Knowles group has also expanded the PCET activation strategy to include alkene carboaminations.61 In a similar fashion as depicted in Scheme 18, the produced nitrogen-centered amidyl radical 89 cyclizes onto the pendant olefin to produce carboncentered radical 90. However, in the presence of a Michael acceptor (92), efficient trapping of this radical occurs to ultimately give the carboamination product 91 (Scheme 19). These studies highlight the powerful nature of PCET in photoredox catalysis for carrying out the direct homolytic activation of unactivated N−H bonds, thereby providing access to nitrogen-centered amidyl radicals from readily accessible starting materials. HAT processes are a well-established concept in organic free radical chemistry and have been frequently exploited in photocatalysis.63,64 The Knowles65 and Rovis66 groups recently independently disclosed visible light-induced methods for the functionalization of C(sp3)−H bonds that relied on a 1,5-HAT strategy (Scheme 20). In the report by Knowles and co-workers, the vital nitrogen-centered radical was generated from benzamides 95 using [Ir(dF{CF3}ppy)2(5,5′-{dCF3}bpy)]+

(97) as photocatalyst in combination with Bu4NOP(O)(OBu)2. However, Rovis’ and Chu’s approach utilized trifluoroacetamides 98, [Ir(dF{CF3}ppy)2(dtbbpy)]+ (4) as the photocatalyst, and K3PO4 as the base. Photoredox-mediated oxidative generation of the amidyl radical 100 allowed for directed formation of a distal aliphatic carbon-centered radical (101) through 1,5-HAT. Concomitant C−C bond formation through trapping of the produced carbon radical 101 with an appropriate Michael acceptor (92) followed by SET from the reduced photocatalyst (IrII) eventually delivers the alkylated product 96 or 99. The developed photoredox protocols demonstrate that HAT events can facilitate selective C−C bond formation at remote unactivated C(sp3)−H bonds and represent catalytic alternatives of the Hofmann−Löffler−Freytag reaction (see Scheme 1).

5. PHOTOCHEMICAL FORMATION OF AMIDYL AND IMIDYL RADICALS UNDER TRANSITION METAL-FREE CONDITIONS 5.1. Organophotocatalytic Functionalization of Olefins and Arenes. Transition metal-free photocatalytic approaches to hydro- and oxyamination have also been developed as illustrated by the recent works from the Chen67 and Leonori68,69 laboratories.70 Expanding on the established platforms for the generation of nitrogen-centered hydrazonyl radicals from β,γunsaturated hydrazones,48−50 Chen and co-workers developed a metal-free catalytic system for oxyamination (Scheme 21).67 Here, a cooperative strategy involving photoredox and TEMPO 5011


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ACS Catalysis Scheme 18. Visible Light-Mediated Alkene Hydroamination Enabled by Proton-Coupled Electron Transfer

a

30 mol % thiophenol.

Scheme 19. Photocatalytic Alkene Carboamination via Oxidative Proton-Coupled Electron Transfer

catalysis was applied to β,γ-unsaturated hydrazones 104 to enable selective oxidative radical oxyamination using O2 as the terminal oxidant and an oxygen source. Investigation of the reaction parameters revealed that the mesityl acridinium

organophotocatalyst 107 in combination with TEMPO, K2CO3 as the base, and blue light irradiation under O2 atmosphere provided the optimal conditions. The catalytic protocol was shown to tolerate a range of substituted β,γ5012


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ACS Catalysis Scheme 20. Amide-Directed Functionalization of Remote C(sp3)−H Bondsa

a

PMP = p-methoxyphenyl. tAmOH = tert-amyl alcohol. 5013


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ACS Catalysis Scheme 21. Organophotocatalytic Oxidative Radical Oxyamination of β,γ-Unsaturated Hydrazones

Scheme 22. Transition Metal-Free Hydroamination of Aryloxy Amides

serves as a key intermediate in the reaction. On the basis of these observations, the authors proposed a mechanism where the photoexcited acridinium catalyst (Mes-Acr*+) undergoes SET with TEMPO to produce Mes-Acr and TEMPO+. Subsequent oxidation of substrate 104 by TEMPO+, facilitated by the base, produces nitrogen-centered hydrazonyl radical 108, which undergoes 5-exo-trig radical cyclization to give a carbon-centered radical (109). Trapping of radical 109 with O2 affords an alkyl hydroperoxy radical (110), which is presumably converted to

unsaturated hydrazones, including electron-donating and electron-withdrawing aromatic moieties, as well as linear or branched aliphatic hydrazones. To confirm the origin of the oxygen in the cyclized products 105 and 106, an experiment was performed using 18,16O2. The 18O-labeling experiment provided the isotope-labeled product in 56% yield, indicating that O2 indeed participates in the reaction. Furthermore, alkyl hydroperoxide 111 could be isolated and was subsequently transformed into 105 upon treatment with PPh3, suggesting that 111 5014


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ACS Catalysis Scheme 23. N-Arylation of Aryloxy Amides Using Eosin Y as the Organophotocatalyst

respectively, in good yields. A plausible mechanism for Narylation is shown in Scheme 23 and commences with SET to the aryloxy amide 122, which promotes N−O bond scission and furnishes the nitrogen-centered amidyl radical 125. This is followed by radical addition to the arene (123) to produce radical 126. Subsequent oxidation of radical 126 by the oxidized organophotocatalyst (EY+) and deprotonation of arenium ion 127 gives the desired arylation product 124.68 5.2. Photocatalyst-Free Systems for the Generation of Amidyl Radicals. Leonori and co-workers subsequently attempted to extend the hydroamination protocol to include 5exo-dig cyclizations. Although control experiments demonstrated that the transformation was suppressed by the absence of visible light, it was evident that the organophotocatalyst eosin Y was not required, giving 5-methylenepyrrolidinones 129 by simply irradiating 128 in the presence of K2CO3 and 1,4-CHD (Scheme 24). DFT studies suggested that the radical 5-exo-dig cyclizations

alkyl hydroperoxy species 111 via a SET event with the reduced organophotocatalyst (Mes-Acr). Finally, reduction of 111 by PPh3 delivers the target compound 105 (Scheme 21). Leonori and co-workers recently disclosed a transition-metalfree system for cyclization of iminyl radicals derived from aryloximes using eosin Y (114) as a photocatalyst and 1,4cyclohexadiene (1,4-CHD, 118), which had a dual role being both a hydrogen atom donor and SET reductant.71 Inspired by this work, the authors questioned whether a similar activation mode could be applied to aryloxy amides for the generation of amidyl radicals.68 Guided by electrochemical and density functional theory (DFT) studies, aryloxy amides 112 were selected due to their ease of synthesis and favorable SET reduction. The optimized reaction conditions consisted of eosin Y as the photocatalyst, 1,4-CHD, K2CO3 as the base, and acetone as the reaction medium under green light irradiation. The catalytic platform was shown to tolerate a variety of different Nsubstituted aryloxy amides and also enabled the preparation of cyclic carbamates (Scheme 22). The developed method was assumed to commence with SET reduction of amide 112 upon excitation of eosin Y by visible light irradiation. This process facilitates N−O bond fragmentation to generate the desired nitrogen-centered amidyl radical 115, which produces carboncentered radical 117 after 5-exo-trig cyclization. Concomitant hydrogen atom abstraction from 1,4-CHD (118) gives the hydroamination product 113 and a CHD-based radical (119) that can participate in SET with the oxidized photocatalyst (EY•+), thereby closing the photoredox cycle (Scheme 22). In addition to designing a hydroamination protocol, the authors also reported that intermolecular N-arylation could be achieved by simply exposing aryloxy amides 122 to electron-rich arenes (123) in the presence of eosin Y and K2CO3 under irradiation with green light (Scheme 23). An assortment of electron-rich (heter)aromatics, such as azaindole (123a), anthracene (123b), azulene (123c), and naphthalene (123d), were aminated in moderate to excellent yields. The catalytic conditions could also successfully be applied to the therapeutically active ergot derivatives nicergoline (123e) and metergoline (123f), giving the C2-functionalized products 124e and 124f,

Scheme 24. Synthesis of 5-Methylenepyrrolidinones via 5-exodig Hydroamination

were less favorable than the previously developed 5-exo-trig cyclizations, providing a rationale for the somewhat diminished yields of the cyclized products 129.69 The MacMillan laboratory employed the related dinitrophenylsulfonyloxy (ODNs) group, a subunit that can be chemoselectively activated using a simple household lightbulb, in a 5015


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ACS Catalysis Scheme 25. Photoinduced Asymmetric α-Amination of Aldehydes

photoinduced strategy for the asymmetric α-amination of aldehydes.72,73 The authors identified amine catalyst 133 as the optimal organocatalyst for the transformation and the combination with carbamate 131, housing the photolabile ODNs unit, afforded high levels of enantiocontrol in the aldehyde−amine coupling platform (Scheme 25). The mechanism presumably involves direct excitation of the ODNs-based reagent 131 to yield 131*, which acts as a single-electron oxidant, resulting in mesolytic cleavage of the N−O bond upon SET. The resultant nitrogen-centered radical 135 can engage in coupling with the πrich enamine 134 to give an α-amino radical species (137). Radical chain propagation occurs through oxidation of this radical by a second equivalent of 131*, thereby delivering iminium ion 138 and produces a second equivalent of the nitrogen-centered radical coupling partner 135. Finally, hydrolysis of 138 releases organocatalyst 133 and furnishes the enantioenriched α-amino aldehyde product 132 (Scheme 25).72 An important feature of the disclosed catalytic protocol is that the mild reaction conditions enable direct enantioselective access to α-amino aldehyde adducts, compounds that have proven to be susceptible to racemization. Additional catalyst-free platforms for the generation of nitrogen-centered imidyl and amidyl radicals consist of visible light-induced activation of N-bromosaccharins74,75 and Nbromoamides.76 Luo and co-workers disclosed a photolytic protocol for imidation of (hetero)arenes. Here, N-bromosaccharin (139) was identified as a viable imidyl radical precursor that underwent homolytic cleavage in the presence of ambient light (Scheme 26).74 The Alexanian laboratory demonstrated that N-bromobenzamide 142 in combination with visible light could be employed for carrying out intermolecular, aliphatic C− H bromination.76 Benzamide 142 and its derivatives are stable solids and can be easily prepared from the corresponding amides. The developed protocol allowed for the C−H bromination of a variety of cycloalkanes (Scheme 27). The authors subsequently explored the potential for site-selective C−H functionalization. Using bulky N-tBu amide reagents, such as 142, provided

Scheme 26. Catalyst-Free Photolytic Imidation of (Hetero)arenesa

a

3 equivs of the arene were used unless otherwise noted. b1.5 equiv of the (hetero)arene was used.

excellent levels of methylene (secondary) functionalization, while N-bromo-N-trifluoroethyl derived reagents favored functionalization of the weakest C−H bonds (tertiary). This highlights the ability to tailor the site selectivity by fine-tuning the N-substituent of the N-bromoamide reagent. With amide reagent 142, high levels of steric selectivity with a number of hydrocarbon substrates was achieved. Electronic site selectivity was also accomplished with a set of linear functionalized hydrocarbons, providing good to high selectivity for the δ site. The protocol also allowed for late-stage functionalization of the N-phthalimide derivative of memantine (141g) and the terpenoid natural product (+)-sclareolide (141h), giving the bromination products 143g and 143h in 70% and 67% yields, 5016


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ACS Catalysis Scheme 27. Visible Light-Mediated Intermolecular, Aliphatic C−H Bromination

Scheme 28. Application of a Radical C−H Chlorination Method in the Synthesis of (+)-Chlorolissoclimide (146)

Scheme 29. Photoinduced Aliphatic C−H Xanthylationa

a

1 equiv of xanthylamide 147 was used unless otherwise noted. b2 equivs xanthylamide 147 were used.

respectively. The high efficiency of the light-mediated C−H functionalization protocol permits the use of the hydrocarbon substrate as the limiting reagent, an essential feature for potential future applications in streamlining complex molecule synthesis. Expanding on the developed C−H functionalization platform, the Alexanian and Vanderwal laboratories reported a related siteselective radical C−H chlorination strategy using N-chloroamide 144, which was also applied to a synthesis of (+)-chlorolisso-

climide (146), a potently cytotoxic labdane diterpenoid (Scheme 28).77 The C−H bromination and chlorination strategies have also been adapted to allow for aliphatic C−H xanthylation through the use of blue LEDs and the easily prepared Nxanthylamide 147 (Scheme 29).78 Nitrogen-centered amidyl radicals can also be generated through the use of iodine reagents.79−84 An advancement in this area was made by the Muñiz group when a photomediated 5017


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ACS Catalysis Scheme 30. Iodine-Catalyzed Visible Light-Induced C−H Amination

a

10 mol % I2. mCBA = 3-chlorobenzoate.

circumvent the limitations and harsh reaction conditions associated with the Hofmann−Löffler−Freytag reaction include the recent work by Nagib and co-workers (Scheme 31). Here, a

oxidative amination protocol for the straightforward access to saturated nitrogen heterocycles (150) was reported.79 The authors found that employing only a single equivalent of the iodine(III) reagent PhI(mCBA)2 (mCBA = 3-chlorobenzoate) in combination with only 2.5 mol % I2 was sufficient to provide almost quantitative yields of pyrrolidine 150a. It was also noted that a neater reaction outcome was achieved when using a substoichiometric quantity of I2 compared to a superstoichiometric reagent combination consisting of I2/PhI(OAc)2. The reaction dependence on the light source was also investigated, and it could be concluded that an external light bulb was not required and that ambient irradiation was sufficient to drive the reaction. The operationally simple iodine-catalyzed oxidative amination protocol displayed a broad scope and tolerated a variety of functional groups (Scheme 30). The mechanism for the iodine-catalyzed method was proposed to proceed through two intertwined synergistic catalytic cycles. The reaction unites a visible light-mediated radical chain process, involving iodine atom transfer from intermediate 151 to carbon-centered radical 153, with a reaction manifold that proceeds within a iodine(I/ III) redox shuttle. The radical chain propagation was confirmed experimentally, giving a quantum yield of 44. This process also accommodates the rate-limiting step of the reaction, the intramolecular hydrogen abstraction in intermediate 152, which was determined to have a primary kinetic isotope effect of 4.0 through isotopic-labeling experiments. Upon chain termination, reinitiation is accomplished by photolytic homolysis of 151 (Scheme 30). The Muñiz laboratory subsequently applied the iodine catalysis protocol in intramolecular C−H amination of arenes80 and also disclosed a modified system relying on Niodosuccinimide as the promoter.81 Recent advances include the development of a dual light-activated system through the use of I2 and photoredox catalysis,85 as well as a protocol for selective piperidine formation.86 Additional synthetic strategies to

Scheme 31. Triiodide-Mediated C−H Amination

broad range of functionalized pyrrolidines was synthesized using a triiodide (I3−)-mediated strategy. Replacing the commonly employed electron-transfer mediator I2 with I3−, produced in situ from NaI and PhI(OAc)2, dramatically reduced the typically observed byproducts and allowed for C−H amination of a variety of structurally relevant scaffolds.83 Although the classical Hofmann−Löffler−Freytag reaction is restricted to strongly acidic media under refluxing conditions, the ongoing advances in catalytic, selective halide-mediated remote C−H amination 5018


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ACS Catalysis

Matsuura (Ludwig-Maximilians-Universität, Munich) for helpful discussions and feedback on this manuscript.

through 1,5-HAT highlight the potential of halide catalysis as a conceptual alternative for streamlining complex molecule synthesis.

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6. CONCLUSIONS AND OUTLOOK Free radicals are ubiquitous intermediates in biological systems and are involved in an array of enzymatic reactions. The perception that radical reactions are nonselective has often discouraged researchers from using radical intermediates in synthetic organic chemistry. However, this belief has gradually changed, and radical-based routes are now routinely being considered in contemporary organic syntheses as the advantages of radical chemistry have become more apparent. This is mainly due to the availability of cheap and convenient LED devices and the resurfacing of visible light photocatalysis. The recognition that low-energy visible light can be used to mediate a broad array of photocatalytic reactions has emerged as a vivid area of research and has enabled creative new activation modes for nontraditional bond constructions. From a historical perspective, the quintessential strategy for generating nitrogen-centered radicals revolved around the homolysis of nitrogen−halogen bonds, typically in refluxing acidic media. Although these harsh reaction conditions limit the applicability and functional group compatibility, these methods have allowed a number of prominent syntheses.87,88 In the past decade or so, the development of visible light-mediated photocatalytic technologies have provided new catalytic activation modes for the mild and selective generation of nitrogen-centered radicals. Significant progress in this field has been achieved, and imaginative protocols for the efficient generation of amidyl, hydrazonyl, and imidyl radicals from a wide range of different precursors have been reported. These radicals have been documented to promote various conceptually challenging synthetic transformations, including radical amination and remote carbon−hydrogen bond functionalization, thereby enabling novel and elaborate reaction manifolds to be realized for the construction of diversely functionalized nitrogen-containing scaffolds. Furthermore, protocols for selectively activating unactivated nitrogen−hydrogen bonds in amide adducts have also been developed. These visible light-mediated photocatalytic methods represent valuable additions to the chemical toolbox and serve as indispensable resources for exploring new reactivity concepts and chemical endeavors. Despite the advances, a collection of challenges still remains, including the development of asymmetric procedures, the use of more atom-economical amidyl radical precursors, and the utilization of more sustainable photocatalysts. Given the wide variety of reaction manifolds that can be accessed through visible light photocatalysis, a rapid expansion in design principles and innovative solutions are likely to be seen in the near future.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Markus D. Kärkäs: 0000-0002-6089-5454 Notes

The author declares no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the Swedish Research Council (6372013-7314) is gratefully acknowledged. I thank Dr. Bryan S. 5019


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Photochemical Generation of Nitrogen-Centered Amidyl, Hydrazonyl

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