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.
Aldehyde Derivatives for Ketyl(-Type) Radical Generation
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.
Ketyl-Type Radical Precursors
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).
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).
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 NiIII species that reductively eliminates the silyloxymethylated product 13, with the resulting NiI species engaging in SET with the reduced state photocatalyst to complete both catalytic
cycles. Although the authors proposed this Ni0/NiI/NiIII 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 NiI to form an aryl-NiIII 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).
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 NiI complex provides a NiIII intermediate that is reduced to NiII by the reduced state of the photocatalyst. Capture of 20 by the NiII 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]
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 IrIII catalyst, leading to ketyl radical 22 through loss of BF3. Reaction of 22 with a Ni0 species produces a NiI intermediate that undergoes oxidative addition with the aryl bromide to generate
a NiIII species. Reductive elimination then yields the benzylic alcohol product 21. Finally, SET between the resulting NiI species and the reduced IrII 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.
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).
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.
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.
