Catalytic α-C–H functionalization of carbonyl compounds via SET-induced formation of α-carbonyl radicals

Anupam Kumar Singh ^ab and Sukalyan Bhadra *^ab
aInorganic Materials and Catalysis Division, CSIR-Central Salt and Marine Chemicals Research Institute, G. B. Marg, Bhavnagar 364002, Gujarat, India. E-mail: sbhadra@csmcri.res.in
^bAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India

First published on 13th August 2025

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Anupam Kumar Singh

Anupam Kumar Singh pursued his Master's degree in chemistry (2017) from Indian Institute of Engineering Science and Technology, Shibpur (India). Since October 2018, he has been working as a project assistant at CSIR-CSMCRI and joined the PhD program in 2020 under the supervision of Dr S. Bhadra. His research projects focus on the development of carbonyl functionalizations via α-carbonyl radicals, giving access to fine and specialty chemicals.

Sukalyan Bhadra

Sukalyan Bhadra earned a PhD degree under the supervision of Professor Brindaban C. Ranu at IACS (India) in 2011 and moved to TU Kaiserslautern (Germany) for postdoctoral research in the group of Professor Lukas J. Goossen. In 2013, he joined Chubu University (Japan) as a JSPS postdoctoral fellow in the group of Professor Hisashi Yamamoto. He returned to India, in 2016, to begin his independent career at CSIR-CSMCRI Bhavnagar, where he currently works as a Principal Scientist. His research interest revolves around exploring radical-promoted organic transformations, asymmetric catalysis and the synthesis of fine chemicals, APIs and agrochemicals having industrial significance.

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1. Introduction

Chemists acquire fundamental knowledge of carbonyl compounds from as early as the first semester of their study. Carbonyl compounds, including aldehydes, ketones, carboxylic acids, esters, amides, and their synthetic equivalents, have long been familiar as vastly amendable starting materials in organic synthesis. A large number of reactions of carbonyl compounds are based on α-functionalization, wherein new C–C and C–heteroatom bonds are formed at the carbonyl α-position.¹ Traditionally, α-functionalization of carbonyl compounds is realized with the use of an electrophilic coupling partner via enolate chemistry demanding a strong base (typically pK_a > 25), e.g. lithium amides (LDA, LiHMDS, etc.), in (over)stoichiometric quantities.² The use of a strong base often causes issues related to chemoselectivities for competing functional groups of the substrate. Furthermore, for α-functionalization with heteroatom based nucleophilic substituents (O, N, S, etc.), the carbonyl α-position is, at first, prefunctionalized with a leaving group, e.g. a bromo substituent, which is exchanged by the heteroatom nucleophile through S_N2 substitution in an additional synthetic sequence.³ In this context, the catalytic direct functionalization of carbonyl compounds via α-carbonyl radicals formed upon the oxidative cleavage of the α-C–H bond constitutes an atom-economic approach. The latter class of strategy enables the installation of both electrophilic and nucleophilic C- and heteroatom-based substituents at the carbonyl α-position in a favourable and selective manner.

Since the pioneering work by Kharash et al. as early as 1948 on the methyl radical induced generation of the α-carbonyl radical, from α-bromo acetates, and its addition to unactivated alkenes, numerous related α-alkylations have appeared.⁴ These methods indeed provide a convenient route to α-alkylated carbonyl compounds, although the α-bromination of carbonyl compounds prior to the radical debromination renders the approach atom- and step-intensive. A more straightforward alkylation of ketones and active methylene compounds with alkenes involves the direct cleavage of the α-C–H bond via enolate formation with subsequent one-electron oxidation or by direct α-hydrogen atom abstraction. Related developments on these approaches have been documented in few reviews.⁵ However, those reviews do not feature the progress in the functionalization of many carbonyl substrate classes, including carboxylic acid equivalents and/or derivatives, among others.

One of the prime objectives of our research is to develop catalytic functionalization of common organic building blocks via C-centred radicals.⁶ Encouraged by our early findings on transformations via single electron transfer (SET) induced formation of a C-centred radical adjacent to an azole, in the alkyl side chain of 2-alkylazoles, we reasoned to expand the scope to the generation of α-carbonyl radicals from ketones and carboxylic acid equivalents.⁷ The present article presents recent progress in the catalytic functionalization of various carbonyl compounds, including carboxylic acid equivalents, via SET induced formation of α-carbonyl radicals, developed by us and other researchers. SET-induced transformations of α-carbonyl radicals via transition metal catalysis and photoredox catalysis are featured in the current article. Thus, examples of transformations through stoichiometric oxidant induced SET oxidation of α-C–H bonds are not included.⁸

2. General mechanistic considerations on the SET-induced formation of α-carbonyl radicals and their reactivity profiles

Scheme 1 presents a generalized reaction pathway for carbonyl α-functionalization through the formation of C-centered radicals. Carbonyl compounds, including aldehydes, ketones and carboxylic acid esters, amides, etc. containing an enolizable α-proton, can produce C-centered radical I via SET-induced α-C–H bond cleavage. This is achieved by employing an appropriate electron acceptor/radical initiator, typically a transition metal catalyst and/or oxidant, or by means of photo-redox catalysis. The resulting α-carbonyl radical species I undergoes C–C and/or C–heteroatom bond formation in the presence of a dissimilar C- and/or heteroatom-centered radical intermediate, respectively, via radical cross-coupling (path A). Alternatively, the C–C and C–heteroatom bond formation step can also take place on a metal catalyst. The second pathway (path B) comprises an attack of I to an alkene or alkyne to form another active intermediate, II, featuring a C-centered radical at the γ-position with regard to the carbonyl group. Consequently, the γ-radical is trapped by a dissimilar radical or a hydrogen atom via hydrogen atom transfer (HAT) to give a new C–C coupled product. In the third approach (path C), active species I undergoes subsequent one-electron oxidation to form carbocation III, which reacts with a nucleophile to give the α-functionalized product. However, the formation of an electrophilic carbonyl α-position, i.e. umpolung of the carbonyl α-position, is often thermodynamically unfavourable and demands strong oxidizing agents or electrochemical oxidation. Nonetheless, this process allows direct installation of nucleophiles at the carbonyl α-position in a step- and atom-economic fashion. In the subsequent sections, we discuss various catalytic approaches on the SET induced formation and succeeding transformations of α-carbonyl radicals under metal catalysis and photo-redox catalysis.

3. Transformations through the metal-catalysed SET-induced formation of α-carbonyl radical intermediates

The metal-catalysed intermolecular α-alkylation of aldehydes, ketones and active methylene compounds, using unactivated alkenes as the alkylating source, is a significant transformation of fundamental importance.⁹ Previously, numerous research groups have documented the α-alkylation of carbonyl compounds with unfunctionalized alkenes using peroxides as the oxidant or catalyst.¹⁰ While these processes are transition-metal free offering α-alkylated carbonyl compounds in an economical manner, they employ a large excess of carbonyl compounds with respect to the alkene partner to prevent undesired side reactions, e.g. double or more addition (telomerization) accompanied by the required mono-addition product; also, the radical coupling process terminates the desired product formations.

Another way to produce α-carbonyl radicals is a transition metal promoted one-electron oxidation process. A general schematic illustration of the metal-mediated SET-induced formation of the α-carbonyl radical is shown in Scheme 2. The α-carbonyl radical, thus formed in situ, reacts with an alkene to form the γ-radical species C, which subsequently combines with a hydrogen atom from the surrounding (HAT) to give the α-alkylated product D. Alternatively, the radical species C can undergo further one-electron oxidation to form carbocation E, which eventually produces alkene F or G via deprotonation. Combinations of various transition metals, typically silver, copper and manganese, with oxidants have been employed to achieve α-alkylation reactions relying on the above strategy. Thus, the groups of Heiba, Nikishin, Malek, Linker, Nishiguchi and Ishii, among others, have independently studied α-alkylation reactions via metal-promoted formation of α-carbonyl radicals.^11–16 These developments have been discussed in detail in the recent review by Kobayashi et al.⁵

3.1. Transformations of ketones and aldehydes

3.2. Transformations of carboxylic acid equivalents and derivatives

The α-proton in carboxylic acids, their equivalents and derivatives is much less acidic compared to ketones. Therefore, the formation of an α-carbonyl radical from carboxylic acids often requires a strong base, typically Li-amides, leading to the corresponding lithium enolate via α-C–H abstraction/enolization.²⁸ The resulting lithium enolate can then be oxidized by a SET process, in the presence of a suitable one-electron oxidant, to give the corresponding α-carbonyl radical intermediate, which can be trapped subsequently to give thermodynamically stable products. In 2000, Jahn et al. reported a tandem lithium amide conjugate addition/radical 5-exo cyclization reaction that afforded functionalized pyrrolidines as the product.²⁹ The reaction employed ferrocenium hexafluorophosphate 34 as the SET oxidant for α-amino lithium enolate 33 (Scheme 16). For the radical termination process, a TEMPO free radical was used, as it reacts at a slower rate with α-carbonyl radicals 37 in comparison to alkyl radicals 38. Thus, oxygenated derivatives of pyrrolidines 35 were obtained as the predominant products, which have opportunities for further derivatizations. However, the α-carbonyl radical 37 can also be trapped by TEMPO, although at a slower rate, to form an acyclic α-oxygenated product, 39, as the minor product.

Based on the above concept, Jahn et al. subsequently reported the stereoselective synthesis of N,2,3,4-tetrasubstituted pyrrolidines and extended the method to cyclopentane derivatives from ω-silyl ester enolates.^29c Further, the addition of TEMPO to α-carbonyl radicals generated from acid esters was also studied. While these strategies constitute the earlier examples of the formation of α-carbonyl radicals from acid esters, ferrocenium hexafluorophosphate 34 was employed in over-stoichiometric amounts as the one-electron oxidant.

Furthermore, in the above reactions, carboxylic acid derivatives were oxygenated in the form of Li-enolates, which were generated in the presence of a slight excess of a strong base, e.g. LDA or LiHMDS (KHMDS for K-enolates). To deprotonate a less acidic α-proton (RCH₂COOH) in the presence of a more acidic proton of carboxylic acid (RCH₂COOH), at least two equivalents of a Brønsted base would be necessary for efficient enolization.²⁸ The use of a strong base in (over)stoichiometric quantities causes undesired side reactions, particularly for substrates bearing additional carbonyl functions. Moreover, although unsubstituted carboxylic acids can be hydroxylated upon treatment with a base and subsequently with oxygen, aldehyde and benzoic acid derivatives are concomitantly formed through dehydrative decarboxylation, specifically for α-arylacetic acids as substrates. On the other hand, alkali metal carboxylates undergo decarboxylation to give alkyl radical species under redox-active conditions. Therefore, catalytic activation of carboxylic acids and subsequent functionalization through one-electron oxidation is a challenging task.

In this context, Ohshima et al. reported a chemoselective catalytic activation of carboxylic acid via a one-electron oxidation process.³⁰ The enolization of carboxylic acid proceeded in the presence of an iron-based catalyst system without the addition of a strong base using a 4 Å molecular sieve as the desiccant. A large number of carboxylic acids, including functionalized pharmaceuticals, were oxygenated with TEMPO under the optimized conditions. The resulting α-oxygenated compounds were isolated in the form of the corresponding methyl esters by the addition of TMSCHN₂ in the reaction mixture (Scheme 17).

Recently, we have achieved a regioselective copper catalysed C(sp³)–H/C(sp³)–H cross-coupling of arylacetic acid equivalents with diverse methylarenes (Scheme 18).³¹ The reaction proceeds in the presence of copper(I) bromide as the catalyst and di-tert-butyl peroxide (DTBP) as the terminal oxidant via the formation of α-carbonyl radicals from arylacetic acids bearing a pyridine group, giving access to α,β-diaryl propionic acids. Numerous arylacetic acids were coupled with a diverse range of methylarenes in an efficient manner. The use of methylarene as the solvent gave the best results. However, almost the same yields were obtained if the methylarene was used in 10 equivalents with respect to the arylacetic acid.

To understand the reaction mechanism, a series of experiments were conducted. The outcome of radical scavenging experiments with 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) or 2,6-di-tert-butyl-4-methylphenol (BHT) (2.0 equiv. each) suggested the intermediacy of an α-carbonyl radical, formed from the arylacetic acid equivalent and benzyl radical, obtained from toluene. H/D scrambling in the arylacetic acid substrate was observed in the presence of methanol-d₄, indicating the formation of an enolate intermediate. Furthermore, a significant kinetic isotope effect (KIE) of 3.66 was observed, suggesting C–H cleavage as the rate determining step.

Based on the mechanistic study, a plausible mechanism has been outlined, as in Scheme 19. In the proposed mechanistic cycle, the Cu(I) catalyst 46 is initially oxidized by DTBP to form Cu(II) species 47, which readily coordinates to the pyridine group of 43, furnishing intermediate 48. Subsequently, the enolate equivalent 50 is formed from 48 through base-promoted deprotonation. The resultant intermediate 50 undergoes a SET oxidation to generate the radical cation 51 and subsequently 51′. Next, the benzyl radical 44′, formed upon the action of a tBuO˙ radical on toluene derivatives 44, reacts with 51′ leading to the formation of 52. The Cu(II)-center in 52 is next oxidized by the C-centered radical to provide a putative copper(III)-intermediate, 53. Finally, 53 undergoes reductive elimination of the C–C coupled product 45 to regenerate the Cu(I)-catalyst 46.

The strategy, using toluene as the arylmethylating partner, was extended to an analogous cross-coupling of arylbenzyl ketones, which have slightly lower deprotonation energies than that of 43 for the α-C–H bond (Scheme 20). Thus, various complex molecules, featuring aryl benzyl ketones, were successfully derivatized by applying this strategy.

Furthermore, we have observed that a cobalt based catalyst system allowed for the formation of α-carbonyl radical species in the arylacetic acid equivalents 43 via enolization and subsequent SET oxidation (Scheme 21).³² The resulting α-carbonyl radical 56, when trapped with molecular oxygen, produced the peroxo-species 57, which upon weak O–O bond cleavage furnished α-hydroxyarylacetic acid 55 in a convenient manner. Mild conditions, a wide substrate scope and exceptional chemo- and regioselectivity have made the α-hydroxylation approach distinct and beneficial over the state-of-art base-mediated benzylic hydroxylation strategies.

A plausible mechanism is depicted in Scheme 22. The reaction begins with the formation of an active Co(III)-species, 58, via silver-mediated oxidation and carboxylate exchange with AdCO₂H on the Co(II) catalyst. Subsequently, the pyridyl group of the substrate coordinates to the Co(III) catalyst and underwent chelation-assisted enolization to form the enolate equivalent 61. The resulting intermediate 61 underwent SET induced oxidation by Ag(I) to produce the radical cation 62, which consequently gave the α-carbonyl radical species 56. Next, the radical species 56 is trapped by molecular O₂ to form the peroxyl radical 63, which, in the presence of HFIP, generated the transient peroxide intermediate 57. Finally, the weak O–O bond cleavage in 57 led to the formation of α-hydroxy arylacetic acid 55 and regenerates the active Co(III) catalyst 58.

3.3. Metal-catalysed synthesis of oxindoles via α-carbonyl radicals

Oxindoles are common motifs in numerous approved drugs and natural products. In addition, the oxindole moiety can be structurally modified to diversely-substituted heterocyclic molecules.³³ While the synthesis of oxindoles via 5-exo type cyclization of an aryl radical to an internal alkene or alkyne is known since the 1980s, that via the formation of α-carbonyl radicals from N-aryl amides has appeared within the past two decades.³⁴ The latter type of strategy proceeds through two common pathways: 1. N-aryl amides 64, in the presence of a transition metal mediator, directly undergo SET-induced formation of α-carbonyl radicals, which successively cyclize to give the oxindoles;³⁵ 2. N-arylacrylamides 67, at first, react with a dissimilar radical, generated in situ, to furnish the α-carbonyl radical that consequently cyclizes with the N-aryl ring (Scheme 23).³⁶ However, both pathways demand customized amide substrates for the formation of the α-carbonyl radical.

While the conversion of N-aryl amides 64 into substituted oxindoles generally requires (over)stoichiometric quantities of a transition metal (Scheme 23A), N-arylacrylamides 67 can be converted into oxindoles using a transition metal catalyst (Scheme 23B). In the latter type of transformation, the requisite electrophilic radicals, which attack the α,β-alkenyl double bond, have been generated by oxidative cleavage of a C–H bond in alkanes, active methylene compounds, methyl ketones, etc. or a heteroatom–H bond in benzenesulfinic acid/alkylsulfinic acids, carbazates, diphenylphosphine oxides, etc., as summarized in Scheme 24.

4. Photoredox-catalysed SET-induced transformations through α-carbonyl radical intermediates

In the past two decades, visible light photo-redox catalysis has emerged as an indispensable tool for the construction of various C–C and C–heteroatom bonds. Since MacMillan's pioneering work on the enantioselective alkylation of aldehydes through the combination of aminocatalysis with photoredox catalysis, alkylations of ketones, 2-acylimidazoles and silyl enol ethers with α-halocarbonyl compounds under light irradiation have been documented.^37,38 These reactions proceed via the attack of enamine to the C-centered radicals, formed through a visible light photo-redox catalysed SET process. Recently, examples of α-functionalization of carbonyl compounds, via the photoredox-catalysed cleavage of the α-C(sp³)–H bond, generating α-carbonyl radicals as one of the key steps, have appeared in the literature. Upon photo-irradiation, the excited photocatalyst can often induce SET in electron-rich enolates and their equivalents, such as silyl enol ether, imine, etc., and thereby promote the α-functionalization of the parent carbonyl compounds swiftly under mild conditions. Studies by Curran (1989) and later by Fensterbank and Ollivier (2011) as well as Ma and Cheng (2016) demonstrate that photoreductive transformation of C–X bonds (X = Cl, Br, I, O, NR, etc.) in α-haloketones, keto epoxides, keto aziridine, etc. can occur through the formation of the corresponding α-carbonyl radicals.^39–41 However, these examples are not included in this article, as they do not involve direct carbonyl α-C–H bond cleavage. In addition, advancements, reported up to 2024, in the α-alkylation of ketones, acids and esters with diverse alkenes via the formation of the corresponding α-carbonyl radicals under ultraviolet and/or visible light irradiation are also not included as they were recently reviewed by Kobayashi et al.⁵

4.1. Transformations of ketones, acids, and esters

In 2017, Dixon and co-workers reported a novel approach for the α-alkylation of N-diphenylphosphinoyl ketimines with α-bromo carbonyl compounds. The reaction employs [Ru(bpy)₃]Cl₂·6H₂O and [NiCl₂(PPh₃)₂] as the co-catalytic system and proceeds under irradiation with blue light. Various (substituted) acetophenone derived ketimines were coupled at the α-position with alkyl bromides giving 4-imino acid derivatives and 4-imino ketones (Scheme 25).⁴² However, moderate yields of the desired product were obtained possibly due to E and Z enamine formation and dialkylation of the ketamine substrates (Scheme 25).

In 2024, Wan and co-workers developed a photo-redox catalysed approach for C(sp³)–H/C(sp³)–H homo- and cross-coupling of the α-carbonyl radical intermediates generated from α-hydroxy ketones. The reaction uses an organic dye, such as Rose Bengal, as the photo-redox catalyst in combination with DBU as the base and air as the oxidant to deliver (unsymmetrical) 1,2-diacyl vicinal diols in moderate to good yields (Scheme 26).⁴³ The advantages of this transition metal-free photo-redox catalytic approach combine the use of low-cost reagents and catalysts with mild reaction conditions and provide unconventional access to vicinal diols.

Mechanistic studies indicated that both the base (DBU) and dioxygen are essential components for the reaction. Thus, the proposed mechanism involves the base-promoted generation of enol anion 91 via the reaction of α-hydroxy ketones 87 or 88 with DBU. The resulting enol anion 91 undergoes SET-induced oxidation in the presence of photoexcited Rose Bengal (RB*), leading to the O-centered enol radical 92. Subsequent isomerization of 92 results in the formation of α-hydroxy carbonyl radical 93, which forms the desired product upon dimerization or reacts with the dissimilar α-carbonyl radical. The photoredox cycle is completed by the oxidation of dioxygen to generate superoxide (Scheme 27).

Tan and co-workers developed an α-oxyamination of β-keto esters with TEMPO under photo-redox catalysis. The reaction proceeds via Rose Bengal catalysed SET-induced formation of α-carbonyl radicals from β-keto esters upon fluorescent light (11 W) irradiation and subsequent radical cross-coupling with TEMPO. The strategy was further extended to access α-fluoro-α-hydroxy acid derivatives containing a tetra-substituted α-carbon centre (Scheme 28).⁴⁴ However, the involvement of oxygen as an oxidant was ruled out via a controlled experiment in a glove box, which provided the same yield of the product in the absence of oxygen.

Recently, Ye et al. achieved an (organo)photo-redox catalysed hydroarylation of olefins with 4-hydroxycoumarins 98 as the arylating partner. The reaction proceeds via alcohol assisted 5,6-bis(5-methoxythiophen-2-yl)pyrazine-2,3-dicarbonitrile (DPZ)-promoted SET-induced oxidation of 4-hydroxycoumarins, converting them to α-keto radicals 101. Addition of the α-keto radical to the unactivated olefin 99, followed by hydrogen atom transfer (HAT) from 2,4,6-triisopropylbenzenethiol (TRIPSH), provided the C–C coupled product (Scheme 29).⁴⁵

4.2. Transformations of silyl enol ethers

Silyl enol ethers are shelf-stable synthetic equivalents of enolates that can be readily functionalized at the α-position of the former carbonyl compound. Furthermore, silyl enol ethers are broadly recognized as a protected form of aldehydes, ketones and esters. In 1988, Gassman and coworkers achieved a photoinitiated deprotection of trimethylsilyl enol ether, derived from cyclohexanone, to cyclohexanone.⁴⁶ This method employed biphenyl and 1-cyanonaphthalene, each in 0.5 equivalents with respect to the silyl enol ether to give cyclohexanone in good yield (up to 74%). The photoinitiated removal of the trimethylsilyl group (i.e., desilylation) was highly selective for silyl enol ethers. Thus, the di-O-silylated compound, derived from 4-hydroxycyclohexanone, was successfully transformed into 4-(trimethylsilyloxy)cyclohexanone in 63% yield. The treatment of cyclohexanone trimethylsilyl enol ether 103 with the photoexcited 1-cyanonaphthalene 105*, which is an adequately powerful oxidant to eliminate an electron from 103 (E^ox_1/2 = 1.29 V), furnished the cation-radical 106. The loss of the trimethylsilyl cation from 106 gave the α-carbonyl radical 107, which produced cyclohexanone via hydrogen atom transfer (Scheme 30).

In 1992, Mattay et al. realized the photoinduced oxidative cyclization of δ,ε- and ε,ζ-unsaturated silyl enol ethers via photoinduced electron transfer (PET) using 9,10-dicyanoanthracene (DCA) as a sensitizer (Scheme 31).⁴⁷ From the mechanistic standpoint, the sensitizer DCA in its singlet excited state is a dominant oxidant (E^red_1/2 = −1.28 V vs. Ag/AgNO₃) to remove one electron from silyl enol ether 108 or 112, 113 (E^ox_1/2 = +1.60 V vs. Ag/AgNO₃). The resulting C-centered radical 110 or 115 attacks the alkene intramolecularly, leading to the generation of the cyclohexyl radical cation 111 or 116. Elimination of the trialkylsilyl cation with subsequent hydrogen atom transfer produces the ketone derivatives 109 or 114 in moderate yields (Schemes 31 and 32).

Recently, in 2021, Kobayashi and co-workers have achieved a photo-redox catalytic α-alkylation of silyl enol ethers with alkenes to access α-alkylated ketones (Scheme 33).⁴⁸ The intermediacy of an α-carbonyl radical was proposed, which was generated upon the one-electron oxidation of the silyl enol ether by an excited-state organophoto-redox catalyst (4CzIPN*), in the presence of water.

4.3. Transformations of O-vinylhydroxy amine derivatives

Recently, O-vinylhydroxy amine derivatives have been recognized as important synthons to ketone enolates. In 2020, Hong and co-workers realized the photochemical carbopyridylation of alkenes with O-vinylhydroxy amine derivatives, such as N-alkenoxypyridinium salts.⁴⁹ In this reaction, the photoreduction of the N-alkenoxypyridinium salt furnished α-carbonyl radicals upon the N–O bond cleavage by means of an iridium photo-redox catalyst. The reaction was applicable to a broad range of substrates, giving the coupled products in good to high yields. The strategy also enabled late-stage derivatization of complex molecules and drugs (Scheme 34).

The proposed mechanism is shown in Scheme 35. Upon irradiation with blue LED light, the excited-state Ir* catalyst, formed in situ, facilitates the cleavage of the N–O bond in 121 via a single electron reduction process to form α-carbonyl radical 124′. The subsequent addition of 124′ to the alkene 122 leads to the formation of the radical intermediate 125. The resulting (relatively nucleophilic) alkyl radical 125 then attacks the pyridinium salt 121 to produce an unstable radical cation, 126. Subsequently, 126 may undergo deprotonation, followed by homolytic cleavage of the N–O bond, to give the desired product 123 and α-carbonyl radical 124′, which can begin a new catalytic cycle. On the other hand, a SET-induced oxidation of 126 by [Ir^IV] can form intermediate 127 and regenerates the catalytically active iridium complex. Finally, a SET from [Ir^III*] leads to the formation of product 123 along with the regeneration of 124′.

Shin and co-workers reported a strategy for the intramolecular tandem cyclization of the N-enoxybenzotriazoles to 9-phenanthrols by means of an iridium photo-redox catalyst.⁵⁰ The reaction proceeds through the formation of α-carbonyl radicals under mild reaction conditions using EtOH as the hydrogen atom donor (Scheme 36). A diverse range of 9-phenanthrols were prepared using this strategy.

The reaction pathway involves the homolytic cleavage of the N–O bond in N-enoxybenzotriazoles due to the energy transfer from the excited-state Ir* catalyst, leading to the formation of α-carbonyl radical intermediate 132 and benzotriazolyl radical 130′, which is quenched by hydrogen atom transfer from ethanol. The α-carbonyl radical 132, thus generated, undergoes intramolecular radical addition to the aromatic ring, forming the radical intermediate 133. Abstraction of the α-hydroxy radical, while quenching the benzotriazolyl radical, facilitates aromatization to the desired product and regenerates ethanol. Alternatively, α-hydroxy radical 131 may undergo oxidation to form acetaldehyde and hydrogen gas (Scheme 37).

5. Conclusion and outlook

The present article summarizes catalytic approaches for the α-functionalization of carbonyl compounds, such as ketones, acids, esters, amides and their synthetic equivalents, via the formation of α-carbonyl radicals. It appears that, in the majority of transformations, the α-carbonyl radicals are formed from ketones via the SET-induced oxidation of α-C–H bonds or one-electron oxidation of enolates under transition metal catalysis. The resulting α-carbonyl radicals have been subjected to typically addition reactions with electron-rich alkenes, dioxygen, etc. However, an analogous reaction mode for carboxylic acid equivalents/derivatives is explored to a much less extent, possibly due to featuring less enolizable α-protons. In this context, our group has developed 3d-metal catalysed formation and transformation of α-carbonyl radicals of arylacetic acid equivalents and aryl ketones. We have shown that while these α-carbonyl radicals can directly undergo addition to dioxygen, their cross-coupling with a dissimilar C-centered radical species, i.e., C–C bond formation, took place on a metal catalyst, opening a new avenue in the area of transition metal catalysed cross-coupling reactions via radical chemistry. Current literature also suggests that a few photoredox catalysts can also enable transformations of α-carbonyl radicals; however, most of these transformations demand ketones and their synthetic equivalents as substrates. Nonetheless, photoredox catalysis has the potential to realize α-functionalization of carboxylic acids and/or equivalents via α-carbonyl radicals. Together, these metal-catalysed and photoredox-catalysed strategies can be used for the synthesis and late stage functionalization of structurally diverse complex molecules. Despite the many successes, the scope of the asymmetric variants of these SET induced processes is thus far inadequate. Alternatively, the selective one-electron oxidation of enol, which exists in equilibrium with its keto form, can be realized by understanding the associated electrochemistry aspects. While the selective coupling of ethylcyanoacetate with unactivated alkenes by means of Mn³⁺-mediated anodic oxidation has appeared as early as 1990s, relatively fewer efforts have been made on the conversion of electrochemically generated α-carbonyl radicals.^51,52 Nonetheless, these gaps may be filled in the near future. It should be noted that a few transformations are also known to involve SET oxidation of α-C–H bonds of enamines under visible light photo-redox catalysis.⁵³ However, further efforts are required to be made in this direction to achieve more useful strategies in organic synthesis. We firmly believe that the SET induced α-C–H bond functionalization that proceeds through an α-carbonyl radical intermediate will surely modernize the classical organic synthesis and be worthwhile in both academia and industry.

Conflicts of interest

There are no conflicts to declare.

Data availability

No primary research results are included and no new data were generated or analysed as part of this review.

Acknowledgements

We sincerely thank the CSIR (CSMCRI project no. MLP 0077, fellowship to AKS), ANRF (erstwhile SERB, grant no. CRG/2022/003868), and CSIR-CSMCRI communication no. 107/2025.

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