Umpolung Difunctionalization of Carbonyls via Visible-Light Photoredox Catalytic Radical-Carbanion Relay

Article abstract of DOI:10.1021/jacs.0c00629

The combination of photoredox catalysis with the Wolff-Kishner (WK) reaction allows the difunctionalization of carbonyl groups by a radical-carbanion relay sequence (photo-Wolff-Kishner reaction). Photoredox initiated radical addition to N-sulfonylhydrazones yields α-functionalized carbanions following the WK-type mechanism. With sulfur-centered radicals, the carbanions are further functionalized by reaction with electrophiles including CO2 and aldehydes, whereas CF3 radical addition furnishes a wide range of gem-difluoroalkenes through β-fluoride elimination of the generated α-CF3 carbanions. More than 80 substrate examples demonstrate the broad applicability of this reaction sequence. A series of investigations including radical inhibition, deuterium labeling, fluorescence quenching, cyclic voltammetry, and control experiments support the proposed radical-carbanion relay mechanism.

Full text of DOI:10.1021/jacs.0c00629

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Article
Umpolung Difunctionalization of Carbonyls via Visible-
light Photoredox Catalytic Radical-Carbanion Relay
Shun Wang, Bei-Yi Cheng, Matea Srsen, and Burkhard König
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c00629 • Publication Date (Web): 01 Apr 2020
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Umpolung Difunctionalization of Carbonyls via Visible-light
Photoredox Catalytic Radical-Carbanion Relay
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Shun Wang, Bei-Yi Cheng, Matea Sršen, Burkhard König*
Institute of Organic Chemistry, Faculty of Chemistry and Pharmacy, University of Regensburg, D-93040 Regensburg, Germany
ABSTRACT: The combination of photoredox catalysis with the Wolff-Kishner (WK) reaction allows the difunctionalization of
carbonyl groups by a radical-carbanion relay sequence (photo-Wolff-Kishner reaction). Photoredox initiated radical addition to N-
sulfonylhydrazones yields α-functionalized carbanions following WK-type mechanism. With sulfur-centered radicals, the carbanions
are further functionalized by reaction with electrophiles including CO2 and aldehydes, whereas CF3 radical addition furnishes a wide
range of gem-difluoroalkenes through β-fluoride elimination of the generated α-CF3 carbanions. More than 80 substrate examples
demonstrate the broad applicability of this reaction sequence. A series of investigations including radical inhibition, deuterium label-
ling, fluorescence quenching, cyclic voltammetry and control experiments support the proposed radical-carbanion relay mechanism.
remained unexplored although its realization represents a desir-
able synthetic tool for carbonyl group functionalization.
1. INTRODUCTION
The inversion of the inherent polarity of organic functionalities,
Scheme 1. Umpolung Generation of Alkyl Carbanions from
Carbonyls
termed as umpolung, is a key bond-forming strategy in organic
synthesis.1 The umpolung of a carbonyl group places a negative
charge on the carbon atom, making it nucleophilic and prone to
attack electrophiles. Carbonyl umpolung is achieved in many
ways: Acyl anion equivalents are obtained by the umpolung of
electrophilic aldehydes in stoichiometric dithiane chemisty2 and
catalytic N-heterocyclic carbene (NHC) chemistry3. Syntheti-
cally important alkyl carbanion intermediates can be obtained
from carbonyl groups using the Wolff-Kishner (WK) reduction.
The polarity inversion is accomplished by sequential hydrazone
formation, tautomerization and N2-extrusion to generate a nu-
cleophilic alkyl carbanionic species (Scheme 1A). With elegant
4
modifications from Huang Minlon and others,5 the WK pro-
cess has evolved over the past century into a powerful carbonyl
deoxygenation tool in the synthesis of complex molecules.5 De-
spite being a very effective way producing carbanions, syn-
thetic applications of this chemistry have long been underex-
plored considering that the alkyl carbanion in such an umpolung
can, in principle, react with many electrophiles other than a pro-
ton. Few examples based on modified WK process have been
developed for the construction of C-C bonds, wherein highly
reactive alkyllithium reagents were empolyed to react with sul-
fonylhydrazones.6 More recently, pioneering work by Li and
co-workers demonstrated the direct functionalization of the car-
banion in a Wolff-Kishner reaction by nucleophilic addition to
9
carbonyl compounds,7 imines,8 CO2 and Michael acceptors10
under ruthenium catalysis. The same group utilized such car-
banions in metal-catalyzed Negishi-type coupling,11 Heck-type
As part of our ongoing research activities in photoredox cata-
coupling,12 Tsuji-Trost alkylation13 and olefination reactions14
or metal-free C-C bond forming reactions.15 In these cases, the
functional groups are installed through metal-assisted nucleo-
philic trapping of non-functionalized alkyl carbanions (Scheme
1B). Inspired by the facile generation of carbanions in the clas-
sic WK process, we questioned if functionalized carbanions can
be produced catalytically for a subsequent nucleophilic reaction
allowing the simultaneous installation of two functional groups
at a geminal position. The scope of such a reaction sequence has
lytic generation of functionalized carbanions from carbonyls,16
we envisioned that a combination of a conventional WK process
with photoredox catalysis might furnish functionalized alkyl
carbanions for a subsequent derivatization. In the anticipated
radical-carbanion relay sequence, radicals generated by the
photoredox catalytic system would be captured by N-sulfonyl-
hydrazone,17 thus installing the first functional group. Subse-
quently, the diazene intermediate, resulting from radical frag-
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mentation,17a, 17c, 18 enters a similar reaction sequence as in-
After systematic screening of all reaction parameters (see SI for
details), we were delighted to obtain the desired functionalized
volved in the WK reduction to give functionalized carbanions,
which offers a second opportunity for further transformations
(Scheme 1C，a). Herein we report the successful implementa-
tion of this radical-carbanion relay functionalization concept.
The combination of photoredox catalysis with a Wolff-Kishner
process allows the facile generation of α-sulfenyl and α-CF3
carbanions that undergo further nucleophilic attack or fragmen-
tation, respectively (Scheme 1C, b).
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carboxylic
acid
3a
in
81%
yield
using
[Ir(dFCF3ppy)2dtbbpy]PF6 (1 mol%) under 3 atm of CO2 in
DMSO (Table 1, entry 1). Polar solvents like DMSO and DMF
were effective for this thiocarboxylation reaction (see SI, Table
S2). Moreover, we successfully converted p-tolualdehyde into
the desired product 3a in one pot by means of a condensation
and photocatalytic sequence with similar efficiency (Table 1,
entry 2). Rigorous control experiments revealed that photocata-
lyst, base and light were crucial for the transformation to occur
(Table 1, entries 6-8).
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2. RESULTS AND DISCUSSION
2.1.
Generation of α-Sulfenyl Carbanions and Their
reactions with Electrophiles.
With the optimized reaction conditions in hand, we examined
the scope of the method. (Table 2) The reaction gave good
yields of the corresponding products with a series of aromatic
aldehyde-derived N-tosylhydrazones bearing electron-neutral
(3a-c, 3f-g, 3j and 3l), -donating (3d, 3h and 3o) or -withdraw-
ing (3i, 3k and 3n) groups at para-, meta- or ortho- positions.
The reaction was compatible with N-tosylhydrazones contain-
ing two substituents on the aromatic ring, affording the desired
carboxylic acids (3m-3o) in reasonable yields (43-58%). Heter-
ocyclic and naphthalene-containing substituents were also well
tolerated by the catalytic system (3p-3q).
Carbon-sulfur bonds are found in pharmaceuticals or natural
products and are widely used in synthesis. Recent years wit-
nessed increasing attention to develop an efficient approach to
forge C–S bonds.19 We postulate that photogenerated thiyl rad-
icals20 from various thiols can engage in the radical-carbanion
relay functionalization sequence. Such a process would yield
synthetically useful α-sulfenyl carbanions, which are tradition-
ally produced through deprotonation of sulfides with strong ba-
ses such as nBuLi and NaNH2.21 Building on the facile carban-
ion trapping by CO222 and our continued interest in utilization
of CO2 as the C1 feedstock for photocatalytic carboxylation re-
actions,22e, 23 we selected N-tosylhydrazone as the radical accep-
tor in the anticipated sequence based on the following consid-
erations: 1) they can be easily prepared through condensation
of carbonyl compounds with TsNHNH2; 2) after radical addi-
tion to N-tosylhydrazone, rapid β-sulfone elimination was an-
ticipated to produce a sulfinyl radical which should undergo sin-
gle-electron transfer with the photocatalyst.17,24 We commenced
our study by utilizing aldehyde hydrazone 1a, thiophenol 2a
and CO2 as model substrates for the optimization of the reaction
conditions.
Table 2. Scope of N-Tosylhydrazones for Thiocarboxyla-
tiona
Table 1. Screening of Reaction Conditions for Thiocarbox-
ylation of N-Tosylhydrazonea
Entry
Change from standard conditions
Yieldb
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5
6
7
8
none
one-pot process
81%
80%c
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
MeCN instead of DMSO
THF instead of DMSO
4CzIPN instead of Ir-F
without Cs2CO3
without PC
aReaction conditions: Unless otherwise noted, all reactions were
carried out with 1 (0.2 mmol), 2a (0.3 mmol), Cs2CO3 (0.6 mmol),
[Ir(dFCF3ppy)2dtbbpy]PF6 (1 mol%) and 3 atm of CO2 in 2 mL
DMSO, irradiation with blue LED (455 nm) at 25 oC for 24 hours,
and isolated yields were shown.b6 mmol scale, CO2 was bubbled
in the dark
aReaction conditions: Compound 1a (0.2 mmol), 2a (0.3 mmol),
Cs2CO3 (0.6 mmol), [Ir(dFCF3ppy)2dtbbpy]PF6 (1 mol%) and 3
atm of CO2 in 2 mL of solvent, irradiation with blue LED (455 nm)
at 25 oC for 24 hours. n.d. = not detected. bYields were determined
by 1H NMR analysis of the crude reaction mixture using 1,3,5-tri-
methoxybenzene as internal standard. c1a was formed in one pot
starting from p-tolualdehyde and used directly without purification.
4CzIPN = 2,4,5,6-tetra(carbazol-9-yl)isophthalonitrile. Ir-F =
[Ir(dFCF3ppy)2dtbbpy]PF6. PC = photocatalyst.
c
o
into the reaction continously. Reaction was conducted at 0 C in
DMF (2 mL)
The reaction system could also be extended to N-tosylhydra-
zones derived from ketones, affording a wide range of carbox-
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ylic acids with quarternary carbon-centers (3r to 3ae). Gratify-
carbon forming reactions utilizing the nucleophilic attack of or-
ganometallic species to carbonyl compounds.26 Using slight
modified reaction conditions, we discovered that photo-Wolff-
Kishner generated carbanions can be efficiently trapped with a
wide range of aldehydes (Table 4). Benzaldehyde reacted
smoothly to give the desired alcohol 6a in 78% yield. We were
delighted to find that heteroaryl aldehydes readily participated
in the coupling reaction to give products 6b-d. When ketone-
derived N-tosylhydrazones were employed, densely functional-
ized sulfides (6e-f) were constructed in synthetically useful
yields. Besides aromatic aldehydes, aliphatic aldehydes bearing
short or long chains were suitable electrophiles in our system,
giving the desired products in moderate yields (6g-o).27 Nota-
bly, solid paraformaldehyde reacted to provide the desired
product (6g) in 48% yield. This transformation was however
sensitive to steric hindrance. The presence of additional substit-
uents at the α-carbon on the trapping aldehyde decreased the
yield considerably (6m-o) and only trace amount of the product
was detected when pivalaldehyde was employed. Moreover, ke-
tones failed to trap the generated carbanion in the catalytic sys-
tem, which may be explained by the undesired deprotonation of
the α-protons to the carbonyl yielding benzyl phenyl sulfide.28
ingly, functional groups including phenyl (3s), halogen (3t and
3x), thiophene (3u), benzofuran (3v) and methoxy (3y) on the
aromatic rings of substrates were well tolerated. The reaction
proceeded with similar efficiencies for electron-rich or elec-
tron-poor substrates. Moreover, N-tosylhydrazones bearing
more sterically hindered substituents at the α-position such as
ethyl (3aa), isopropyl (3ab), cyclopropyl (3ac) gave the desired
products in good yields, but longer reaction times were re-
quired. The reaction could be utilized for the thiocarboxylation
of N-tosylhydrazone derived from 4-chromanone, yielding the
heterocyclic product 3ad in 43% yield. To our delight, N-to-
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o
sylhydrazone derived from an aliphatic ketone reacted at 0 C
yielding product 3ae in moderate yield. The decreased effi-
ciency and required low reaction temperature were rationalized
by the instability of the aliphatic α-sulfenly carbanion. Im-
portantly, this reaction is easily scalable, as demonstrated by the
gram scale synthesis of 3a in 75% yield.
Next, we explored the scope of the reaction with respect to thi-
ols. As shown in Table 3, thiophenols bearing either electron-
donating (4a-c) or electron-withdrawing groups (4e) on the
para position of aromatic ring reacted smoothly to generate the
expected products in mostly good yields. Both ortho and meta-
substituted thiophenols were suitable substrates, affording the
products in high yields (71%-85%). However, 4-nitro-thiolphe-
nol failed to give the desired product. Notably, besides aromatic
thiophenols, our method could be extended to primary, second-
ary and tertiary aliphatic thiols (4j-l), albeit with moderate effi-
ciencies.
Table 4. Scope of the Aldehydes for Thiohydroxyalkylationa
Table 3. Scope of the Thiols for Thiocarboxylationa
aReaction conditions: Unless otherwise noted, all reactions were
carried out with 1 (0.2 mmol), 2a (0.3 mmol), 5 (0.8 mmol),
Cs2CO3 (0.3 mmol), [Ir(dFCF3ppy)2dtbbpy]PF6 (1 mol%) in 2 mL
DMSO, irradiation with blue LED (455 nm) at 25 oC for 24 hours,
and isolated yields were shown. b6 mmol scale. cParaformaldehyde
(0.8 mmol) and DMSO (4 mL) were used.
2.2.
Generation of α-CF3 Carbanions and Their Frag-
aReaction conditions: Unless otherwise noted, all reactions were
carried out with 1a (0.2 mmol), 2 (0.3 mmol), Cs2CO3 (0.6 mmol),
[Ir(dFCF3ppy)2dtbbpy]PF6 (1 mol%) and 3 atm of CO2 in 2 mL
DMSO, irradiation with blue LED (455 nm) at 25 oC for 24 hours,
and isolated yields were shown.
mentation Reactions
Organic molecules containing a fluorine moiety generally ex-
hibit improved reactivity, bioactivity and metabolic stability
compared to their non-fluorinated counterparts.29 An important
privileged fluoro-containing group is the gem-difluoroethylene
moiety based on their unique property in medicinal chemistry.30
Moreover, gem-difluoroalkenes are versatile building blocks
for the synthesis of other fluorine-containing molecules.31 Tra-
ditional methods such as Wittig32and Julia33 reactions for the
synthesis of 1,1-difloroalkenes generally suffer from limited
After successful application of this radical-carbanion relay se-
quence for carboxylation, we tested other electrophiles, like al-
dehydes or ketones to realize a visible-light driven Barbier-type
reaction.22b, 25 Barbier-type reactions are well-known carbon-
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scope, modest efficiency or harsh conditions. Another efficient
difluoroalkenes in moderate to good yields. The reactions of so-
dium triflinate with cycloketone-derived N-tosylhydrazones led
to the corresponding products 9a-9e in 38-73% yields. Interest-
ingly, strained substrate like azetidinone-derivatized N-tosylhy-
drazone could be successfully functionalized yielding difluoro-
alkene 9e in modest yield.40 Our method could be also extended
to acyclic N-tosylhydrazones. For instance, tosylhydrazone de-
rived from 3-hexadecanone performed well in our reaction af-
fording the desired product 9f in 62% yield. Moreover, the mild
reaction conditions were compatible with ketone-based tosylhy-
drazones bearing a wide range of functional groups including
alkene (9g), phenol (9h) and amide (9j-9l). With N-tosylhydra-
zones derived from phenylacetones, functional groups such as
phenyl, methoxy and trifluoromethyl on the aromatic ring were
pathway is the gem-difluorination of diazo compounds under
metal catalytic34 or metal free reaction conditons.35 This strat-
egy is generally restricted to aromatic diazo compounds or di-
azo esters. Recently, several elegant defluorination strategies
starting from α-trifluoromethyl alkenes based on metal cataly-
sis36 or photoredox catalysis37 have been developed for the syn-
thesis of gem-difluoroalkenes. Nevertheless, this route requires
the presence of trifluoromethyl groups on the alkene moieties
and the product scope is limited by the accessibility of such tri-
fluoromethylated alkenes.
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Following the proposal shown in Scheme 1C and encouraged
by the success in generation of α-sulfenyl carbanions as de-
scribed in section 2.1, we wondered whether difluoroalkenes
could be produced involving CF3 radicals in the radical-carban-
ion relay sequence. The feasibility of this approach was sup-
Table 6. Scope of the gem-Difluoroolefination of N-tosylhy-
drazonesa
ported by the facile E1cB elimination of α-CF3 carbanions to
38
yield the difluoroalkenes.37a-f,
We used sodium triflinate
(Langlois reagent, CF3SO2Na), a bench-stable and commer-
cially available trifluoromethylation reagent as the CF3 radical
precursor and N-tosylhydrazone 7a as the model substrate.39
The optimized conditions (see SI, Table S5-7), which include
the use of [Ir(dFCF3ppy)2dtbbpy]PF6 (2 mol%) as photocatalyst
and Cs2CO3 (1.5 eq.) as the base in 1 mL of solvent
(DMSO/acetone = 1/1), delivered the desired 1,1-difluoroal-
kene 9a in 77% yield (Table 5, entry 2). Likewise, this transfor-
mation demonstrated retained efficiency when the reaction was
carried out in a one-pot process (Table 5, entry 3). Control ex-
periments indicated that the base, photocatalyst and light irradi-
ation were essential for this reaction (Table 5, entries 4-6).
Table 5. Screening of Reaction Conditions for the 1,1-
Difluoroolefination of N-Tosylhydrazonea
Entry
Change from standard conditions
none
Yieldb
70%
77% (73%)c
75%d
n.d.
1
2
3
4
5
6
PC (2 mol%)
one-pot, PC (2 mol%)
without Cs2CO3
without PC
n.d.
in the dark
n.d.
aReaction conditions: Unless otherwise noted, all reactions were
carried out with 7 (0.2 mmol), 8 (0.3 mmol), Cs2CO3 (0.3 mmol),
[Ir(dFCF3ppy)2dtbbpy]PF6 (2 mol%) in (DMSO/acetone = 1/1) 1
mL, irradiation with blue LED (455 nm) at 25 oC for 24 or 30 hours,
a
Reaction conditions: Compound 7a (0.2 mmol), 8 (0.3 mmol),
Cs2CO3 (0.3 mmol), [Ir(dFCF3ppy)2dtbbpy]PF6 (1 mol%) in 1 mL
solvent, irradiation with blue LED (455 nm) at 25 oC for 24 hours.
n.d. = not detected. b Yields were determined by 19F NMR analysis
of crude reaction mixture using 4,4’-difluorobenzophenone as in-
ternal standard. c Isolated yield. d7a was formed in one pot starting
from corresponding ketone and used directly without purification.
PC = photocatalyst.
b
and isolated yields were shown. 8 mmol scale, reaction time: 48
hours.
well tolerated (9m-o). A sterically hindered substrate 7p partic-
ipated in the reaction well to yield the gem-difluoroalkene. To-
sylhydrazones derived from aromatic ketones were also appli-
cable affording the desired products (9q-u) in reasonable yields.
The reactions proceeded smoothly with heterocycle-containing
substrates (e.g., pyrazole 7i and pyridine 7u). Notably, ester
groups on the carbon chain remained untouched (9v). This cat-
alytic system was also suitable for aliphatic aldehyde-based N-
Using the optimized reaction conditions for the gem-difluo-
roolefination, the scope of this methodology was evaluated. As
summarized in Table 6, the reaction proceeded smoothly with a
variety of N-tosylhydrazones, affording the expected gem-
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tosylhydrazones, delivering the corresponding products in mod-
cited state of [IrIII(dFCF3ppy)2dtbbpy]+ (E1/2 [*IrIII/II] = +1.21 V
vs SCE)42 is reductively quenched by sodium triflinate (Eox=
erate to excellent yields (9w-aa). The utility of this method was
further demonstrated by applying it to functionalize structurally
and functionally complex natural products like Nabumetone,
Zingerone and Stanolone, providing the desired products (9ab-
ad) in good yields.
Scheme 2. Mechanistic Studies
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2.3.
Reaction Mechanism
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To gain insights into the reaction mechanism, a series of spec-
troscopic investigations and control experiments were con-
ducted. First, no desired products were detected when the radi-
cal scavenger TEMPO (2.5 eq.) was added to the thiocarboxy-
lation or gem-difluoroolefination reaction. The radical nature of
this-type of reaction was further confirmed by the formation of
TEMPO-SPh and TEMPO-CF3 adducts, which were detected
by the HRMS (Scheme 2A and SI). Based on our results and
literature reports about the radical functionalization of N-sul-
fonylhydrazones,17 we postulate that the sulfur-centered radical
and CF3 radical follow a similar mechanism to react with N-
tosylhydrazones to give the carbanions. We chose the thiocar-
boxylation reaction as a model reaction to study the mechanism
more closely.
A control experiment using sodium thiophenolate in place of
the corresponding thiophenol 2a yielded the desired carboxylic
acid 3a in 73% yield. Moreover, we found that the product
could be generated in 50% yield with sodium thiophenolate
even in the absence of Cs2CO3, suggesting that the base
(Cs2CO3) merely serves to deprotonate the thiols (Scheme 2B).
The Stern–Volmer luminescence quenching experiments re-
vealed that sodium thiophenolate quenches the excited state of
the photocatalyst much more efficiently than N-tosylhydrazone
1a and thiophenol 2a (see SI, Figure S8-11). Light “on-off” ex-
periments indicated that continuous light irradiation was essen-
tial for the reaction to proceed (see SI). Additionally, the quan-
tum yield of this transformation was determined to be 2.1%.
Hence, a radical chain process is unlikely for this reaction. The
combined results suggest a transient sulfur-centered radical,
generated by single-electron oxidation of thiophenolate by the
excited state of photocatalyst in a reductive quenching photo-
catalytic cycle.
+1.05 V vs. SCE) 22a or thiophenolate (Eox=~0.75 V vs. SCE),43
formed through the deprotonation of thiophenol by base, afford-
ing a sulfur-centered radical and a CF3 radical, respectively.
Subsequent radical addition to the C=N bond of N-tosylhydra-
zone generates the aminyl radical species A.44 Fragmentation of
the arenesulfonyl radical from intermediate A leads to a func-
tionalized diazene intermediate B18 and the following Wolff-
Kishner type N2 extrusion process proceeds to give α-CF3 or
Further control experiments showed that (4-methylbenzyl)(phe-
nyl)sulfide could be obtained in 69% yield in the absence of
CO2 (Scheme 2C). This finding suggests that the sulfur-cen-
tered radical could interact with N-tosylhydrazone 1a irrespec-
tive of the existence of CO2. The result is in accordance with
the hypothesis that a transient α-sulfenyl carbanion might occur
in the reaction process. On this basis, we conducted isotope-la-
belling experiments. Indeed, when D2O was added in the ab-
sence of CO2, up to 88% deuterium incorporation into sulfide
was observed (Scheme 2D). In addition, a carbanion intermedi-
ate should in principle undergo E1cB elimination when the ad-
jacent carbon atom bears an appropriate leaving group.41 There-
fore, N-tosylhydrazones bearing a methoxyl group at the vicinal
carbon were prepared and subjected to the standard reaction
conditions in the absence of CO2 giving the corresponding al-
kenes 11a and 11b in good yields (Scheme 2E).
Scheme 3. Proposed Mechanism of the Photo-Wolff-Kish-
ner Carbanion Generation
Based on the above experimental evidence and mechanistic
pathways reported in literature, we propose a plausible mecha-
nism as depicted in Scheme 3 for the reported photocatalytic
generation of functionalized carbanions. Initially, the photoex-
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40, 231-237. (c) Smith, A. B.; Adams, C. M., Evolution of Dithiane-
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sulfur carbanion C for further reactions. In the case of the α-
sulfenyl carbanion, subsequent nucleophilic attack to CO2 or al-
iphatic aldehydes give carboxylic acids or alcohols. When α-
CF3 carbanions were produced, β-fluoride elimination occurred
to furnish the gem-difluoroalkenes. Finally, single electron
transfer (SET) from the reduced photoredox catalyst IrII (E1/2
3. (a) Bugaut, X.; Glorius, F., Organocatalytic Umpolung: N-heterocy-
clic Carbenes and Beyond. Chem. Soc. Rev. 2012, 41, 3511-3522. (b)
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[IrIII/II] = −1.37 V vs SCE)42 to the arenesulfonyl radical (Ered
=
+0.50 V vs. SCE)24b yields a sulfinate anion and regenerates the
photocatalyst.
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4. Minlon, H., A Simple Modification of the Wolff-Kishner Reduction.
J. Am. Chem. Soc. 1946, 68, 2487-2488.
3. CONCLUSION
In summary, we have established a new reaction sequence for
the generation of α-functionalized alkyl carbanions through the
merger of photoredox catalytic radical generation with the clas-
sic Wolff-Kishner (WK) reaction. This radical-carbanion relay
for carbonyl functionalization involves the radical addition to
N-sulfonylhydrazones, which enables the formation of α-sub-
stituted carbanion intermediates. Subsequent reaction with elec-
trophiles including CO2 and aldehydes or fragmentation results
in thiocarboxylation, thio-hydroxyalkylation, gem-difluoroole-
fination with broad substrate scope and good tolerance of many
functional groups. Mechanistic studies support the hypothesis
that a tandem photocatalytic radical addition/Wolff-Kishner
process starting from N-sulfonylhydrazones facilitates the for-
mation of the carbanion. This strategy greatly expands the syn-
thetic potential of Wolff-Kishner reaction. Further studies aim-
ing to generate non-stabilized carbanions by this strategy are
currently under investigation.
5. Lewis, D. E., The Wolff-Kishner Reduction and Related Reactions:
Discovery and Development. Elsevier: 2019.
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ASSOCIATED CONTENT
Experiments and spectral details for all new compounds and all re-
actions reported.
This Supporting Information is available free of charge via the In-
ternet at http://pubs.acs.org.
11. Tang, J.; Lv, L.; Dai, X.-J.; Li, C.-C.; Li, L.; Li, C.-J., Nickel-Cat-
alyzed Cross-Coupling of Aldehydes with Aryl Halides via Hydrazone
Intermediates. Chem. Commun. 2018, 54, 1750-1753.
12. Lv, L.; Zhu, D.; Li, C.-J., Direct Dehydrogenative Alkyl Heck-
Couplings of Vinylarenes with Umpolung Aldehydes Catalyzed by
Nickel. Nat. Commun. 2019, 10, 715.
AUTHOR INFORMATION
Corresponding Author
*burkhard.koenig@ur.de
13. Zhu, D.; Lv, L.; Li, C.-C.; Ung, S.; Gao, J.; Li, C.-J., Umpolung of
Carbonyl Groups as Alkyl Organometallic Reagent Surrogates for
Palladium-Catalyzed Allylic Alkylation. Angew. Chem. Int. Ed. 2018,
57, 16520-16524.
Notes
The authors declare no competing financial interests.
14. Wei, W.; Dai, X.-J.; Wang, H.; Li, C.; Yang, X.; Li, C.-J.,
Ruthenium(II)-Catalyzed Olefination via Carbonyl Reductive Cross-
Coupling. Chem. Sci. 2017, 8, 8193-8197.
ACKNOWLEDGMENT
This work was supported by the German Science Foundation
(DFG) (KO 1537/18-1). This project has received funding from the
European Research Council (ERC) under the European Unions
Horizon 2020 research and innovation programme (grant agree-
ment No. 741623). S. W. (CSC student number 201606280052)
and B. C. thank the China Scholarship Council (CSC) for a pre-
doctoral fellowship. We thank Dr Rudolf Vasold (University of Re-
gensburg) for his assistance in GC-MS measurements and Ms Re-
gina Hoheisel (University of Regensburg) for her assistance in cy-
clic voltammetry measurements
15. Zeng, H.; Luo, Z.; Han, X.; Li, C.-J., Metal-Free Construction of
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Togni’s Reagent under Mild Conditions. Org. Lett. 2019, 21, 5948-
5951.
16. Wang, S.; Lokesh, N.; Hioe, J.; Gschwind, R. M.; König, B.,
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