Recent Advances in Photoinduced Ketyl and Ketyl-Type Radical Generation from Aldehyde Derivatives

Abstract

Ketyl radical generation from carbonyls is an important strategy in organic synthesis that enables common electrophilic functional groups to be transformed into nucleophilic radicals. However, the large negative reduction potentials of carbonyls mean that direct conversion to ketyl radicals by single-electron reduction is challenging and requires strongly reducing conditions. As a result, alternative strategies to access these useful radical intermediates have been developed that circumvent traditional reductive pathways. For example, recent reports have demonstrated that aldehydes can be converted into various activated aldehyde derivatives that are readily transformed to ketyl radicals or protected ketyl (ketyl-type) radicals through mechanistically distinct pathways, including photoinduced single-electron oxidation and halogen atom transfer. Herein, we review the synthesis and applications of different aldehyde derivatives that have been developed to allow facile access to ketyl and ketyl-type radicals under mild visible-light photochemical conditions.

 

MissingLinkText

Keywords

Ketyl radicals - Ketyl-type radicals - Photocatalysis - Photoredox catalysis - Halogen atom transfer - Dual photoredox/nickel catalysis

1

Introduction

Ketyl radicals are valuable reactive intermediates that are traditionally generated by single-electron reduction of carbonyl compounds.[1] Importantly, these nucleophilic radicals provide umpolung reactivity compared to inherently electrophilic carbonyls, thus significantly expanding the diversity of synthetic transformations of these readily available functional groups. However, the reductive formation of ketyl radicals from carbonyls is challenging due to their large negative reduction potentials ([Scheme 1]).[2] This necessitates the use of forcing reaction conditions, including powerful metal reductants (e.g., SmI₂),[3] UV irradiation in the presence of stoichiometric electron donors,[4] or deeply reductive electrochemistry.[5] Whilst these methods have found widespread synthetic utility, the use of such strongly reducing conditions inevitably limits functional group compatibility. Recent advances in visible-light photocatalysis have provided milder methods to form ketyl radicals, although these are mostly limited to aromatic aldehydes and ketones, and typically require additional Brønsted or Lewis acid activation of the carbonyl for productive single-electron reduction.[6] [7]

Scheme 1 Ketyl radicals by direct reduction of carbonyls.

An alternative approach to ketyl radical generation from aldehydes that avoids the challenging direct single-electron reduction is via initial activation to form aldehyde derivatives ([Scheme 2]).[8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] These activated intermediates can afford ketyl radicals via mechanistically distinct pathways that are less energetically demanding than carbonyl reduction.[16] [17] [18] [19] Moreover, ketyl-type radicals, where the oxygen atom is functionalized with a protecting group, can also be generated from aldehyde derivatives, and display similar reactivities to unprotected ketyl radicals.[8] [9] [10] [11] [12] [13] [14] [15] In recent years, the application of aldehyde derivatives to enable generation of ketyl(-type) radicals from both aromatic and aliphatic aldehydes has significantly expanded the synthetic utility of these valuable reactive intermediates. In this short review, we summarize the key developments in this area, focusing on the generation of ketyl and ketyl-type radicals from aldehyde derivatives using visible-light photocatalysis. It is important to note that ketyl and ketyl-type radicals can also be accessed by photoinduced hydrogen atom transfer (HAT) from the α-position of alcohols and ethers, respectively.[20] However, herein we focus on reactions of ketyl radicals derived from aldehydes.

Scheme 2 Ketyl and ketyl-type radical generation via aldehyde derivatives.

 

MissingLinkText

2

Aldehyde Derivatives for Ketyl(-Type) Radical Generation

This short review is arranged into two main sections based on the type of ketyl radicals that are formed from the aldehyde derivatives: ketyl radicals or ketyl-type radicals. Aldehyde derivatives that have been developed for the generation of ketyl-type radicals can be divided into four different classes: α-hydroxy silanes,[8] α-alkoxy trifluoroborates,[9] α-silyloxy sulfinates,[10] [11] and α-acyloxy halides ([Fig. 1a]-[1]).[12] [13] [14] [15] With the exception of α-hydroxy silanes, all these aldehyde derivatives have a protecting group on the oxygen that is preserved throughout the ketyl-type radical formation and subsequent reaction. For α-hydroxy silanes, a radical-mediated [1,2]-silyl (Brook) rearrangement leads to α-silyloxy radicals, thus providing an alternative in situ hydroxy protection strategy for ketyl-type radical formation.[8] The development and applications of these ketyl-type radical precursors are discussed in Section 3 of this review.

In contrast to aldehyde derivatives that have been applied to the formation of ketyl-type radicals, application of this approach to the generation of unprotected ketyl radicals is less well developed. To date, only three classes of aldehyde derivatives have been reported: α-hydroxy trifluoroborates,[16] [17] α-hydroxy carboxylic acids,[18] and α-hydroxy sulfinates ([Fig. 1a]-[2]).[19] In all these cases, unprotected ketyl radical or ketyl radical anion intermediates are generated, leading to alcohol products. The aldehyde derivatives that provide access to unprotected ketyl radicals are discussed in Section 4.

An advantage of the use of aldehyde derivatives as precursors to ketyl(-type) radicals is that they circumvent the challenging direct single-electron reduction that is traditionally required for ketyl radical formation from carbonyls. The mechanisms for converting aldehyde derivatives into their respective ketyl(-type) radicals most commonly require single-electron oxidation ([Fig. 1b], left), contrasting the established reductive pathway. This oxidation triggers either a rearrangement (e.g., radical Brook rearrangement) or an extrusion event (e.g., deboronation, decarboxylation, or desulfination). Alternatively, halogen atom transfer (XAT) reactions have been applied to the formation of ketyl-type radicals from α-acyloxy halides ([Fig. 1b], right). Importantly, these mechanistically distinct pathways for ketyl(-type) radical formation avoid strongly reducing reaction conditions, which provides opportunities for their application to the synthesis of products that are inaccessible using conventional ketyl radical chemistry.

Fig. 1 Overview of aldehyde derivatives as precursors to ketyl and ketyl-type radicals.

When comparing the synthetic utility of aldehyde derivatives to classic reductive ketyl(-type) radical formation, an important factor to consider is their ease of synthesis. For example, most of the reported aldehyde derivatives require multi-step synthesis and isolation before use.[8] [9] [10] [11] [16] [17] However, several examples exist that can be generated in situ directly from aldehydes and used without isolation ([Fig. 1c]),[12] [13] [14] [15] [19] thus significantly simplifying their applications.

Another important factor that must be considered during the development of reactions of aldehyde derivatives is the reactivities of the radicals that they produce, which, in the context of ketyl-type radicals can differ substantially from those of unprotected ketyl radicals. This is because the protecting group on oxygen of a ketyl-type radical can have a large impact on its polarity, and, as a result, can dramatically influence its reactivity and potential synthetic applications. Recently, the Nagib group reported computed electrophilicity (ω) values of over 500 radical species, including examples of ketyl and ketyl-type radicals ([Fig. 2]).[21] Although all ketyl-type radicals were calculated to be nucleophilic, their polarities ranged from 0.6 eV (α-alkoxy radicals) to 1.1 eV (α-benzoyloxy radicals), representing dramatically different reactivities (up to 20-fold difference in reaction rates). Therefore, it is possible to modify the oxygen-substituent on ketyl-type radicals to achieve both comparable and complementary reactivity to that of unprotected ketyl radicals.

Fig. 2 Calculated electrophilicity (ω) values of ketyl(-type) radicals.

 

MissingLinkText

3

Ketyl-Type Radical Precursors

3.1

α-Hydroxy Silanes

In 2017, Smith and co-workers demonstrated the utility of α-hydroxy silanes 1 as ketyl-type radical precursors,[8] providing α-silyloxy radicals via a photoredox-catalyzed [1,2]-Brook rearrangement.[22] These aldehyde derivatives were shown to be versatile reagents, with successful application to both Giese-type additions to electron-deficient olefins and arylations with cyanoarenes.[8] However, a limitation of α-hydroxy silanes is their lengthy synthesis from aldehydes, which requires a four-step process via dithiane intermediates, albeit with typically good overall yields upwards of 60% ([Scheme 3]).

Scheme 3 Synthesis of α-hydroxy silanes from aryl aldehydes.

The [1,2]-Brook rearrangement of α-hydroxy silanes 1 proceeds via a hypervalent silicon intermediate 3, which displays a much more modest oxidation potential than 1 ([Scheme 4]).[8] Therefore, mild photoredox-catalyzed conditions may be used to oxidize 3, producing a silyl-protected ketyl radical 4. For the Giese reactions, [Ir(dF[CF₃]ppy)₂(dtbbpy)]PF₆ (Ir-1) was used as the photoredox catalyst, which reacts via a reductive quenching cycle wherein the excited state catalyst [Ir(III)*] undergoes single-electron transfer (SET) with 3 to trigger Si–C bond cleavage and form 4. Reaction of 4 with an electron-deficient olefin, followed by SET and protonation generates the ketyl–olefin coupling product 2. Steric hindrance at silicon was shown to not affect the yield of this reaction, and various electron-rich aromatic rings on 1 were tolerated, although the reaction was inhibited by electron-withdrawing groups (e.g., CF₃).

Scheme 4 Reaction of α-hydroxy silanes with olefins via ketyl-type radicals (DCE = 1,2-dichloroethane).

Whilst the Giese additions proceeded via reductive quenching of Ir-1 by the hypervalent silicon species 3, oxidative quenching of the excited state of Ir(ppy)₃ (Ir-2) by electron-deficient cyanoarenes was used to achieve arylations of ketyl-type radicals 4 ([Scheme 5]).[8] This oxidative quenching forms an arene radical anion alongside Ir(IV), which is able to oxidise 3 to form 4. Radical–radical coupling followed by elimination of cyanide yields the arylated product 5. Regarding the substrate scope of this reaction, high yields were observed for both election-donating and electron-withdrawing substituents bound to the aromatic ring of α-hydroxy silane 1. Various electron-deficient cyanoarenes were also coupled successfully, including 4-cyanopyridines and benzonitriles bearing esters and sulfones.

Scheme 5 Arylation of α-hydroxy silanes with cyanoarenes via ketyl-type radicals (DMA = N,N-dimethylacetamide).

 

MissingLinkText

3.2

α-Benzyloxy Trifluoroborates

In 2012, the Molander group reported a three-step synthetic route to access α-benzyloxy trifluoroborates 7 from aldehydes ([Scheme 6]).[23] This involves a copper-catalyzed borylation followed by treatment with KHF₂ to generate α-hydroxy trifluoroborates 6, which were protected with benzyl bromide to afford 7 in moderate to excellent yields.

Scheme 6 Synthesis of α-benzyloxy trifluoroborates.

Following this, in 2016, the same group reported a dual photoredox/nickel catalyzed system that provided protected benzylic alcohols 8 by direct cross-coupling of α-benzyloxy trifluoroborates 7 with (hetero)aryl bromides ([Scheme 7]).[9] Deboronative ketyl-type radical generation was achieved by photoinduced SET between 7 and an iridium photoredox catalyst ([Ir(dF[CF₃]ppy)₂(bpy)]PF₆, Ir-3). Subsequent cross-coupling with (hetero)aryl bromides, mediated by a nickel co-catalyst, afforded benzyl-protected secondary benzylic alcohols 8 in moderate to excellent yields. Despite the limited mechanistic detail provided in this report, the mechanism of this transformation is likely analogous to that reported for related dual photoredox/nickel-catalyzed cross-couplings of alkyl trifluoroborates,[24] which is discussed in more detail in Section 4.1 of this review. Multiple alkyl-substituted α-benzyloxy trifluoroborates were successfully coupled, including both linear and α-branched substrates. Various (hetero)aryl halides were tolerated, including those containing potentially reactive functional groups, such as aldehydes, protic nitrogen substituents, and unprotected alcohols. In addition to α-benzyloxy trifluoroborates 7, the authors demonstrated this cross-coupling was applicable to other protected α-hydroxy trifluoroborates, including those bearing pivalate and carbamate protecting groups. However, a limitation was observed during the attempted cross-coupling of benzaldehyde-derived trifluoroborates, which was hypothesized to result from the lower reactivity of the benzylic ketyl-type radicals with the nickel catalyst.

Scheme 7 Dual photoredox/Ni-catalyzed cross-coupling of α-benzyloxy trifluoroborates and (hetero)aryl bromides (dtbbpy = 4,4'-di-tert-butyl-2,2'-dipyridyl).

 

MissingLinkText

3.3

α-tert-Butyldimethylsilyloxy Sulfinates

Rongalite is a commercially available reagent that is easily generated from formaldehyde and sodium dithionite.[25] tert-Butyldimethylsilyl (TBS) protection of the alcohol group of Rongalite provides TBS-Rongalite 9 ([Scheme 8]), which has most commonly been used as a sulfur dioxide dianion (sulfoxylate) equivalent for the synthesis of sulfones and sulfonyl derivatives.[26] However, 9 has recently been employed as a ketyl-type radical precursor, achieved via oxidative desulfination of the sulfinate group.[10] [11]

Scheme 8 Synthesis of TBS-Rongalite from Rongalite

In 2022, Moschitto and co-workers reported the desulfinative silyloxymethylation of pyridine and quinoline N-methoxide salts 10, employing TBS-Rongalite (9) as the alkylating agent.[10] Irradiation of a mixture of 9 and 10, with eosin Y (EY) as the photocatalyst, gave the corresponding silyloxymethylated products 11 in moderate to good yields ([Scheme 9]). Alkylation at the C2 position of the heteroarenes was preferred over C4, and the use of N-methoxide salts was crucial, as simple quinoline and pyridine derivatives gave no desired products. The mechanism proposed for this photocatalytic process is a radical chain pathway initiated through oxidative quenching of photoexcited eosin Y (EY*) by the pyridine/quinoline N-methoxide salts 10, generating pyridine/quinoline and a methoxy radical. Stern-Volmer quenching studies revealed that 10 quenches EY* whilst TBS-Rongalite (9) does not. The methoxy radical then promotes oxidative desulfination of 9 to form primary ketyl-type radical 12, which undergoes Minisci-like addition to 10. Rearomatization through deprotonation and N–O bond cleavage gives product 11 and regenerates a methoxy radical to propagate the radical chain. Interestingly, it was reported that this transformation can proceed in good yields in the absence of photocatalyst and/or light, albeit with longer reaction times. This was proposed to result from the formation an electron donor–acceptor (EDA) complex between 9 and 10, as supported by UV/vis absorption spectroscopy, which enabled SET-induced desulfination of 9 to generate ketyl-type radical 12. The authors demonstrated that this photocatalyst-free protocol was also applicable to a range of pyridine and quinoline N-methoxide salts.

Scheme 9 Desulfinative silyloxymethylation of pyridine and quinoline N-methoxides with TBS-Rongalite via a ketyl-type radical intermediate.

Recently, Lee and co-workers disclosed a dual photoredox/nickel-catalyzed desulfinative cross-coupling of TBS-Rongalite (9) with (hetero)aryl halides to access silyloxymethylated products 13 ([Scheme 10]).[11] Using [Ru(bpy)₃]Cl₂ (Ru-1) as a photoredox catalyst along with a nickel co-catalyst, the authors obtained moderate to excellent yields of 13 with a variety of (hetero)aryl bromides and iodides as coupling partners. In general, (hetero)aryl iodides gave higher yields than bromides, with the exception of very electron-deficient aryl bromides (e.g., 4-bromobenzophenone and 4-bromobenzonitrile). The silyloxymethylation reaction was also successful for alkenyl iodides and triflates, and was demonstrated to be applicable to the late-stage functionalization of a derivative of a pharmaceutical agent, albeit in a relatively low yield. The authors proposed a mechanism involving SET between the excited state photocatalyst and TBS-Rongalite (9) to generate primary ketyl-type radical 12 through desulfination. It was speculated that the excess DBU used was essential for SO₂ sequestration. Radical capture of 12 by a Ni⁰ species followed by oxidative addition of an aryl halide (or oxidative addition followed by reaction with 12) generates a Ni^III species that reductively eliminates the silyloxymethylated product 13, with the resulting Ni^I species engaging in SET with the reduced state photocatalyst to complete both catalytic cycles. Although the authors proposed this Ni⁰/Ni^I/Ni^III cycle, based on the use of the anionic diketonate ligand on nickel, it is likely that an alternative mechanism is involved that proceeds via oxidative addition of the aryl halide to Ni^I to form an aryl-Ni^III bromide, which subsequently reacts with ketyl-type radical 12 to give 13.[24]

Scheme 10 Dual photoredox/Ni-catalyzed cross-coupling of TBS-Rongalite with (hetero)aryl halides (TMHD = 1,1,6,6-tetra-methylheptane-2,5-dione).

 

MissingLinkText

3.4

α-Acyloxy Halides

α-Acyloxy alkyl halides, including chloride, bromide and iodide-derivatives, are readily synthesized from aldehydes and acyl halides. Although their preparation was first reported over a century ago,[27] synthetic utilization of these adducts has remained underdeveloped until recently.[28] Since 2018, there have been numerous reports describing the application of these aldehyde derivatives in photocatalytic dehalogenative carbon–carbon bond forming reactions via ketyl-type radical intermediates.[12] [13] [14] [15]

Scheme 11 Synthesis of α-acetoxy iodides.

In 2018, Nagib and co-workers disclosed the seminal report of photocatalytic ketyl-type radical generation from α-acetoxy iodides, which was achieved using a halogen atom transfer (XAT) approach.^12a The α-acetoxy iodides 14 can be synthesized via electrophilic activation of aldehydes by acetyl iodide under solvent-free conditions, and isolated after aqueous workup ([Scheme 11]). However, an important advance provided by this report was the demonstration that these aldehyde derivatives could be generated in situ, which allowed direct access to ketyl-type radicals from aldehydes ([Scheme 12]). The authors developed an atom transfer radical addition (ATRA) reaction of the α-acetoxy iodide intermediates 14 with terminal alkynes using a manganese XAT photocatalyst, yielding synthetically useful alkenyl iodides 15 with high Z-selectivities. The proposed mechanism for this reaction is initiated by photolysis of Mn₂(CO)₁₀ to generate a manganese radical species ([Mn]^•), which undergoes XAT with 14 to form a manganese iodide and α-acetoxy (ketyl-type) radical 16. Addition of 16 to the alkyne affords an alkenyl radical intermediate 17, which reacts with the manganese iodide by XAT to give alkenyl iodide 15 and close the catalytic cycle. Of note, high Z-selectivities were observed due to a Mn-catalyzed post-reaction isomerization. A broad range of aliphatic aldehydes were successfully coupled with both activated and unactivated alkynes. Furthermore, the aldehyde derivatives also reacted with activated olefins, affording γ-acetoxy iodides in moderate to good yields, but with low diastereoselectivities, a process that has recently been applied to a one-pot synthesis of oxetanes.[29]

Scheme 12 Halogen-atom-transfer (XAT)-mediated coupling of α-acetoxy iodides with alkynes via ketyl-type radicals.

The Nagib group later extended this XAT photocatalytic strategy to reductive couplings of in situ-generated α-acetoxy iodides with imines, aldehydes, and electron-deficient olefins and alkynes ([Scheme 13]).^12b For these reductive reactions, a tertiary amine and zinc were employed as sacrificial reductants to facilitate product formation and enable turnover of the manganese catalytic cycle. This strategy was recently extended to the synthesis of acetyl-protected propargyl alcohols through coupling of α-acetoxy iodide-derived ketyl-type radicals with alkynyl sulfones.[30]

Scheme 13 Halogen-atom-transfer (XAT)-mediated reductive coupling of α-acetoxy iodides with imines, aldehydes, olefins, and alkynes.

In 2022, Glorius and co-workers reported a related process for the generation of ketyl-type radicals by XAT from α-benzoyloxy bromides 19, which were prepared in situ from aldehydes and benzoyl bromide and applied to dual photoredox/nickel-catalyzed cross-couplings with aryl bromides ([Scheme 14]).[13] The reactions used [Ir(dF[CF₃]ppy)₂(dtbbpy)]PF₆ (Ir-1) and a nickel–bipyridine complex as the catalysts and employed tris(triethylsilyl)silane as the XAT reagent. The proposed mechanism involves single-electron oxidation of a bromide anion by the excited state photocatalyst to form a bromine radical, which undergoes hydrogen atom transfer (HAT) with the silane to produce a nucleophilic silyl radical. Subsequent XAT between the silyl radical and 19 gives α-benzoyloxy radical 20. For the nickel catalytic cycle, oxidative addition of the aryl halide to a Ni^I complex provides a Ni^III intermediate that is reduced to Ni^II by the reduced state of the photocatalyst. Capture of 20 by the Ni^II species, followed by reductive elimination gives the cross-coupled product 18. A broad range of aliphatic aldehydes and electron-deficient aryl bromides underwent successful cross-couplings, whereas attempts at generating ketyl-type radicals from ketones were unsuccessful.

Scheme 14 Dual photoredox/Ni-catalyzed cross-coupling of aldehydes and aryl bromides via α-benzoyloxy bromide intermediates (L1 = 4,4′-dimethoxy-2,2′-bipyridine).

Subsequent reports have extended the application of α-benzoyloxy and α-acetoxy bromides in dual photoredox/nickel-catalyzed cross-couplings,[14] including enantioselective arylations and acylations using chiral nickel complexes.[15] Additionally, the ketyl-type radicals generated from these aldehyde derivatives have been applied to allylation,[31] alkenylation,[32] and cyclopropanation reactions.[33]

 

MissingLinkText

 

MissingLinkText

4

Ketyl Radical Precursors

4.1

α-Hydroxy Trifluoroborates

As discussed above, the Molander group reported a one-pot, two-step synthesis of α-hydroxy trifluoroborates 6 from aldehydes ([Scheme 6]).[23] A range of alkyl and aryl aldehydes were transformed into the corresponding α-hydroxy trifluoroborates, which are easy-to-handle solids that can be stored on the benchtop under ambient conditions. In 2017, the same group demonstrated their application in dual photoredox/nickel-catalyzed cross-couplings with aryl bromides, providing direct access to secondary benzylic alcohols 21 via ketyl radical intermediates 22 ([Scheme 15]).[16] This method expanded on the group’s aforementioned deboronative cross-coupling of α-benzyloxy trifluoroborates (see section 3.2),[9] using similar conditions with a nickel–bipyridine catalyst and [Ir(dF[CF₃]ppy)₂(bpy)]PF₆ (Ir-3) as the photocatalyst. The proposed mechanism involves single-electron oxidation of 6 by the excited state Ir^III catalyst, leading to ketyl radical 22 through loss of BF₃. Reaction of 22 with a Ni⁰ species produces a Ni^I intermediate that undergoes oxidative addition with the aryl bromide to generate a Ni^III species. Reductive elimination then yields the benzylic alcohol product 21. Finally, SET between the resulting Ni^I species and the reduced Ir^II catalyst completes both the nickel and photoredox catalytic cycles. The iridium photocatalyst was reported to be crucial for effective coupling, with numerous organic photocatalysts resulting in either no desired product or low yields. The addition of a base (K₂HPO₄) was found to be essential for achieving high yields, which was attributed to its role in sequestering the BF₃ formed during deboronative ketyl radical generation. A wide range of electron-poor aryl bromides, and a single electron-rich aryl bromide, were successfully coupled with the α-hydroxy trifluoroborates. Numerous electrophilic functional groups were tolerated, including aldehydes, ketones and lactones, all of which would be incompatible with the traditional approach to the same products via addition of aryl Grignard reagents to carbonyls. The authors also showed that various aliphatic α-hydroxy trifluoroborates could engage in the cross-coupling with aryl halides, including sterically demanding substrates bearing adjacent tertiary alkyl groups.

Scheme 15 Dual photoredox/Ni-catalyzed cross-coupling of α-hydroxy trifluoroborates with (hetero)aryl bromides via ketyl radical intermediates.

In the same year, Molander and co-workers reported a photoredox-catalyzed method for generating gem-difluoroalkenes 24 by reaction of a range of radical precursors with trifluoromethyl-substituted alkenes 23 ([Scheme 16]).[17] Two examples of successful reactions of α-hydroxy trifluoroborates 6 were included, one of which proceeded via a secondary ketyl radical intermediate (aldehyde-derived) and the other via a tertiary ketyl radical intermediate (ketone-derived). The gem-difluoroalkenes 24 were obtained in good yields when the organic photocatalyst 4CzIPN was used. For the mechanism, SET-induced deboronation of 6 by the excited state photocatalyst generates ketyl radical 22, which adds to the alkene of 23. Single-electron reduction of the resulting benzylic radical to a carbanion by the reduced-state photocatalyst, followed by E1cB-type fluoride elimination yields the gem-difluoroalkene product 24.

Scheme 16 Deboronative coupling of α-hydroxy trifluoroborates with trifluoromethyl alkenes via ketyl radical intermediates.

 

MissingLinkText

4.2

α-Hydroxy Carboxylic Acids

In 2024, the Luisi group reported the photoredox-catalyzed decarboxylation of α-hydroxy carboxylic acids 25 to form unprotected ketyl radicals, which were engaged in Giese reactions with electron-deficient olefins ([Scheme 17]).[18] Whilst the α-hydroxy carboxylic acids used in this study should not be regarded as aldehyde derivatives because they were not prepared from aldehydes, we have included this class of ketyl radical precursors in this review because many are commercially available and derived from natural chemical feedstocks. The authors used the organic photoredox catalyst 4CzIPN, which promotes oxidative decarboxylation of α-hydroxy carboxylate 27 (formed upon deprotonation of 25) to generate ketyl radical 22. Addition of the nucleophilic radical 22 to the electrophilic olefin forms alkyl radical 28, which is reduced by the radical anion of 4CzIPN and protonated to give the alcohol product 26. Several classes of olefins were shown to react in high yields, including acrylates, acrylamides, enones, vinyl aromatics, alkenyl phosphonates, and various alkenyl sulfur derivatives. In addition, a range of α-hydroxy carboxylic acids were successfully applied to the decarboxylative couplings, including several naturally occurring examples, which provided efficient access to primary, secondary, and tertiary alcohol products. Of note, a rare example of a C1 homologation was demonstrated using glycolic acid, which reacted efficiently with a variety of alkenes via a hydroxymethyl radical intermediate.

Scheme 17 Decarboxylative coupling of α-hydroxy carboxylic acids with olefins via ketyl radical intermediates (EWG = electron-withdrawing group).

 

MissingLinkText

4.3

α-Hydroxy Sulfinates

In 2024, our group reported the use of α-hydroxy sulfinates 29 as precursors for ketyl radical generation.[19] These sulfinate salts are synthesized via nucleophilic activation of aldehydes by sulfoxylate (SO₂ ²⁻), which is released from thiourea dioxide (TDO) in aqueous hydroxide solution ([Scheme 18]). For example, the benzaldehyde-derived α-hydroxy sulfinate 29a could either be isolated by precipitation on a gram scale in 71% yield or generated quantitively in situ on a reaction-relevant scale. Cyclic voltammetry analysis of 29a revealed its low oxidation potential (E _p/2 = 0.33 V vs. SCE in H₂O/MeCN), highlighting the facile single-electron oxidation of these sulfinate aldehyde derivatives.

Scheme 18 Synthesis of α-hydroxy sulfinates.

We demonstrated the application of α-hydroxy sulfinates 29 in photoredox-catalyzed aldehyde–olefin coupling reactions, using eosin Y (EY) as the photocatalyst ([Scheme 19]).[19] For the proposed mechanism, the in situ-generated aldehyde derivative 29 is oxidized by photoexcited eosin dianion (*EY ^2–) in the presence of hydroxide to generate sulfonyl radical 31, which eliminates SO₂ to form ketyl radical anion 32. Given the basic reaction conditions and the relatively high acidity of ketyl radicals (pK _a ∼ 8),[34] radical anion 32 should be favored over the neutral ketyl radical 22. Addition of 32 to the olefin and protonation of the alkoxide by H₂O gives alkyl radical 33, which is reduced to carbanion 34 by the photocatalyst and protonated to give the coupled product 30. A broad range of aromatic aldehydes and electron-deficient aromatic olefins were demonstrated to undergo successful coupling, and this sulfoxylate-mediated strategy was also applicable to intramolecular aldehyde–olefin couplings. This report constituted the first example of unprotected ketyl radical formation from in situ-generated aldehyde derivatives, therefore providing a practically simple, yet mechanistically distinct, alternative to traditional reductive ketyl radical formation from carbonyls.

Scheme 19 Reductive coupling of aldehydes with olefins via ketyl radical anions generated by desulfination of in situ formed α-hydroxy sulfinates.

 

MissingLinkText

 

MissingLinkText

5

Conclusions

In conclusion, we have summarized recent advances in photoinduced generation of ketyl(-type) radicals from aldehyde derivatives and their applications in a diverse range of carbon–carbon bond forming reactions, including alkylations, (hetero)arylations, alkenylations, allylations, and (aza)-pinacol couplings. In general, single-electron oxidation and halogen atom transfer approaches have been employed to afford the reactive intermediates, thus avoiding the challenging single-electron reduction pathways that have historically dominated ketyl radical formation from carbonyls.

Both ketyl and ketyl-type radicals have been shown to display similar nucleophilic reactivities, including in additions to electron-deficient olefins and in nickel-catalyzed cross-couplings. For ketyl-type radicals, given their radical polarities can differ substantially depending on the protecting group on oxygen,[21] those with strongly electron-withdrawing protecting groups have been shown to display somewhat ambiphilic reactivity, with α-acetoxy radicals also adding to unactivated π-systems.^12a However, a systematic comparison of the reactivities of different ketyl-type radicals across a broader range of transformations has not been performed,^9a yet could identify opportunities for tailoring the reactivity of ketyl-type radicals to favor specific reaction pathways.

With respect to the versatility of the different aldehyde derivatives that have been used to access ketyl(-type) radicals, limitations still exist. For example, reactions of α-hydroxy silanes and α-hydroxy sulfinates have been limited to aromatic aldehydes.[8] [19] [35] Conversely, only aliphatic aldehydes are suitable for reactions of α-benzyloxy trifluoroborates,[9] α-hydroxy trifluoroborates,[16] [17] and α-acyloxy halides.[12] [13] [14] [15] [29] [30] [31] [32] Whereas, α-silyloxy sulfinates have only be applied to the synthesis of formaldehyde-derived primary alcohol products.[10] [11] Whilst α-hydroxy carboxylic acids should not currently be considered as aldehyde derivatives, they have displayed the greatest versatility, with successful application to the synthesis of both benzylic and aliphatic alcohols, including primary, secondary and tertiary examples.[18] For the aldehyde derivatives where limitations were reported, some insights have been provided: Reductive couplings of aromatic aldehyde-derived α-acetoxy halides with imines failed because reduction of the ketyl-type radical outcompeted carbon–carbon bond formation;^12b,29 reactions α-benzoyloxy bromides are limited to aliphatic aldehydes due to the unsuccessful activation of benzaldehydes with benzoyl bromide;[31] and nickel-catalyzed cross-couplings of benzylic α-benzyloxy trifluoroborates were postulated to be inefficient because the enhanced stability of the ketyl-type radical hinders reaction with the nickel catalyst.^9a

In terms of their synthetic utility, most of the aldehyde derivatives reported to date require separate synthesis and isolation before use, which is because of the incompatibilities between the conditions required for their synthesis and subsequent radical reactions. However, ketyl-type radicals are accessible from α-acyloxy halides generated in situ from aldehydes and acyl halides, which represents an attractive practical advantage over other strategies and has resulted in a significant increase in reports of their use over the last five years. In addition, the recent application of α-hydroxy sulfinates in aldehyde–olefin couplings has demonstrated that in situ aldehyde derivative formation can be extended to reactions of unprotected ketyl radicals. We expect the employment of aldehyde derivatives as precursors to ketyl and ketyl-type radicals will continue to broaden the landscape of radical-based carbonyl transformations and provide valuable alternatives to traditional approaches that leverage single-electron reduction for ketyl radical formation.

 

MissingLinkText

 

MissingLinkText

Zhihang Li

Zhihang Li studied chemistry at Imperial College London (BSc, 2020), completing his final year project in the group of Prof. Anthony Barrett. He then completed his MPhil studies (2021) at the University of Cambridge in the group of Prof. Michele Vendruscolo. In 2022, he joined the Noble group at the University of Bristol to work on photoredox methodologies upon completion of the 8-month training by the EPSRC Centre for Doctoral Training (CDT) in Technology Enhanced Chemical Synthesis.

Harry Meats

Harry Meats graduated from the University of Sheffield with an MChem degree in Chemistry (2022), completing his final year project in the group of Dr. Benjamin Partridge. In 2023, he joined the EPSRC Centre for Doctoral Training (CDT) in Technology Enhanced Chemical Synthesis at the University of Bristol, and upon completion of the 8-month Technology and Automation Training Experience, joined the Noble group to work on the development of photoredox methodologies.

Tomos Alderman

Tomos Alderman graduated with an MChem degree from Durham University in 2023, completing his Master’s research project as a visiting student in Queen’s University, Canada, under the supervision of Prof. P. Andrew Evans. Following this, he started his Ph.D. in the Noble Group at Bristol University in 2024, where he works on photoredox catalysis.

Adam Noble

Adam Noble graduated from the University of Nottingham with an MSci degree in Chemistry (2008) and completed his Ph.D. at University College London under the supervision of Prof. Jim Anderson (2012). He then carried out postdoctoral research with Prof. David MacMillan at Princeton University (2012–2014) and with Prof. Varinder Aggarwal at the University of Bristol (2014–2017). In 2017, he became the Research Officer in the Aggarwal group at the University of Bristol. He was promoted to Research Fellow in the Aggarwal group in 2022 and then to an independent lectureship in 2025. His group’s research interests include the development of synthetic methodologies using visible-light photochemistry, focusing on radical anion chemistry and carbon–carbon bond cleavage reactions.

Conflict of Interest

The authors declare that they have no conflict of interest.

• References

• 1 Péter Á, Agasti S, Knowles O, Pye E, Procter DJ. Chem Soc Rev 2021; 50: 5349
• 2 Roth HG, Romero NA, Nicewicz DA. Synlett 2016; 27: 714
• 3a Beemelmanns C, Reissig H-U. Chem Soc Rev 2011; 40: 2199
• 3b Streuff J. Synthesis 2013; 45: 281
• 3c Szostak M, Fazakerley NJ, Parmar D, Procter DJ. Chem Rev 2014; 114: 5959
• 3d Bongso A, Roswanda R, Syah YM. RSC Adv 2022; 12: 15885
• 4a Belotti D, Cossy J. Tetrahedron 2006; 62: 6459
• 4b Seo S, Jamison TF. Org Lett 2019; 21: 10159
• 5a Shono T, Mitani M. J Am Chem Soc 1971; 93: 5284
• 5b Shono T, Kashimura S, Mori Y, Hayashi T, Soejima T, Yamaguchi Y. J Org Chem 1989; 54: 6001
• 5c Hu P, Peters BK, Malapit CA, Vantourout JC, Wang P, Li J, Mele L, Echeverria P-G, Minteer SD, Baran PS. J Am Chem Soc 2020; 142: 20979

For selected examples of photoredox-catalyzed ketyl radical formation from aromatic aldehydes and ketones, see:
• 6a Rono LJ, Yayla HG, Wang DY, Armstrong MF, Knowles RR. J Am Chem Soc 2013; 135: 17735
• 6b Petronijević FR, Nappi M, MacMillan DWC. J Am Chem Soc 2013; 135: 18323
• 6c Nakajima M, Fava E, Loescher S, Jiang Z, Rueping M. Angew Chem, Int Ed 2015; 54: 8828
• 6d Fava E, Millet A, Nakajima M, Loescher S, Rueping M. Angew Chem, Int Ed 2016; 55: 6776
• 6e Qi L, Chen Y. Angew Chem, Int Ed 2016; 55: 13312
• 6f Lee KN, Lei Z, Ngai M-Y. J Am Chem Soc 2017; 139: 5003
• 6g Cao K, Tan SM, Lee R, Yang S, Jia H, Zhao X, Qiao B, Jiang Z. J Am Chem Soc 2019; 141: 5437
• 6h Ye C-X, Melcamu YY, Li H-H, Cheng J-T, Zhang T-T, Ruan Y-P, Zheng X, Lu X, Huang P-Q. Nat Commun 2018; 9: 410
• 6i Chi Z, Liao J-B, Cheng X, Ye Z, Yuan W, Lin Y-M, Gong L. J Am Chem Soc 2024; 146: 10857

Visible-light photocatalyzed carbonyl–olefin couplings of aliphatic ketones have also been reported using excited state organic radicals as strong reductants. However, under these highly reducing conditions, ketyl radical formation may not occur due to the preferential reduction of the olefin substrate over the ketone:
• 7a Venditto NJ, Liang YS, El Mokadem RK, Nicewicz DA. J Am Chem Soc 2022; 144: 11888
• 7b Edgecomb JM, Alektiar SN, Cowper NGW, Sowin JA, Wickens ZK. J Am Chem Soc 2023; 145: 20169
• 8 Deng Y, Liu Q, Smith AB. J Am Chem Soc 2017; 139: 9487
• 9a Karimi-Nami R, Tellis JC, Molander GA. Org Lett 2016; 18: 2572
• 9b Tellis JC, Primer DN, Molander GA. Science 2014; 345: 433
• 10 Laha R, Patel TI, Moschitto MJ. Org Lett 2022; 24: 7394
• 11 Keum M, Kim D-K, Um H-S, Lee J, Lee C. Asian J Org Chem 2024; 13: e202300546
• 12a Wang L, Lear JM, Rafferty SM, Fosu SC, Nagib DA. Science 2018; 362: 225
• 12b Rafferty SM, Rutherford JE, Zhang L, Wang L, Nagib DA. J Am Chem Soc 2021; 143: 5622
• 13 Huang H-M, Bellotti P, Erchinger JE, Paulisch TO, Glorius F. J Am Chem Soc 2022; 144: 1899
• 14 Zhu C, Lee S-C, Chen H, Yue H, Rueping M. Angew Chem Int Ed 2022; 61: e202204212
• 15a Ji H, Lin D, Tai L, Li X, Shi Y, Han Q, Chen L-A. J Am Chem Soc 2022; 144: 23019
• 15b Li C, Cheng J, Wan X, Li J, Zu W, Xu Y, Huang Y, Huo H. J Am Chem Soc 2024; 146: 19909
• 15c Wen S, Bu J, Shen K. J Org Chem 2024; 89: 16134
• 16 Alam R, Molander GA. J Org Chem 2017; 82: 13728
• 17 Lang SB, Wiles RJ, Kelly CB, Molander GA. Angew Chem Int Ed 2017; 56: 15073
• 18 Pasca F, Gelato Y, Andresini M, Romanazzi G, Degennaro L, Colella M, Luisi R. Chem Sci 2024; 15: 11337
• 19 Li Z, Tate JA, Noble A. J Am Chem Soc 2024; 146: 26616
• 20a Xia Q, Dong J, Song H, Wang Q. Chem Eur J 2019; 25: 2949
• 20b Capaldo L, Ravelli D, Fagnoni M. Chem Rev 2022; 122: 1875
• 21 Garwood JJA, Chen AD, Nagib DA. J Am Chem Soc 2024; 146: 28034
• 22 Gao L, Yang W, Wu Y. Song Z. In Organic Reactions, Vol. 102 . Evans PA. Ed John Wiley & Sons; 2020: 1-612
• 23 Molander GA, Wisniewski SR. J Am Chem Soc 2012; 134: 16856
• 24 Yuan M, Song Z, Badir SO, Molander GA, Gutierrez O. J Am Chem Soc 2020; 142: 7225
• 25 Ali R. ChemistrySelect 2023; 8: e202302903
• 26a Um H-S, Min J, An T, Choi J, Lee C. Org Chem Front 2018; 5: 2158
• 26b Kim D-K, Um H-S, Park H, Kim S, Choi J, Lee C. Chem Sci 2020; 11: 13071
• 27 Neuenschwander M, Bigler P, Christen K, Iseli R, Kyburz R, Mohle H. Helv Chim Acta 1978; 61: 2047
• 28a Chou T-S, Knochel P. J Org Chem 1990; 55: 4791
• 28b Giese B, Damm W, Dickhaut J, Wetterich F, Sun S, Curran DP. Tetrahedron Lett 1991; 32: 6097
• 28c Lee JY, Kim S. Bull Korean Chem Soc 2006; 27: 189
• 28d Quiclet-Sire B, Zard SZ. Molecules 2023; 28: 7561
• 29 Gatazka MR, Parikh SG, Rykaczewski KA, Schindler CS. Synthesis 2024; 56: 2513
• 30 Xing Z-X, Chen S-S, Huang H-M. Org Lett 2024; 26: 9949
• 31a Bellotti P, Huang H-M, Faber T, Laskar R, Glorius F. Chem Sci 2022; 13: 7855-7862
• 31b Huang H-M, Bellotti P, Kim S, Zhang X, Glorius F. Nat Synth 2022; 1: 464
• 32 Sun M-Q, Zhai S-J, Nie J, Cheng Y, Deng X, Ding G, Cahard D, Ma J-A, Zhang F-G. ChemCatChem 2025; 17: e202401622
• 33a Boyle BT, Dow NW, Kelly CB, Bryan MC, MacMillan DWC. Nature 2024; 631: 789
• 33b Ngo DT, Garwood JJA, Nagib DA. J Am Chem Soc 2024; 146: 24009
• 34 Solar S, Getoff N, Holcman J, Sehested K. J Phys Chem 1995; 99: 9425

During the revision of this manuscript, Shen and co-workers reported the extension of α-hydroxy silane-derived ketyl-type radicals to perfluoroalkyl aldehydes, which were used in enantioselective dual photoredox/Ni-catalyzed cross-couplings with aryl halides:
• 35 Niu Y, Jin C, He X, Deng S, Zhou G, Liu S, Shen X. Angew Chem Int Ed 2025; 64: e202507789

Publication History

Received: 01 May 2025

Accepted after revision: 16 June 2025

Accepted Manuscript online:
17 June 2025

Article published online:
30 July 2025