Radical C(sp3)–H functionalization and cross-coupling reactions

Abstract

C─H functionalization reactions are playing an increasing role in the preparation and modification of complex organic molecules, including pharmaceuticals, agrochemicals, and polymer precursors. Radical C─H functionalization reactions, initiated by hydrogen-atom transfer (HAT) and proceeding via open-shell radical intermediates, have been expanding rapidly in recent years. These methods introduce strategic opportunities to functionalize C(sp³)─H bonds. Examples include synthetically useful advances in radical-chain reactivity and biomimetic radical-rebound reactions. A growing number of reactions, however, proceed via "radical relay" whereby HAT generates a diffusible radical that is functionalized by a separate reagent or catalyst. The latter methods provide the basis for versatile C─H cross-coupling methods with diverse partners. In the present review, highlights of recent radical-chain and radical-rebound methods provide context for a survey of emerging radical-relay methods, which greatly expand the scope and utility of intermolecular C(sp³)─H functionalization and cross coupling.

Graphical Abstract

Radical reaction pathways have evolved sufficiently that C(sp³)─H bonds may now be viewed as strategic "reagents" for bond formation in synthetic organic chemistry. This Review highlights the diverse approaches for C(sp³)–H functionalization and cross-coupling reactions, emphasizing radical-relay reactions.

Introduction

Efficient synthesis of organic molecules is crucial to drug discovery and development, materials synthesis, and many other domains. C─H functionalization methods provide a means to streamline synthetic routes by avoiding substrate preactivation, accessing target molecules in fewer steps, and providing efficient strategies to diversify existing chemical structures, including modification of their physicochemical properties and three-dimensional structures. Multiple mechanistic pathways are available for C(sp³)─H functionalization, including those initiated by organometallic C─H activation^1-4; atom-transfer methods^5-7, such as carbene and nitrene C─H insertion; and those initiated by hydrogen-atom transfer (HAT) to generate radical intermediates^4,8-10. The synthetic utility of radical C─H functionalization reactions was historically viewed with skepticism¹¹, owing to the challenges in controlling reaction selectivity; however, recent advances have changed this perception. Radical pathways are featured in a growing number of synthetically useful methods that enable site-selective functionalization of C(sp³)─H bonds. C─H functionalization reactions that feature a one-for-one replacement of a hydrogen atom with another functional group, such as a halogen, pseudohalogen, or oxygen atom, have been complemented by C─H cross-coupling reactions that permit efficient access to dozens, if not hundreds, of derivatives via reaction of the C─H substrate with broad classes of reaction partners, such as aryl halides, boronic acids, alcohols, and amine derivatives. The latter reactions represent an important class of reactions for pharmaceutical and agrochemical discovery efforts due to their ability to enable rapid elaboration of simple building blocks, core structures of moderate complexity, and late-stage structures and bioactive compounds.

Multiple mechanisms are available for radical C─H functionalization reactions. Radical-chain mechanisms (FIG. 1Aa) are involved in a number of large-scale industrial processes, including chlorination of methane and autoxidation of hydrocarbons, such as cyclohexane and cumene^12,13. These reactions feature three general steps: initiation, propagation, and termination. The initiation step generates new radical species, typically by thermal or photochemical cleavage of a weak bond in dihalogens (e.g., Cl₂ and Br₂), peroxides, or specialized reagents, such as such as AIBN (2,2'-azobis(2-methylpropionitrile). Propagation steps account for net transformation of the starting material into the reaction product(s). These steps regenerate the radical carrier without net consumption of radical species. The chain process ends in termination steps that consume radicals, such as the direct coupling of two radicals. Recent advances have highlighted the utility of radical-chain reactions for selective functionalization of more complex molecules, benefiting from the development of new reagents that lead to improved site selectivity in the HAT propagation step^14-17.

Fig. 1 ∣. Mechanisms and components of radical-chain, radical-rebound, and radical-relay reactions.

Aa ∣ General mechanism of radical-chain reaction. Ab ∣ Representative initiators/reagents for radical-chain reactions. Ba ∣ General catalytic cycle of radical-rebound reactions. Bb ∣ Representative iron and manganese catalysts for radical-rebound reactions. Ca ∣ General mechanism of radical-relay reactions involving radical trapping reagents. Cb ∣ General mechanism of catalytic radical-relay reactions. Cc ∣ Representative oxidants and HAT reagents for radical-relay reactions. Cd ∣ Representative radical trapping reagents. Ce ∣ Representative catalytic radical-relay coupling partners. [O] = O₂/2e⁻, H₂O₂, or other O-atom transfer reagent. NFSI, N-fluorobenzenesulfonimide; Selectfluor I (R = CH₂Cl), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate); Selectfluor II (R = CH₃), 1-fluoro-4-methyl-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate); TMP, 5,10,15,20-tetramesitylporphyrin; TPFPP, 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin; PDP, N,N′-bis(2-pyridylmethyl)-2,2′-bipyrrolidine; HAT, hydrogen atom transfer; ET, electron transfer; TBPB, tert-butyl peroxybenzoate; DTBP, di-tert-butyl peroxide; NHPI, N-hydroxyphthalimide; B₂cat₂, bis(catecholato)diboron.

The radical-rebound mechanism (FIG. 1Ba) is closely associated with iron-containing heme enzymes such as cytochrome P450 (CYP) and related non-heme iron enzymes in biology¹⁸. This collection of biological and synthetic reactions involves high-valent metal-oxo species generated via reaction of a reduced metal complex with oxygen-atom donors, including O₂, H₂O₂, alkyl or acyl hydroperoxides, and PhI=O. HAT from a C(sp³)─H bond to the reactive metal-oxo is followed by rapid recombination (i.e., rebound) of the resulting carbon-centered radical with the incipient metal-hydroxide to afford the oxygenated product. Variations of this reaction pathway can lead to other products if the organic radical recombines with a different ligand within the metal coordination sphere. For example, C─H halogenation products can arise from HAT by a metal oxo, followed by reaction of the organic radical with a halide ligand rather than the hydroxide ligand. Analogous C─H amination reactivity is possible with metal-nitrene intermediates derived from the reaction of a reduced metal complex with nitrogen-atom donors, including organic azides¹⁹ and PhI=NR reagents²⁰. Recent advances include the discovery of new catalysts that promote radical-rebound reactions with complex molecules.

Radical-relay reactions (FIG. 1C) complement radical-chain and radical-rebound reactions and significantly expand the scope of accessible synthetic transformations. An HAT step generates a diffusible organic radical, which is then functionalized by a second reagent or catalyst. In some cases, the radical undergoes direct coupling with a substrate partner or radical trapping reagent (FIG. 1Ca). In other cases, the radical undergoes metal-catalyzed coupling, reacting by one of several possible mechanisms (FIG. 1Cb). It can undergo radical-polar crossover, in which electron-transfer (ET) generates a carbocation that reacts readily with diverse nucleophiles. Alternatively, the carbon-centered radical can react by one of two possible pathways with a transition-metal catalyst containing Ni^II, Cu^II, or another metal ion: (a) direct addition of the radical to a coordinated ligand on the transition-metal complex, or (b) radical addition to the metal center and subsequent reductive elimination with the coordinated coupling partner. Each of these pathways support C─H cross-coupling reactions that generate new carbon-carbon and carbon-heteroatom bonds via reaction with diverse reaction partners. Recent advances have introduced new methods to access HAT reagents from chemical oxidants and photoactive reagents, in addition to new catalyst systems that support diverse product formation.

The intermolecular C(sp³)─H functionalization and cross-coupling methods represented by these reaction classes provide valuable strategies to diversify organic molecules ranging from simple building blocks to complex molecules^21-23. Intramolecular reactions, such as Hoffmann-Loeffler-Freitag and related reactions^24-26, feature closely related mechanisms but are outside the synthetic scope of this review. The content herein begins with a survey of new radical-chain and radical-rebound reactions, followed by a presentation of radical-relay reactions that use C─H bonds as latent nucleophiles in carbon─carbon and carbon–heteroatom bond-forming reactions. Cross-coupling methods include those that feature direct C─H cross coupling, in addition to those that proceed via stepwise C─H functionalization/diversification sequences. Mechanistic features of these reactions are presented, emphasizing those with implications for the synthetic scope of the reactions.

Radical-chain and radical-rebound reactions

Radical chain.

Conventional radical-chain reactions involving Cl₂ and Br₂ often lack the selectivity required to support synthetically useful, site-selective C─H functionalization of complex molecules. Over the past decade, however, a number of N─X (X = F, Cl) reagents have been shown to promote radical-chain C─H fluorination and chlorination with improved yields and selectivity (FIG. 2Aa). N-Fluorobenzenesulfonimide (NSFI) and Selectfluor reagents are featured in a number of C(sp³)─H fluorination methods, and they have been paired with various initiators, including azobisisobutyronitrile (AIBN)²⁷, BEt₃/O₂²⁸, and copper(I)²⁹ (FIG. 2Ab, condition 1). Reactions using Fe(acac)₂/Selectfluor³⁰ (acac = acetylacetonate) and CuOAc/NFSI³¹ support selective fluorination of benzylic C─H bonds and the reactivity is consistent with a radical-chain pathway. A multicomponent Cu(bis-imine)/Selectfluor/N-hydroxyphthalimide (NHPI) catalyst system with KB(C₆F₅)₄ as an anionic phase-transfer catalyst supports fluorination of stronger aliphatic C─H bonds³². N─F reagents have also been paired with photocatalysts, including diarylketone³³ and tetrabutylammonium decatungstate (TBADT)^27,34. These reagents are capable of promoting HAT from C─H substrates (FIG. 2Ab, condition 2 and 3), and the resulting carbon-centered radicals can react with fluorinating reagents to afford the desired C─F bonds. It is possible that HAT could proceed via both radical-chain and photocatalyst-promoted steps in these reactions. Fluorination of benzylic C(sp³)─H bonds has been achieved using 1,2,4,5-tetracyanobenzene, although this photocatalyst is proposed to initiate an electron transfer pathway³⁵. Collectively, these methods provide effective routes to monofluorinated benzylic and aliphatic C(sp³)─H products. The reactions show good selectivity for benzylic C─H bonds in the photocatalyzed (e.g., diaryl ketone, TBADT) and metal-initiated radical chains. Difluorination can be achieved under more forcing condition and by employing additional Selectfluor and diaryl ketone as photocatalyst³³.

Fig. 2 ∣. Late-stage C(sp³)─H functionalization reactions via radical chain and radical rebound.

Aa ∣ General mechanism for radical-chain reaction with a N─X reagent. Ab ∣ Fluorination reactions of C(sp³)─H bonds. Ac ∣ Site-selective aliphatic C─H halogenation and xanthylation reactions with N─X reagents. Ad ∣ Benzylic C(sp³)─H hydroxylation reaction. B ∣ Iron-catalyzed C─H oxidation reaction. Ca ∣ Manganese-non-heme catalyzed chiral desymmetrization of cyclohexane. Cb ∣ Manganese-catalyzed benzylic amination reaction. Cc∣ Manganese-porphyrin or -salen catalyzed C─H functionalization reactions. HFIP, hexafluoroisopropanol; PDP, N,N′-bis(2-pyridylmethyl)-2,2′-bipyrrolidine; ^TIPSmcp, N,N′-dimethyl N,N′-bis(2-(5-triisopropylsilylpyridyl)methyl)-1,2-trans-diaminocyclohexane; Pc, phthalocyanine; TMP, 5,10,15,20-tetramesitylporphyrin; TMS, trimethylsilyl.

Complementary reagents have been developed to support selective radical-chain chlorination. A sterically encumbered N-chloroamide reagent supports chlorination of aliphatic C(sp³)─H substrates under visible-light irradiation, taking advantage of difference in electronics and sterics of various C─H bonds to achieve improved selectivity relative to conventional chlorination methods (FIG. 2Ac, X = Cl)¹⁴. Steric modulation of aryl ring of the N-chloroamide reagent, by shifting two trifluoromethyl groups from meta to ortho positions with respect to the carbonyl group, alters regioselectivity in the chlorination of aliphatic C─H bonds³⁶. A sterically hindered, 2,2,6,6-tetramethylpiperidinium N─Cl reagent (cf. FIG. 1Ab) is an effective chlorinating reagent and chain carrier for photoinitiated C─H chlorination³⁷. The electrophilicity and steric hindrance of the aminium radical confers excellent selectivity in reactions with less sterically hindered methylene C─H sites and with weaker tertiary C(sp³)─H bonds. Radical-chain chlorination of primary or secondary benzylic C─H bonds with N-chlorosuccinimide (NCS) has been initiated by reductive activation of NCS with an acridinium-based photocatalyst to generate a nitrogen-centered radical³⁸. In addition to N–Cl reagents, tert-butyl hypochlorite (tBuOCl) has been used with a phenanthroline (phen)-ligated silver catalyst to chlorinate C(sp³)─H bonds³⁹. The reaction has been proposed to proceed via silver-mediated C─Cl bond formation; however, a radical-chain pathway could also account for the observed reactivity. In the latter pathway, a carbon-centered radical generated by HAT could react via chain propagation with tBuOCl.

Radical-chain reactions have been developed for selective conversion of C(sp³)─H bonds into C─Br, C─S, and C─O bonds. Variants of the N-chloroamide reagent in FIG 2Ac in which N─Cl is replaced with N─Br or N─xanthyl (xanthyl = −S(C=S)OEt) supports C─H bromination¹⁵ and xanthylation¹⁶, respectively. Xanthylated products are versatile intermediates in two-step C─H functionalization/diversification reactions in which the xanthyl group may be displaced in a second step by other groups, including allyl, vinyl, CF₃, D, NR₂, N₃, OH, and SR (FIG. 2Ac)^16,40. Bis(methanesulfonyl) peroxide supports radical-chain C─H oxygenation of benzylic C(sp³)─H bonds in the presence of a copper(I) initiator, and the resulting benzyl mesylates undergo facile displacement by water in the presence of hexafluoroisopropanol (HFIP) to afford benzyl alcohols (FIG. 2Ad).¹⁷

Collectively, these synthetic methods and reagents highlight the emergence of numerous synthetically useful radical-chain reactions. Sterically and electronically tailored N─X and O─X reagents (X = heteroatom substituent) have begun to overcome historical limitations of radical-chain reactions involving simple Cl₂, Br₂, and related reagents. Moreover, recent applications of radical-chain reactivity have demonstrated the ability to employ C─H substrates as the limiting reagent and exhibit good site selectivity and compatibility with functional groups that are sensitive to polar reagents.

Radical rebound.

Radical-rebound C(sp³)─H functionalization takes inspiration from heme and non-heme iron oxygenase enzymes^18,41. Early studies of model complexes for non-heme iron enzymes investigated reactions with hydrogen peroxide as the oxidant and provided clear evidence for generation of high-valent iron-oxo species^42-46. For example, stereospecificity observed in the hydroxylation of alkanes supports rapid rebound of the organic radical with an intermediate Fe─OH species generated via HAT (cf. FIG 1Ba)^46-47,48. These and related studies established a foundation for more recent synthetic applications of this reactivity using similar catalyst systems. Nitrogen-ligated iron catalysts have been developed for stereo- and site-selective oxidation of aliphatic C─H bonds in molecules containing multiple secondary and tertiary C─H bonds⁴⁹. The C─H substrate is used as the limiting reagent in these reactions, distinguishing these reactions from the earlier studies, which used excess hydrocarbon substrate with limiting oxidant. Electronic, steric, and stereoelectronic factors contribute to site selectivity,⁵⁰ with reactivity favored at electron-rich and less hindered sites, in addition to sites that relieve strain in the HAT step^51,52. These catalyst systems have been implemented for hydroxylation of structurally complex molecules^49,52-54, and modification of the ligand structure allows for enhanced and/or altered site-selectivity (FIG. 2B). Manganese catalysts analogous to the Fe-based catalyst systems have also been employed in synthetically important radical-rebound oxygenation reactions^55-57. Enantioselective oxidation of methylene C─H bonds has been achieved by using a chiral tetradentate nitrogen ligand to support enantioselective HAT (FIG. 2Ca)⁵⁸. Carboxylic acid additives contribute significantly to the reaction outcome by promoting O─O bond cleavage of the hydroperoxide intermediate to afford the reactive metal-oxo species and by replacing a metal-bound hydroxide with a carboxylate ligand that influences both site-selectivity and enantioselectivity in C─H oxidation reactions^{49,51-54,58-61}.

Various manganese-based catalysts show that the radical-rebound pathway can provide the basis for aliphatic C(sp³)─H functionalization beyond oxygenation (FIG. 2Cb). Mn-porphyrin and Mn-salen complexes support chemoselective halogenation (fluorination, chlorination)^62-65 and pseudohalogenation, with azide⁶⁶and isocyanate⁶⁷ sources. Most of these reactions employ iodosylbenzene (PhIO) as the oxidant. The radical-rebound mechanism is not limited to oxygen-centered HAT species. A Mn-phthalocyanine catalyst supports sulfonamidation of benzylic C(sp³)─H bonds using a trichloroethoxysulfonamide-derived hypervalent iodine reagent (PhI=NTces)²⁰ (FIG 2Cb). The reaction is highly selective for benzylic sites in the presence of other aliphatic C─H bonds and exhibits good functional group tolerance. These efforts showcase synthetically useful applications of the radical-rebound mechanism to achieve site-selective carbon-heteroatom bond forming reactions.

Radical-relay reactions involving direct coupling with a substrate partner or radical trapping reagent

The development of radical-relay reactions in recent years has significantly expanded the scope of C(sp³)─H functionalization. The term "radical relay" is used here to describe non-chain radical C─H functionalization reactions in which the HAT species does not incorporate the group or reagent that undergoes coupling with the intermediate organic radical (cf. FIG. 1). The first class of radical-relay reactions, summarized in this section, feature direct addition of an organic radical to a trapping reagent or coupling partner. The HAT species used to generate the organic radical may be generated one of several different pathways, including redox processes that lead to generation an oxyl radical (e.g., via oxidation of an O─H bond or reductive cleavage of an N─O bond); photochemical excitation of decatungstate anion or aryl ketones; photon-induced ligand-to-metal charge transfer of a transitional metal reagent, resulting in homolytic cleavage of a M─OR or M─Cl bond; reductive activation of N─F reagents, such as NFSI or Selectfluor reagents; among others.

Radical-relay C─H oxygenation reactions may be achieved by combining an HAT reagent with O₂ or another oxygen-atom source as the radical trap^4,68,69. These methods often exhibit improved selectivity relative to conventional autoxidation methods. A prominent example of this concept features the use of N-hydroxyphthalimide (NHPI), which generates the HAT species phthalimido-N-oxyl (PINO) in the presence of O₂ and a cobalt catalyst (FIG. 3Aa)^70,71. PINO-mediate HAT from weak C(sp³)─H bonds generates a carbon-centered radical that reacts rapidly with O₂, ultimately affording ketones, carboxylic acids, or other oxygenation products. This reactivity was initially demonstrated with simple hydrocarbons⁷⁰, but it has recently been applied to oxygenation of heterobenzylic C─H bonds in pharmaceutically relevant building blocks⁷¹. The scope of alkylated heterocycles was extended by the development of an iron, rather than cobalt, cocatalyst⁷². The oxygenation of methylarenes under Co/NHPI/O₂ conditions typically generates benzoic acid derivatives; however, the use of an HFIP solvent system enables selective formation of benzyaldehydes. Hydrogen bonding from HFIP is proposed to polarize the carbonyl group of the aldehyde to prevent further oxidation to benzoic acid⁷³. Decatungstate (DT) photocatalysts serve as an effective HAT reagent upon near-ultraviolet irradiation, and they support reactivity at C(sp³)─H bonds stronger that those typically reactive with PINO. The excited-state DT species is an electrophilic HAT reagent, and protonated amines undergo reaction at C─H bonds remote from the electron-withdrawing ammonium group, forming ketones in the presence of H₂O₂ (FIG. 3Ab)⁷⁴. TBADT has been used as an HAT photocatalyst to support oxygenation of (hetero)benzylic and aliphatic C─H bonds in the presence of O₂ under batch⁷⁵ and continuous flow⁷⁶ conditions.

Fig. 3 ∣. Radical relay involving radical addition to trapping reagents.

Aa ∣ Oxygenation with Co/NHPI cocatalysts. Ab ∣ Oxygenation with decatungstate photocatalysts. Ba/b ∣ PINOylation methods. Ca ∣ Azidation/cyanation via radical trapping with sulfonyl–X reagents (X = N₃, CN). Cb ∣ Thiol coupling via radical trapping with sulfonylthiolates. Da ∣ Amination of heterobenzylic C(sp³)─H bonds with DEAD. Db ∣ Amination initiated by LMCT with Ce^IV reagents. Ea ∣ Giese-type alkylation with decatungstate photocatalysts. Eb ∣ Polarity reversal HAT/Giese-type alkylation. Fa ∣ Minisci reaction with decatungstate photocatalyst. Fb ∣ Photochemical Minisci-type pyridylation. G ∣ Photochemical borylation. NHPI, N-hydroxyphthalimide; DEAD, diethyl azodicarboxylate; LMCT, ligand-to-metal charge transfer; TFA, trifluoroacetic acid; (TRIPS)₂, bis(2,4,6-triisopropylphenyl) disulfide; PFBI–OH, hydroxyl perfluorobenziodoxole; HFIP, hexafluoroisopropanol; B₂cat₂, bis(catecholato)diboron; ClB(cat), B-chlorocatecholborane; DT, decatungstate.

PINO is a meta-stable radical, and, in addition to serve as an HAT reagent, it can trap carbon-centered radicals to afford PINOylated products (FIG. 3B). This reactivity has been achieved by combining catalytic copper(I) chloride, (diacetoxyiodo)benzene (PhI(OAc)₂), and NHPI with the C─H substrate (FIG. 3Ba)⁷⁷. Similar reactivity has been achieved with a reaction system comprising catalytic copper(II) acetate, Selectfluor, and NHPI (FIG. 3Bb)⁷⁸. The mechanism of these reactions is not well understood, but reactive HAT species could be generated by oxidation of NHPI or reductive activation of the stoichiometric oxidant, and the Cu catalyst could contribute to each of these processes. Ultimately, the PINOylation product may be formed by coupling of the carbon-centered radical derived from HAT with PINO.

Sulfonyl–X reagents (X = N₃, CN, SR, SCF₃, SePh, Cl, CH=CHSO₂Ph, and C≡Ar) react with carbon-centered radicals to afford C─X bonds, and they are employed in a number of radical-relay C(sp³)─H functionalization reactions. Various methods may be used to generate the radical via HAT from an C(sp³)─H bond. Azidation of aliphatic C─H bonds can proceed under metal-free conditions, using potassium persulfate as the HAT precursor with an arylsulfonyl azide trapping reagent (FIG. 3Ca)⁷⁹. Photoexcited decatungstate has been used to promote HAT in the presence of tosyl cyanide to support C─H cyanation (FIG. 3Ca, bottom)⁸⁰. DT-mediated HAT has also been used other radical traps, including sulfur dioxide⁸¹, (trifluoromethylthio)phthalimide⁸², and other sulfonyl–X reagents (e.g., methanesulfonyl alkynes⁸³) to achieve C─H functionalization. Reductive activation of the N─F reagent N-(tert-butyl)-N-fluoro-3,5-bis(trifluoromethyl)benzene-sulfonamide by copper(I) has been used to generate a nitrogen-centered radical capable of promoting HAT in the presence of PhSO₂–X reagents (X = SCF₃, SePh, C≡CPh, CN, N₃, Cl, CH=CHSO₂Ph). This reactivity was most extensively demonstrated for thiolation of C(sp³)─H bonds (FIG. 3Cb)⁸⁴. This chemistry is closely related to Cu/NFSI-based C─H functionalization methods elaborated below, with the distinction that the carbon-centered radical intermediate directly adds to the sulfonyl–X reagent rather than undergoing Cu-catalyzed functionalization (see FIG. 1Ca/b and content below for additional context).

Dialkyl azodicarboxylate reagents react as radical traps to support amination of C(sp³)─H bonds. A copper(II)/organic HAT catalyst system using diethyl azodicarboxylate (DEAD) has been used to achieve site selective amination of heterobenzylic C(sp³)─H bonds (FIG. 3Da)⁸⁵. Copper(II) acts as a Lewis acid catalyst to enhance the reactivity of heterobenzylic positions, leading to high selectivity in presence of weaker benzylic C─H bonds. Photoinduced ligand-to-metal charge transfer (LMCT) in cerium(IV)–X reagents has been use to generate reactive heteroatom-based radicals that promote HAT from C(sp³)─H bonds. The initial reports proposed formation of an oxygen-centered radical via LMCT within a cerium(IV)-alkoxide complex^86,87; however, a subsequent study implicated the formation of chlorine radical via LMCT involving a Ce^IV─Cl fragment⁸⁸. In both proposed mechanisms, the heteratom radical promotes HAT, and the resulting carbon-centered radical adds to the dialkyl azodicarboxylate reagent to form a C─N bond. This steps leads to formation of an adjacent nitrogen-centered radical that is proposed to be reduced by cerium(III) and undergo protonation to afford the final product (FIG. 3Db)⁸⁷. The N─N bond is subjected to hydrogenolysis over Raney Ni to afford the primary amine derivative. DT photocatalysis has also been used to support HAT from C─H bonds in the presence of dialkyl azodicarboxylate to afford the C─N coupling products^89,90. A photoreactor with high intensity LED light has been used to achieve this reactivity under flow conditions⁹¹.

Electron-deficient alkenes can serve as radical traps that provide the basis for C(sp³)─H alkylation. The addition to carbon-centered radicals to alkenes ("Giese reactions"^92-94) generates a new carbon-centered radical that can react with a hydrogen-atom donor (e.g., a thiol or other reagnet) or undergo one-electron reduction and protonation to afford the alkylate product. Light-promoted LMCT from copper(II)⁹⁵, cerium(IV)^86,87, and iron(III)⁹⁶ reagents and DT photocatalysts^97-100 have been used to generate reactive species that support HAT from the C─H substrate. A DT-catalyzed Giese-type radical addition reaction was implemented in continuous flow to forge new C(sp³)─C(sp³) bonds between light alkanes, including methane, ethane, propane, and isobutane, and electron-deficient alkenes (FIG. 3Ea)¹⁰¹. HAT reagents typically consist of electrophilic radicals that favor reaction at electron-rich C─H bonds (e.g., 3° aliphatic and benzylic C─H bonds); however, polarity-reversed HAT¹⁰² from acidic C─H bonds adjacent to electron-withdrawing groups was enabled by using an amine-borane catalyst under photochemical conditions (FIG. 3Eb)¹⁰³. The organic radical subsequently adds to an unactivated alkene followed by abstracting a hydrogen atom from a thiol-based H-atom donor to afford the C(sp³)─C(sp³) coupling product.

Electron-deficient arenes and heterocycles, such as pyridinium groups, also react readily with nucleophilic radicals ("Minisci reactions"^104,105). This reactivity may be used to support (hetero)arylation of C(sp³)─H bonds by generating carbon-centered radicals via HAT. Representative HAT reagents that have been used in Minisci-type coupling reactions include oxygen-and nitrogen-centered radicals derived from peroxides/alcohols and amides^106-109, DT photocatalysts^110-113, azide radical¹¹⁴, and hypervalent iodine¹¹⁴. For example, a ruthenium photoredox catalyst can undergo SET with hydroxyl perfluorobenziodoxole (PFBI–OH) to generate an oxygen-centered radical¹¹⁴. HAT generates a carbon-centered radical that adds to a protonated N-heteroarene, and subsequent loss of an electron and proton from the adduct affords the Minisci coupling product (FIG. 3Fa). In another example, anthraquinone proved superior to TBADT and benzoquinone as a photocatalyst/HAT reagent in the direct coupling of alkanes with N-aminopyridinium salts¹¹⁵. The radical adds to the electron-deficient heterocycle, similar to Minisci reactions, with C4 selectivity (FIG. 3Fb). The reaction employs 5 equiv of alkane, aldehyde, and other coupling partners (e.g., P─H, Si-H substrates).

A primary-selective C─H borylation is initiated by photoinduced electron transfer upon irradiating N-(trifluoroethoxy)phthalimide in the presence of bis(catecholato)diboron (B₂cat₂), 10 equiv of the C─H substrate, and 20 mol% B-chlorocatecholborane [ClB(cat)] (FIG. 3G)¹¹⁶. Mesolytic cleavage of the N─O bond affords a trifluoroethoxy radical that is proposed to react with ClB(cat) to generate the reactive HAT species. The lack of a photoredox catalyst supports radical, rather than radical-polar crossover, reactivity. Carbon-boron bond formation arises from reaction of the intermediate organic radical with B₂cat₂. High primary C─H selectivity, even in the presence of weaker secondary tertiary C─H bonds, is rationalized by the involvement of a chlorine radical–boron ‘ate’ complex that selectively cleaves sterically unhindered C─H bonds.

Kharasch-Sosnovsky reactions: Early examples of catalytic radical relay

The Kharasch-Sosnovsky (K-S) allylic oxidation reaction, first reported in 1958, represents a seminal precedent for catalytic radical-relay reactivity (FIG. 1Cb)^117,118. The original transformation used copper(I) bromide and tert-butyl peroxybenzoate (TBPB) to achieve allylic oxidation of cyclohexene, 1-hexene, and 1-octene, affording the allylic benzoate derivatives (FIG. 4a). The proposed mechanism involves Cu^I-mediated activation of the peroxide, allylic HAT by tBuO• and coupling of the allylic radical with Cu^II-benzoate (FIG. 4b)¹¹⁹. Asymmetric C─O coupling, which was initially achieved by using a catalytic amount of L-proline as a chiral ligand (40% yield, 30% ee)¹²⁰, implicates inner-sphere coupling of the C─O bond via radical addition to Cu^II and C─O reductive elimination (FIG. 4c). Improved enantioselectivity was achieved by using chiral bis- or trisoxazoline ligands (FIG. 4e)^121_124. Most K-S reactions use excess C─H substrate relative to the peroxide reagent. Low temperatures (e.g., −20 °C) are needed to enhance enantioselectivity, but these conditions often result in multiple-day reaction times. K-S oxidation methods have been used in synthetic chemistry, for example, to access triterpene natural products (FIG. 4d)^125,126. These reactions and later oxidation of the sesquiterpene valencene^127,128 are among the few examples of K-S reactions that use the C─H substrate as the limiting reagent (FIG. 4j). Adaptation of K-S-type reactivity has led to oxidation of aliphatic C─H bonds. For example, di-tert-butyl peroxide (DTBP) has been used as an oxidant in combination with nitrogen-ligated Cu complexes to achieve tert-butyletherification of cyclohexane¹²⁹ and dehydrogenative coupling of carboxylic acids with cyclohexane¹³⁰. These reactions use a large excess of the C─H substrate (≥ 10 equiv).

Fig. 4 ∣. Timeline of representative Kharasch-Sosnovsky (K-S)-type reactions.

a ∣ Original Kharasch-Sosnovsky reaction. b ∣ Kharasch-Sosnovsky reaction mechanism. c ∣ First asymmetric allylic oxidation. d ∣ Synthesis of triterpenes. e ∣ Examples of asymmetric allylic oxidation. f ∣ Cross-coupling reaction of benzylic C─H bonds and 1,3-dicarbonyl compounds. g ∣ An alternative HAT reagent. h ∣ C─N bond formation reaction. i ∣ Mechanistic insights for C─N bond formation. j ∣ Allylic oxidation with limiting C─H substrate. k ∣ Cross coupling of benzylic C─H bonds and arylboronic esters. l ∣ Cross coupling of C(sp³)─H and C(sp²)─H bonds. TBS, tert-butyldimethylsilyl; BPhen, bathophenanthroline; N~N, β-diketiminate ligand: 2,4-bis-(2,6-dichlorophenylimino)pentyl; Ad, 1-adamantyl; Phen, phenanthroline; phd, 1,10-phenanthroline-5,6-dione.

K-S-type reactions may be used to achieve C─N bond formation, for example, with amide, sulfonamide, and imide coupling partners (FIG. 4g-i)^118,131-136. The reactions commonly use tert-butyl acylperoxides (i.e., derivatives of TBPB) or DTBP as the oxidant. For example, TBPB derivatives with electron-withdrawing groups on the benzoyl group (3-Cl, 3-CF₃) achieve C─N coupling between primary and secondary sulfonamides and simple methylarenes (25 equiv relative to the nitrogen nucleophile) (FIG. 4h)¹³³. A well-defined diketiminate-ligated Cu complex was used in combination with DTBP to support amination of a small number of aliphatic C─H substrates (indane, ethylbenzene, cyclohexane) with 1-adamantylamine and other aliphatic amines (FIG. 4g)¹³⁴. The amine ligand undergoes exchange with a [Cu]─O^tBu intermediate to form a copper(II)-amido complex, and mechanistic studies indicate that this species can promote direct HAT from the C─H substrate. This reactivity differs from most K-S-type reactions, which feature HAT by an alkoxyl radical. Amination of cyclic and acyclic aliphatic C─H bonds proceeds with various amides, sulfonamides, and phthalimide using a 4,7-dimethoxyphenantronline/CuI catalyst with DTBP as the oxidant (FIG. 4i)¹³⁵. A variant of the conventional K-S mechanism was proposed, in which a Cu^I-amidate activates the peroxide to generate the tBuO•, which promotes HAT from the C─H substrate¹³⁵. The resulting alkyl radical reacts with a Cu^II-amidate species to afford the C─N bond. A photochemical copper(II)-catalyzed method initiates O─O bond homolysis of DTBP at room temperature, supporting C─N coupling of alkanes with various nitrogen nucleophiles under mild conditions¹³⁶. As with the other K-S-type reactions involving aliphatic substrates, a large excess of the C─H substrate (≥ 10 equiv) is used in these reactions.

K-S reactivity may be used to support C─C coupling reactions with various carbon nucleophiles, including 1,3-dicarbonyl compounds, arylboronic esters, and fluorinated arenes. In the reaction of benzylic C─H substrates with TBPB as the oxidant, C─C coupling with 1,3-dicarbonyl compounds proceeds via sequential formation of a benzylic benzoate, followed by nucleophilic displacement of the benzoate (FIG. 4f)¹³⁷. Redox-neutral alkyenylation of C─H bonds adjacent to oxygen in THF (and related cyclic ether solvents) exhibits feature reminiscent of K-S reactions, employing terminal alkynes as coupling partners together with tBuOOH and catalytic Cu^ICl under blue LED irradiation¹³⁸. Arylation of benzylic C─H bonds with arylboronic esters proceeds with DTBP as the oxidant (FIG. 4k)¹³⁹. The reaction is proposed to involve transmetalation between the arylboronic ester and a Cu^II–O^tBu intermediate to afford an arylcopper(II) intermediate, which undergoes coupling with a benzylic radical generated by HAT from tBuO•. This reaction affords a variety of diarylmethane and diarylalkane products. β-Diketiminate copper catalysts support direct C─H/C─H coupling of polyfluoroarenes and allylic, benzylic, and aliphatic C─H substrates using DTBP as the oxidant (FIG. 4l)¹⁴⁰. Each of these reactions employs the C(sp³)─H substrate in excess (e.g., 10 equiv) relative to the coupling partner; however, they have synthetic appeal beyond the related C─O and C─N coupling reactions because the more valuable coupling partner (alkyne, arylboronic acid, fluoroarene) is used as the limiting reagent. Thus, inexpensive cyclic ethers and alkylarenes may be used to support alkylation of valuable coupling partners.

Copper/NFSI-catalyzed radical-relay reactions

The need for excess C─H substrate restricts the synthetic utility of K-S and related oxidative coupling reactions; however, this limitation has been overcome by using NFSI, rather than peroxide-based oxidants, in combination with copper catalysts. These methods show very high selectivity for benzylic C(sp³)─H bonds relative to other positions (e.g., 3° C─H bonds), and they are among the most versatile methods for site-selective C─H functionalization and cross-coupling, leading to the formation of new C─X (X = halide, psueudohalide), C─N, C─O, C─S, and C─C bonds (FIG. 5).

Fig. 5 ∣. Summary of Cu/NFSI-catalyzed radical-relay functionalization, functionalization/diversification, and cross-coupling reactions of benzylic C(sp³)─H bonds.

a ∣ Sulfonimidation. b ∣ Enantioselective cyanation. c ∣ Trifluoromethylation. d ∣ Azidation reaction. e ∣ Amination methods with amides and ammonia surrogates. f ∣ Thiocyanation. g ∣ Isocyanation/amine coupling sequence. h ∣ Fluorination/diversification. i ∣ Chlorination/diversification. j ∣ Cross coupling of benzylic C─H bonds and alcohols. k ∣ Cross coupling of benzylic C─H bonds and azoles with N-site selectivity. l ∣ Enantioselective cross coupling of benzylic C─H bonds and arylboronic acids. m ∣ Enantioselective alkynylation. NFSI, N-fluorobenzenesulfonimide; Selectfluor II, 1-fluoro-4-methyl-1,4-diazoniabicylco[2.2.2]octanebis(tetrafluoroborate); 1-Np, 1-naphthalene; TMS, trimethylsilyl; F-TEDA-PF₆, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate); TBACl, tetrabutylammonium chloride; TMSOTf, trimethylsilyl triflate; TFA, trifluoroacetyl-protected amine.

Cu/NFSI-catalyzed C(sp³)─H functionalization and functionalization/diversification methods.

The first Cu/NFSI benzylic C─H functionalization method led to sulfonimidation of benzylic C─H bonds, using NFSI as the HAT reagent and as the coupling partner (FIG. 5a)¹⁴¹. This method, which is compatible with primary and secondary benzylic C─H bonds, highlighted the use of the benzylic C─H substrates as the limiting reagent. The first demonstration of Cu/NFSI reactivity for oxidative coupling of C─H substrates and a separate nucleophilic reaction partner featured cyanation of benzylic C─H bonds with TMSCN (TMS = trimethylsilyl) (FIG. 5b)¹⁴². These reactions employ a chiral bisoxazoline ligand and achieve high enantioselectivity (many with >90% ee), good functional group compatibility, and very high site selectivity for less hindered secondary benzylic C─H bonds. Density functional theory (DFT) calculations suggest enantioselective C─C bond formation arises from reversible radical addition to a chiral Cu^II–CN species followed by selectivity determining reductive elimination (FIG. 6a, inner sphere radical coupling).

Fig. 6 ∣. Catalytic cycle and radical functionalization mechanisms for Cu/NFSI-catalyzed radical-relay reactions.

a ∣ Inner sphere radical coupling via reductive elimination. b ∣ Radical-polar crossover pathway. c ∣ Radical addition to Cu-bound ligand. NFSI, N-fluorobenzenesulfonimide.

Benzylic C─H trifluoromethylation was demonstrated using a copper(I) source, NFSI or Selectfluor II as the oxidant, and (bpy)Zn(CF₃)₂ as the trifluoromethyl nucleophile (FIG. 5c)¹⁴³. NFSI is generally the most effective oxidant for primary benzylic substrates, but Selectfluor II, which generates a more reactive nitrogen-centered radical, exhibits improved reactivity with electron-deficient substrates. Improved outcomes were observed with secondary benzylic substrates when using Zn(OTf)₂ and Zn(OAc)₂ additives, an effect attributed to more efficient transmetalation of the trifluoromethyl anion to copper(II) and higher concentration of Cu^II–CF₃ species.

Cu/NFSI-catalyzed C─H azidation is achieved by using trimethylsilyl azide (TMSN₃) as the nucleophilic coupling partner (FIG. 5d)¹⁴⁴. The reaction exhibits very high site-selectivity for secondary benzylic C─H bonds over tertiary aliphatic and benzylic C─H bonds. This selectivity, which exceeds that observed with other radical azidation methods^{66, 145, 146} is rationalized by the steric and electronic properties of the sulfonimidyl N-centered radical that promotes HAT. Azide is an effective ammonia surrogate, in addition to serving as a precursor to various heterocycles (FIG. 5d). Complementary Cu/NFSI methods have been developed for coupling with other ammonia surrogates, including carbamates¹⁴⁷, sulfonamides, and primary carboxamides (FIG. 5e)¹⁴⁸. These and several other Cu/NFSI-catalyzed oxidative coupling reactions afford racemic products, even when using chiral bisoxazoline ligands similar to those in the cyanation reaction¹⁴⁴. Experimental and computational data indicate the azidation reaction proceeds via a radical-polar crossover mechanism in which the benzylic radical is oxidized to a cation prior to reaction with an azide nucleophile. The different stereochemical outcomes of these reactions is likely correlated with the influence of different nucleophiles as ligands that modulate the redox properties of the Cu^II species, altering the fate of the radical intermediate.

TMSNCS and TMSNCO are additional effective pseudohalide coupling partners, affording benzylic thiocyanate and isocyanate derivatives (FIG. 5f and 5g)^149,150. Inter- and intramolecular competition studies in the thiocyanation reaction indicate that HAT from benzylic C─H bonds favors 3° > 2° > 1° positions, differing from the azidation reaction, which favors 2° sites. These observations suggest the identity of the HAT reagent may not be identical in all reactions. Both thiocyanate and isocyanate product classes represent versatile precursors to other valuable products. The benzylic thiocyanate products may be converted in two- or three-step sequences, without isolation of the intermediates, into other products, including isothiocyanates, thioureas, trifluoromethylthio, difluoromethylthio, 5-S-benzbromarone-linked tetrazole, and disulfide derivatives. This concept was expanded for benzylic isocyanates through the development of a benzylic isocyanation/amine coupling sequence suitable for implementation in a high-throughput format, enabling efficient access to large numbers of benzylic ureas with drug-like physiochemical properties¹⁵⁰.

The C─H functionalization/diversification strategy illustrated for azides, thiocyanates, and isocyanates in FIGS. 5d, 5f, and 5g, is even more versatile with C─H halogenation methods. C─H fluorination was demonstrated by variation of the original Cu/NFSI conditions, which led to C─H sulfonimidation (FIG. 5h)^31,151. The use of a Brønsted base (Li₂CO₃) and MeB(OH)₂ as an in situ reductant for the copper catalyst (i.e., a "redox buffer"; see mechanistic discussion below) account for the switch in selectivity³¹ via initiation of a Cu^I-promoted radical-chain pathway involving NFSI (see Radical Chain section above for further discussion and additional references). From a synthetic perspective, benzyl fluorides are not inert like many other alkyl fluorides but are quite labile. This feature may be exploited to support nucleophilic displacement of the fluoride, promoted by the presence of a hydrogen-bond donor, such as hexafluoroisopropanol (HFIP), or a Lewis acid, such as boron trifluoride diethyl etherate (BF₃•Et₂O)^152-155. The resulting fluorination/substitution sequence enables the replacement of benzylic C─H bonds with a wide range of oxygen-, nitrogen-, and carbon-based groups¹⁵¹. Similar concepts have been demonstrated with a Cu/NFSI-catalyzed chlorination method (FIG. 5i), in which chlorination/substitution access products that can be difficult to access under the acidic conditions required for fluoride substitution¹⁵⁶. For example, reactions of phenols with benzyl fluorides promoted by HFIP leads to C─C bond formation, with phenol reacting at the ortho position, while reactions with benzyl chlorides under basic conditions leads to C─O bond formation, with phenol reacting at the oxygen atom. These two-step functionalization/diversification methods, initiated by fluorination and chlorination, enable net C─H functionalization with oxidatively sensitive nucleophiles that would not be compatible with a one-step oxidative coupling method using NFSI as the oxidant. This reactivity complements an independent Cu-catalyzed chlorination approach using a dichloramine-T as the oxidant that selectively functionalizes C(sp³)─H bonds in ketones, enones, and alkylbenzenes^157,158. This study also demonstrated nucleophilic displacement of secondary benzyl chlorides with N-Bocpiperazine, demonstrating another example functionalization/diversification.

Variants of NFSI have been developed in which one phenylsulfonyl group in NFSI is replaced with a tert-alkyl group and the other phenysulfonyl is replaced an electron-deficient arylsulfonyl (e.g., 4-CF₃- or 3,5-(CF₃)₂-phenyl). These reagents have been used to achieve complementary radical-relay C─H functionalization, including regio- and enantioselective cyanation of allylic C(sp³)─H bonds with TMSCN (with limiting C─H substrate)¹⁵⁹, and thiolation of C─H bonds with S-aryl benzenethiosulfonates (3 equiv C─H substrate) (see FIG. 3Cb)⁸⁴. In the former study, DFT calculations implicate a Cu^II-bound nitrogen-centered radical as the reactive HAT species, and this species was proposed to account for modulation of site selectivity. This proposal aligns with the observations above that the specific HAT species could be modified under different conditions. Selectfluor is a related N─F reagent that generates an amine radical-cation, which is a stronger HAT reagent than the N-centered radical derived from NFSI. In presence of copper catalysts, Selectfluor enables HAT with aliphatic C─H substrates, used in excess (3 equiv to solvent level) relative to the coupling partner¹⁶⁰. Esterification was achieved with various carboxylic acids as coupling partners in presence of pentanenitrile as additive¹⁶⁰. The Ritter-type amidation product derive from pentanenitrile was obtained when triflic acid was attempted as the coupling partner (i.e., in an effort to use triflate as the nucleophile).

Cu/NFSI-catalyzed C(sp³)─H cross coupling.

Cross-coupling methods that combine reagents from diverse pools of substrates are especially important methods in synthetic chemistry, and several examples of C─H cross coupling have been achieved by using Cu/NFSI catalysis. The coupling of benzylic C─H substrates and alcohols enable access to a diverse scope of benzyl ethers (FIG. 5j)¹⁶¹. Medicinally relevant benzylic C─H substrates undergo cross coupled with sterically and electronically diverse aliphatic alcohols. Mechanistic studies indicate that this reactivity proceeds by a radical-polar crossover mechanism (FIG. 6b). In addition, successful reactivity required inclusion of a dialkyl phosphite additive as a sacrificial reductant to regenerate the reduced catalyst (see mechanistic discussion below). Azoles have also been used as reaction partners in Cu/NFSI-catalyzed benzylic C─H cross-coupling reactions. Pyrazoles exhibit controlled regioselectivity, with different N-site coupling observed when the reaction was conducted in the presence of a tetrabutylammonium halide (TBAX) or silyl triflate additive (FIG. 5k)¹⁶². The kinetically favored N² site selectivity with TBACl as the additive contrasts the N¹ site selectivity more commonly observed, for example, in substitution reactions with pyrazolide reagents^{163, 164}. Various azoles and other nitrogen heterocycles are effective coupling partners.

Cu/NFSI-catalyzed methods enable carbon-carbon bond formation via benzylic C─H cross-coupling with aryl and alkynyl nucleophiles. While K-S-type oxidative coupling of benzylic substrates and aryl boronic acids with DTBP as the oxidant uses excess C─H substrate¹³⁹, the use of NFSI as the oxidant enables reactions to proceed with limiting C─H substrate¹⁶⁵. The latter reactions are effective with electron-deficient arylboronic acids and proceed at ambient temperature, rather than the high temperatures (90 °C) required for K-S-type reaction. Use of a chiral bisoxazoline ligand supports enantioselective arylation of benzylic C─H bonds of alkylnaphthalenes and related derivatives (FIG. 5l)¹⁶⁶. Enantioselective coupling of benzylic C─H bonds and alkynyl silane derivatives is also possible, again using chiral bisoxazoline ligands (FIG. 5m)¹⁶⁷. A modified N─F reagent, in which the two phenyl groups of NSFI were replaced with a 4-fluorophenyl and a 1-naphthyl substituent aryl, led to improvements in the yield and enantioselectivity. The alkylarene is used as the limiting reagent in combination with simple alkynyl trimethoxylsilane derivatives.

Mechanistic features of Cu/NFSI-catalyzed C─H functionalization and cross-coupling methods.

The catalytic cycle for these Cu/NFSI reactions is believed to follow a mechanism similar to that proposed for K-S reactions (FIG. 6)¹⁴². Reductive activation of NFSI by copper(I) initiates the reaction, generating a Cu^II–F intermediate and a nitrogen-centered radical (•NSI). The latter species promotes HAT from the C─H bond to generate a diffusible benzylic radical. Studies of a closely related allylic cyanation reaction, which employed modified N─F reagents, provided evidence for an adduct between Cu^II and the N-centered radical as the HAT reagent¹⁵⁹. Modification of the nitrogen-centered radical in this manner could account for some variations in site selectivity that have been observed in different Cu/NFSI described above.

Functionalization of the organic radical can proceed by several different pathways. In some reactions, the nucleophilic coupling partner (e.g., TMSCN) exchanges with fluoride to generate a Cu^II–Nuc species. Subsequent addition of the benzylic radical to the Cu^II center affords an Cu^III(benzyl)(Nuc) intermediate that can undergo reductive elimination to afford the desired coupling product via an inner-sphere mechanism (FIG. 6a). This pathway rationalizes the enantioselective outcomes of certain coupling reactions, including benzylic cyanation, arylation, and alkynylation. Computational studies of the cyanation reaction suggest radical addition to Cu^II is reversible and stereoselectivity is determined in the reductive elimination step¹⁴². Alternatively, radical functionalization can proceed via a radical-polar crossover pathway (FIG. 6b, radical-polar crossover), involving outer-sphere electron transfer from the radical to Cu^II. The resulting benzyl cation is then trapped by a nucleophile to afford the desired product. This pathway is supported by racemic product formation in many of the reactions in FIG. 5, such as etherification¹⁶¹, which has also been analyzed by DFT computational studies. DFT analysis of the azidation reaction indicated that radical addition the distal nitrogen of a coordinated azide ligand (FIG. 6c) is energetically similar to the radical-polar crossover mechanism¹⁴⁴. As noted above, the electronic/donor properties of different nucleophiles are expected to influence the Cu^II/I redox potential and influence whether a benzyl radical adds to Cu^II to generate a Cu^III intermediate, introducing the possibility of enantioselective bond formation, or it undergoes outer-sphere electron transfer, resulting in racemic product formation.

The •NSI species generated by reductive activation of NFSI by Cu^I can oxidize a second equivalent of Cu^I to generate a Cu^II–NSI species, rather than promoting HAT from the C─H substrate (FIG. 6, bottom cycle). This undesired side reaction leads to unproductive consumption of the NFSI oxidant and Cu^I species, stalling the reaction. This problem was first identified in the study of benzylic etherification¹⁶¹, and it was overcome by identifying dialkylphosphite as a mild reductant that slowly reduces Cu^II to Cu^I during the reaction, without undergoing direct reaction with NFSI. This "redox buffer" concept has been employed in a number of Cu/NFSI radical-relay reactions, including etherification¹⁶¹, isocyanation¹⁵⁰, fluorination³¹, chlorination¹⁵⁶, and azole coupling¹⁶². Reagents that have been used as redox buffers include dialkylphosphites^{150,156,161,162}, MeB(OH)₂, and B₂pin₂^31,151. Not all Cu/NFSI radical-relay reactions require a redox buffer. If the coupling partner, such as TMSCN or ArB(OH)₂ in the cyanation and arylation reactions, can undergo background reduction of Cu^II, for example, via homocoupling to generate cyanogen or biaryls, then no redox buffer is required.

Radical-relay oxidative coupling reactions with catalysts other than copper

Various metals other than copper have been used to support synthetically useful oxidative coupling reactions that proceed via radical intermediates (FIG. 7). Iron(II) chloride and DTBP support the cross coupling of benzylic C─H bonds and 1,3-dicarbonyl compounds¹⁶⁸ and imidazoles¹⁶⁹ (FIG. 7, Fe), and iron(III) chloride and DTBP was used to achieve coupling of 2-benzylbenzoxazoles and anilines¹⁷⁰. Iron(II) acetate with nitrogen donor ligands catalyzes azidation of various C(sp³)─H bonds with a hypervalent azidoiodine(III) reagent¹⁴⁵, often favoring tertiary C─H functionalization. This reactivity was applied to late-stage functionalization of various complex molecules¹⁷¹. Cobalt(II) bromide catalysts support cross-coupling of benzylic C─H bonds with amides and sulfonamides and with DTBP as oxidant (FIG. 7, Co)¹⁷². Two equivalents of the C─H substrate were used in these reactions. A radical-polar crossover pathway involving a benzylic cation was proposed.

Fig. 7 ∣. Radical-relay C─H functionalization and cross-coupling reactions with catalysts other than copper.

DTBP, di-tert-butyl peroxide; dppb, 1,4-bis(diphenylphosphino)butane; L_n, ligands; DCP, dicumyl peroxide; phd, 1,10-phenanthroline-5,6-dione.

Nickel catalysts have been paired with peroxide oxidants to support oxidative alkynylation, arylation, and methylation of C(sp³)─H bonds. A Ni/Cu/Ag-cocatalyst system promotes oxidative C(sp³)─H alkynylation of unactivated alkanes (as a cosolvent), using terminal alkynes as the limiting reagent (FIG. 7, Ni)¹⁷³. Ni/triphenylphosphine catalyst systems promote arylation of aliphatic C(sp³)─H bonds with arylboronic acids coupling partners as the limiting reagent^174,175. Effective C─H substrates include tetrahydrofuran (THF), 1,4-dioxane, and cyclohexane, which are used as the solvent in the reactions. Methylation of C(sp³)─H bonds with limiting C─H substrates is enabled by photosensitization of peroxides and nickel-mediated radical coupling (FIG. 7, Ni)¹⁷⁶. Tertiary alkoxyl radicals generated from O─O homolysis of peroxides undergo HAT with C─H substrates and self-decomposition β-methyl scission to produce methyl radicals. Various reaction parameters, including temperature, concentration, solvent, and structures of peroxides, may be tuned to balance the relative rates of HAT and methyl-radical formation. Protonation of C─H substrates containing basic amines deactivates C(sp³)─H sites adjacent to nitrogen to enable methylation at the benzylic positions. This methylation method creates opportunities to explore “magic methyl” effects on medicinally relevant building blocks and drug molecules¹⁷⁷.

Silver catalysts have also been used in radical reaction reactions (FIG. 7, Ag)¹⁷⁸. A silver-promoted oxidative benzylic C─H trifluoromethoxylation with C─H substrate as the limiting reagent uses potassium persulfate as oxidant¹⁷⁹. The reaction favors functionalization at secondary > primary > tertiary benzylic C─H site and can be modified to introduce a fluorine atom and a trifluoromethoxy group at the same site.

Photochemical radical-relay reactions

Photochemical and visible-light photoredox methods provide a versatile strategy to generate organic radicals from a C(sp³)─H substrate and promote radical-relay coupling with diverse functional groups^180-186. The reactions are initiated by abstraction of a hydrogen atom from the C─H substrate. The HAT reagent is generated by photocatalyst-mediated activation of an oxidant, such as a hypervalent iodine reagent, N-acyloxyphthalimide, or persulfate, or by direct photoactivation of a reagent, such as decatungstate or benzophenone (FIG. 8)¹⁸⁷. The introduction of functional groups, including hydroxyl, ammonia surrogates, trifluoromethyl, alkyl, and aryl groups, can take place by various mechanisms, similar to the methods outlined above (cf. FIG. 1Cb and FIG. 6). Radical-polar crossover reactions, which generate the corresponding cation or anion (FIG. 8a, SET), are used to support subsequent coupling reactions with nucleophiles and electrophiles, respectively. Transition-metal reagents and cocatalysts can promote coupling via radical-polar crossover or inner-sphere coupling pathways (FIG. 8a, Cu, Ni). Iodine has been used to trap and support further functionalization of the alkyl radicals (FIG. 8a, I). Examples of these photochemical radical-relay reactions will be surveyed below, divided into C(sp³)─H functionalization (one-for-one replacement of a C─H bond with another functional group) and cross-coupling reactions (reaction of a C─H bond with a group of similar reagents).

Fig. 8 ∣. Photoredox C(sp³)─H functionalization/cross coupling via radical relay.

a ∣ Four pathways for photoredox-promoted C─H functionalization/cross coupling. b ∣ The photoredox toolbox includes HAT reagents, photocatalysts, and metal-/iodine-based catalysts utilized for representative methodologies. HAT, hydrogen atom transfer; SET, single electron transfer; BI─OH, hydroxyl benziodoxole, PFBI─OH, hydroxyl perfluorobenziodoxole; PIDA, phenyliodonium diacetate; TBADT, tetra-n-butylammonium decatungstate; TBPB, tert-butyl peroxybenzoate; 4CzIPN, 2,4,5,6-tetra(carbazole-9-yl)isophthalonitrile; [Acr⁺Mes], 9-mesityl-1,3,6,8-tetramethoxy-10-phenylacridin-10-ium tetrafluoroborate; bpy, 2,2'-bipyridine; PhI(pBBA)₂, bis(4-bromobenzoyloxy)iodobenzene; p-F-ppy, 5-fluoro-2-(2-pyridinyl-κN)phenyl-κC; dFppy, 2-(2,4-difluorophenyl)pyridine; dtbbpy, 4,4'-di-tert-butyl-2,2’-bipyridyl; 5,5'-dmbpy, 5,5'-dimethyl-2,2'-bipyridyl.

Photoredox C(sp³)─H functionalization reactions.

Photoredox-promoted radical-relay methods have been used to support functionalization of C(sp³)─H bonds with halogens, pseudohalogens, acetate, ammonia surrogates, and a trifluoromethyl group. Nucleophilic fluorination of C(sp³)─H bonds has been achieved in two complementary studies by using Ir-based photoredox catalysts. In one case, single electron transfer (SET) from the excited state photocatalyst promotes reductive activation of N-acetoxyphthalimide¹⁸⁸. N─O cleavage and decarboxylation of the acetoxyl radical generates a methyl radical that promotes HAT from a benzylic or allylic C─H bond. The stabilized carbon-centered radical then undergoes SET oxidation by the Ir^IV photocatalyst to generate a carbocation that can react with Et₃N•HF. A related study employed a peroxide-based oxidant (TBPB) with an Ir photoredox catalyst, resulting in generation of tert-butoxyl radical, which promotes HAT from secondary/tertiary benzylic C─H bonds¹⁸⁹. A similar radical-polar crossover step, involving SET oxidation of the radical by Ir^IV, generates a carbocation that reacts with Et₃N•HF. Both studies prioritized fluorination; however, other nucleophiles were shown to trap the carbocation under the reaction conditions, including chloride, azide, alcohols, thiols, and 1,3,5-trimethoxybenzene (FIG. 9a, SET).

Fig. 9 ∣. Different methods for radical-relay C(sp³)─H functionalization and cross coupling using carbon-centered radicals access via photoredox methods.

a ∣ Photoredox-promoted C─H functionalization/cross-coupling reactions involving single electron transfer. b ∣ Photoredox-promoted C─H functionalization/cross-coupling reactions involving copper catalysts. c ∣ Photoredox-promoted C─H functionalization/cross-coupling reactions involving nickel catalysts. d ∣ Photoredox-promoted C─H functionalization/cross-coupling reactions involving iodine-based catalysts . SET, single electron transfer; PhI(pBBA)₂, bis(4-bromobenzoyloxy)iodobenzene; BI–OH, hydroxyl benziodoxole, PFBI–OH, hydroxyl perfluorobenziodoxole; TFA, trifluoroacetic acid, TBADT, tetra-n-butylammonium decatungstate; NaDT, sodium decatungstate; Ketone-1, 4-methoxy-4'-trifluoromethylbenzophenone; Ketone-2, 4,4'-dichlorobenzophenone, BRSM, based on recovered starting material.

C(sp³)─H oxygenation and amidation has been achieved by pairing photoredox catalysts with hypervalent iodine oxidants. [Ru(bpy)₃]Cl₂ mediates photochemical reduction of benziodoxole (BI─OH) and its perfluorinated analog (PFBI─OH) to generate species that promote HAT from tertiary aliphatic and benzylic C(sp³)─H bonds. The Ru^III state of the photocatalyst then promotes SET oxidation of the organic radical to generate a carbocation, which can react with H₂O to afford the hydroxylation product¹⁹⁰. Inclusion of CH₃CN or PhCN in the reaction mixtures accesses the corresponding acetamide or benzamide products via a Ritter-type mechanism (FIG. 9a, SET)^191,192. Acetoxylation of primary and secondary benzylic C─H bonds proceeds with and acridinium-based photocatalyst and phenyliodonium diacetate (PIDA) as the oxidant and source of acetate¹⁹³. Photoredox-based reductive activation of PIDA is proposed to generate a methyl radical, which undergoes HAT with the C─H substrate. The oxidized photocatalyst can then oxidize the organic radical to a carbocation intermediate, and subsequent reaction of acetate with the carbocation affords the acetoxylated product.

An alternative approach for functionalization of organic radicals involves SET reduction to carbanions, followed by reaction with different electrophiles (FIG. 9a, SET)^194,195. This approach has been used to convert alkylarenes to aryl acetic acids and related products via C─H coupling with CO₂¹⁹⁴ and to homobenzylic secondary and tertiary alcohols via C─H coupling with aldehydes and ketones¹⁹⁵. These reactions use carbazole- or diarylamine-substituted dicyanoarene photocatalysts. The excited-state photocatalyst oxidizes the thiolate of iPr₃SiSH to generate a thiyl radical, which promotes HAT from the activated C─H bond. The reduced photocatalyst then promotes SET reduction of the carbon-centered radical to afford a carbanion that can react with an electrophile (CO₂ or a ketone) to form a C─C bond.

Light-assisted iodine-catalyzed intramolecular C(sp³)─H amination been the focus of considerable development²⁵ Intermolecular amination of C(sp³)─H bonds has been achieved using bis(4-bromobenzoyloxy)iodobenzene as oxidant and trifluoromethanesulfonamide (H₂NTf) as an HAT reagent and ammonia surrogate (FIG. 9d, I)¹⁹⁶. In situ reaction of H2NTf and the hypervalent iodine reagent generates N-iodo triflamide (I–NHTf), which can undergo light-induced homolysis of the N─I bond to afford a sulfonamidyl radical. This step is followed by HAT from the C(sp³)─H substrate, carbon─iodine bond formation, and nucleophilic substitution of the iodide to form the C─N product.

Installation of trifluoromethyl group has also been achieved via a photoredox radical-relay approach with cooperative copper catalysis (FIG. 9, Cu). The CF₃ group was introduced to the benzylic sites by irradiating a reaction mixture of ammonium persulfate and a bench-stable bpyCu(CF₃)₃ complex¹⁹⁷ in mixed organic/aqueous media (acetone/H₂O 1:1) (FIG. 9b, Cu)¹⁹⁸. This strategy was also applied to trifluoromethylation of unactivated C(sp³)─H bonds¹⁹⁹. HAT from C─H substrates could be promoted by sulfate radical anion or trifluoromethyl-based radical, via light-induced homolysis of persulfate or bpyCu(CF₃)₃, respectively. The organic radical then reacts with an equivalent of the Cu─CF₃ species to afford a trifluoromethylated product. C(sp³)─H trifluoromethylation has also been achieved using bpyCu(CF₃)₃ and oxone²⁰⁰. In this case, the mechanism is proposed to involve HAT from the C─H substrate by a trifluoromethyl radical, oxidation of the carbon-centered radical to a carbocation by oxone, and reaction of an anionic trifluoromethyl source with the carbocation. In yet another approach, sodium decatungstate has been used in combination with a copper catalyst (CuCl₂) and a trifluoromethyl hypervalent iodine-based oxidant to convert C(sp³)─H bonds to the corresponding C(sp³)─CF3 products (FIG. 9b, Cu)²⁰¹. The photoexcited decatungstate promotes HAT to form a carbon-centered radical, and a Cu^II─CF₃ species, generated in situ from CuCl₂ and the CF₃ source, is proposed to react with the organic radical to afford the trifluoromethylated products.

Photoredox C(sp³)─H cross coupling.

Photoredox methods enable cross coupling of benzylic and aliphatic C─H substrates with diverse aryl or alkyl halide reaction partners. Three general strategies have been employed to support HAT in these reactions: (a) combining a photocatalyst with a tertiary amine to generate an amine radical cation species, (b) use of a reagent that is capable to promoting HAT from its photoexcited state, and (c) photochemical activation of a nickel halide to generate a halogen radical HAT species.

The first example of this reactivity used 3-acetoxyquinuclidine, an Ir-based photocatalyst, and nickel(II) bromide to support cross coupling of activated C(sp³)─H bonds, such as those adjacent to nitrogen in pyrrolidines, with aryl bromides/chlorides (FIG.9c, Ni)²⁰². SET oxidation of 3-acetoxyquinuclidine by the excited-state Ir^III photocatalyst generates a quinuclidine radical cation capable of promoting HAT from the C(sp³)─H bond. This radical generation process is paired with a Ni-based radical functionalization cycle. The nickel co-catalyst reacts with the organic halide species to afford an organonickel(II) species, which promotes C─C coupling by reaction with the radical derived from the C─H substrate. Cross coupling of activated C(sp³)─H and alkyl halides employing quinuclidine, an Ir-based photoredox catalyst, and nickel(II) bromide has been achieved via similar mechanistic pathway²⁰³. Quinuclidine also promotes HAT from aldehyde²⁰⁴ and the α-C─H bonds of alcohols²⁰⁵ to enable direct arylation and alkylation via Ni-catalyzed cross coupling. Nitrogen-centered radicals from sulfonamides have been shown to abstract hydrogen atoms from C─H bonds adjacent to heteroatoms, generating radicals that undergo Ni-catalyzed cross coupling with alkyl halides to afford alkylated products²⁰⁶. Photoexcited 4CzIPN (1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene) is proposed to oxidize sulfonamide anion to the nitrogen-centered radical, which is responsible for HAT.

TBADT serves as a combined photocatalyst/HAT reagent and supports arylation of strong aliphatic C─H bonds with aryl bromides²⁰⁷. Disproportionation of two singly reduced decatungstate species regenerates the active HAT photocatalyst and the doubly reduced decatungstate species, which can reduce the nickel cocatalyst as needed for activation of the aryl bromide coupling partner. Benzophenone derivatives are similar to TBADT in their ability to promote HAT from their photoexcited triplet state^208,209. This feature has been exploited in combination with nickel catalysis for cross coupling of activated C(sp³)─H bonds with aryl and alkyl halides (FIG. 9c, Ni)²¹⁰. 4,4'-Dichlorobenzophenone (FIG. 8b, Ketone-2) has been used as a photocatalyst to achieve arylation of primary benzylic C(sp³)─H bonds²¹¹. Aryl halides, including chlorides, bromides, and iodides, can be utilized as coupling partners. Benzaldehyde has also been used as a photocatalyst for arylation and alkylation of activated C(sp³)─H bonds (FIG. 9c, Ni)^212,213.

Arylation of activated C(sp³)─H bonds has been achieved by combining an Ir-based photoredox catalyst and Ni cocatalyst, in the absence of an HAT reagent (FIG. 10Ba). In the coupling of aryl bromides with THF and other solvents with activated C─H bonds, the excited-state photocatalyst Ir^III* is proposed to undergo triplet-triplet energy transfer with a ArNi^II–Br species to generate a triplet Ni^II* species. (FIG. 10Aa). HAT from the C(sp³)─H bond may involve a bromine radical or proceed via a concerted four-membered transition state involving the Ni─Br bond. The resulting carbon-centered radical can react at Ni to afford the C(sp³)─C(sp²) bond ²¹⁴. A complementary study, involving the coupling of aryl chlorides with THF and related solvents (FIG. 10Bb) ²¹⁵, proposes that the Ir^III photocatalyst serves as a SET reagent. Oxidation of an ArNi^II–Cl intermediate by the excited state photocatalyst Ir^III* generates a Ni^III species. Subsequent loss of a chlorine atom leads to HAT from the activated C(sp³)─H bond of the solvent to afford an organic radical that can undergo coupling with the arylnickel(II) species (FIG. 10Ab). The synthetic utility of the latter reaction was demonstrated in a separate report in the cross coupling of (hetero)aryl chlorides with 1,3-dioxolane as the solvent²¹⁶. The resulting cross-coupled products are readily converted to (hetero)aryl aldehydes following a mild acidic workup at room temperature. An enantioselective benzylic C─H arylation has been achieved with an Ir-based photocatalyst, nickel(II), and a chiral bis-imidazoline ligand (FIG. 10Bc)²¹⁷. Aryl bromide coupling partners generate ArNi^II–Br, which is proposed to generate bromine radical as the HAT reagent upon irradiation in the presence of a photocatalyst. An enantioselective benzylic C(sp³)─H alkenylation reaction has also been achieved with alkenyl bromides as the coupling partners in presence of an Ir-photoredox catalyst, nickel(II), and a chiral bis-imidazoline-based ligand²¹⁸. Complementary nickel/photoredox dual catalysis enables acylation²¹⁹ and arylation²²⁰ reactions of α-amino C(sp³)─H bonds. In these cases, N-arylpyrrolidine substrates are proposed to generate stabilized α-amino radicals via a more conventional process involving SET oxidation of the substrate.

Fig. 10 ∣. Nickel-catalyzed arylation of C(sp³)─H bonds of inexpensive (co)solvents enabled by in situ generation of HAT reagents.

Aa ∣ Energy transfer pathway for arylation of C(sp³)─H bonds. Ab ∣ Single electron transfer pathway for arylation of C(sp³)─H bonds. Ba ∣ Examples of arylated products involving energy transfer. Bb ∣ Examples of arylated product involving single electron transfer. Bc ∣ Enantioselective arylation of benzylic C(sp³)─H bonds with a chiral bis-imidazoline ligand. EnT, energy transfer; SET, single electron transfer; R.E., reductive elimination; dF(CF₃)ppy, 3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl]phenyl; dtbbpy, 4,4'-di-tert-butyl-2,2'-dipyridyl; BiIM, biimidazoline; DMBP, 4,4'-dimethoxybenzophenone.

Electrochemical radical-relay reactions

Electrochemical methods provide additional strategies to achieve C(sp³)─H functionalization via radical relay^221,222. N-hydroxyphthalimide (NHPI) was first demonstrated as an electrochemical mediator for C(sp³─H) oxygenation in the 1980s^223-225. NHPI undergoes proton-coupled oxidation to phthalimide N-oxyl (PINO) as the electrode, and PINO- mediated HAT then generates an organic radical that can react with O₂ or other oxidants, resulting in C─H functionalization (FIG. 11Aa)²²⁶. These methods complement transition-metal/NHPI cocatalyst systems for C─H oxygenation with O₂^68,71,72. Modified NHPI derivatives can lead to improved performance, evident from the use of tetrachloro-N-hydroxyphthalimide (Cl₄NHPI) as the HAT mediator in electrochemical oxidation of allylic C(sp³)─H bonds (FIG. 11Ab) ²²⁷ , and an electrochemical NHPI/O₂ system proved effective for C─H oxygenation of alkyl-substituted heterocycles that exhibit poor reactivity with a chemical Co/NHPI/O₂ catalyst system (FIG. 11Ac)⁷¹. Flow conditions have been developed for the latter process²²⁸.

Fig. 11 ∣. Radical-relay reactions involving electrochemistry.

Aa ∣ General mechanism for NHPI-mediated electrochemical oxygenation reaction of C(sp³)─H bonds. Ab ∣ Oxygenation of allylic C─H bonds. Ac ∣ Oxygenation of heterobenzylic C(sp³)─H bonds. Ad ∣ Quinuclidine-mediated oxygenation of C(sp³)─H bonds. Ae ∣ N-alkyl ammonium ylides as a new class of HAT-mediators. Af ∣ NHPI-mediated iodination followed by pyridination of alkylarenes. Ba ∣ Oxygenation reactions involving metal-oxo complexes. Bb ∣ Oxygenation of secondary benzylic C(sp³)─H bonds using Fe-TAML complex. Bc ∣ Hydroxylation of C(sp³)─H bonds in amine derivatives using a ruthenium-based catalyst. C ∣ Azidation of C(sp³)─H bonds using Mn^III catalyst. D ∣ Photoelectrochemical azidation reaction of C(sp³)─H bonds. NHPI, N-hydroxyphthalimide; Cl₄NHPI, tetrachloro-N-hydroxyphthalimide; RVC, reticulated vitreous carbon; TBAP, tetrabutylammonium perchlorate; TAML, tetraamido macrocylic ligand; dtbpy, 4,4'-di-tert-butyl-2,2'-dipyridyl; DDQ, 2,3-dichloro-5,6-dicyano-p-benzoquinone; 1,10-Phen, 1,10-phenanthroline; TFA, trifluoroacetic acid.

Different mediators provide a means to expand reactivity beyond activated C─H bonds. Electrochemical oxidation of quinuclidine generates an amine radical cation that promotes HAT and oxygenation of diverse C(sp³)─H bonds under aerobic conditions (FIG. 11Ad)²²⁹. N-alkyl ammonium ylides have been developed as a new class of electrochemical mediators for C(sp³)─H oxygenation through the support of computational method (FIG. 11Ae)²³⁰. These reagents show modified chemo- and site-selectivity relative to previous chemical and electrochemical methods for C(sp³)─H oxygenation.

NHPI has been paired with iodine, rather than O₂, to enable the iodination of methyl arenes²³¹. The resulting benzyl iodide may be employed in subsequent S_N2-base derivatization reactions to access new C─C, C─O, and C─N bonds or undergo in situ substitution, for example, by pyridine (FIG. 11Af). This mediated HAT strategy allows electrochemical C─H functionalization to proceed at electrode potentials 0.7–1.3 V lower than those required by conventional SET-initiated electrochemical benzylic C─H functionalization methods^232,233.

Metal-oxo complexes capable of promoting C─H oxygenation have been generated via electrochemical proton-coupled oxidation of metal-aquo complexes (FIG. 11Ba). Electrochemical oxidation of [(TAML)Fe^III(OH)₂]Na (TAML = tetraamido macrocyclic ligand) generates Fe^IV and Fe^V oxo species. The Fe^V-oxo is more reactive and oxidizes secondary benzylic C─H bonds to ketones using water as oxygen-atom source (FIG. 11Bb)²³⁴. Ruthenium-based oxo species derived from cis-bis(4,4'-di-tert-butylpyridine)ruthenium complex effects electrochemical hydroxylation of C(sp³)─H bonds (FIG. 11Bc)²³⁵. Basic amines are tolerated, owing to the use of acidic reaction conditions that protect the amines as ammonium salts.

Two complementary electrochemical methods have been developed for C(sp³)─H azidation. Manganese(III) porphyrin or salen complexes and sodium azide promote azidation of C(sp³)─H bonds (FIG. 11C)²³⁶. The reaction is proposed to proceed via oxidation of Mn^III to a Mn^IV-diazide species, which promotes HAT from the substrate to generate an organic radical that affords an azide product via coupling with another Mn^IV-diazide complex. An electrophotochemical azidation protocol uses MnF₂ in combination with a ketone-based photocatalyst [e.g. 9-fluorenone, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), bis(4-methoxyphenyl)methanone] and sodium azide (FIG. 11D)²³⁷. The excited-state photocatalyst promotes HAT, and an electrochemically generated Mn^III-azide is proposed to react with the carbon-centered radical.

Conclusion

Radical reaction pathways offer some of the most versatile methods available for C(sp³)─H functionalization and cross-coupling, accessing synthetic scope and utility that is unmatched by other reaction pathways. Major advances have been made in each of the different radical reaction classes, including radical chain, radical rebound, and radical relay. Many of these reactions are able to use the C─H substrate as the limiting reagent, addressing one of the long-standing limitations of this field and supporting application to late-stage functionalization. Radical-relay methods are particularly versatile. These reactions not only enable installation of a specific functional groups, including -CN, ─CF₃, ─N₃, ─OH, ─SCN, ─F, ─Cl, ─NCO, but also provide the basis for sequential functionalization/diversification methods and direct cross-coupling methods that leverage substrates derived from large pools of reaction partners, such as alcohols, amines/amides, arylboronic acids, and aryl halides. The latter feature greatly expands the scope of accessible products relative those obtained from typical C─H "functionalization" methods and has profound implications for drug discovery and medicinal chemistry where access to diverse structures is crucial to the success of the endeavors.