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Zitierweise: Angew. Chem. Int. Ed. 2021, 60, 7275 – 7282

Electrochemistry Internationale Ausgabe: doi.org/10.1002/anie.202015230
Deutsche Ausgabe: doi.org/10.1002/ange.202015230

Electrochemical Arylation of Aldehydes, Ketones, and Alcohols: from

Cathodic Reduction to Convergent Paired Electrolysis
Sheng Zhang,* Lijun Li, Jingjing Li, Jianxue Shi, Kun Xu,* Wenchao Gao, Luyi Zong,
Guigen Li and Michael Findlater*
In memory of Professor Jun-ichi Yoshida (1952–2019)

Abstract: Arylation of carbonyls, one of the most common

approaches toward alcohols, has received tremendous atten-
tion, as alcohols are important feedstocks and building blocks
in organic synthesis. Despite great progress, there is still a great
gap to develop an ideal arylation method featuring mild
conditions, good functional group tolerance, and readily
available starting materials. We now show that electrochemical
arylation can fill the gap. By taking advantage of synthetic
electrochemistry, commercially available aldehydes (ketones)
and benzylic alcohols can be readily arylated to provide
a general and scalable access to structurally diverse alcohols
(97 examples, > 10 gram-scale). More importantly, convergent
paired electrolysis, the ideal but challenging electrochemical
technology, was employed to transform low-value alcohols into
more useful alcohols. Detailed mechanism study suggests that
two plausible pathways are involved in the redox neutral a- Scheme 1. Reductive arylations of carbonyls.
arylation of benzylic alcohols.

Introduction and Wu developed independently a reductive arylation of

As one of most important feedstocks and building blocks
in organic synthesis,[1] alcohols can be readily prepared
utilizing a Barbier or Grignard reaction.[2] However, these
conventional reactions commonly require Schlenk technique
and suffer from low functional-group compatibility owing to
the high reactivity of organometallic reagents (Scheme 1 a).
Reductive arylation of aldehydes or ketones has emerged as
an alternative approach to access secondary or tertiary
alcohols with transition-metal catalysis or photocatalysis
strategies.[3–5] For instance, nickel and rhodium-catalyzed
reductive coupling reaction of aldehydes with aryl halides
have been reported by Weix and Krische, respectively[4b,c]
(Scheme 1 b). With regards to photocatalytic reactions, Xia
[*] Dr. S. Zhang, L. Li, J. Li, J. Shi, Dr. K. Xu, Dr. W. Gao, Dr. L. Zong
Engineering Technology Research Center of Henan Province for
Photo- and Electrochemical Catalysis, College of Chemistry and
Pharmaceutical Engineering, Nanyang Normal University
Nanyang (China)
E-Mail: shengzhang@nynu.edu.cn
kunxu@bjut.edu.cn
Prof. Dr. G. Li, Prof. Dr. M. Findlater
Department of Chemistry and Biochemistry, Texas Tech University
Lubbock, TX 79423 (USA)
E-Mail: Michael.Findlater@ttu.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202015230.
aldehydes and ketones using iridium catalysts (Scheme 1 c).[5]
However, the use of sophisticated metal catalysts, stoichio-
metric reductant in the reductive-coupling reaction or pre-
cious metal-based catalysts in the photocatalytic reaction
limit their practical applications.
Synthetic electrochemistry has been demonstrated to be
an environmentally benign, scalable, and orthogonal tool for
redox transformations,[6] in which substrate can selectively
lose or gain electrons at the electrode surface. In this context,
we sought to develop a cathodically reductive arylation
approach to obviate transition-metal catalysts and reductants,
as part of our continued interest in synthetic electrochemistry
(Scheme 2 b).[7] Moreover, to further exploit the capabilities
of electrochemistry, we considered whether convergent
paired electrolysis could enable a direct a-arylation of
alcohols (Scheme 2 b). This neutral-redox reaction can serve
as an attractive synthetic route to higher value alcohols
starting from benzylic alcohols.[8] MacMillan unveiled a pho-
tocatalyzed C@H arylation by using a novel union of thiol
catalyst and iridium photoredox catalyst, which proved to be
effective for a range of benzylic ethers and a few benzylic
alcohols (Scheme 2 a).[9] Nevertheless, to the best of our
knowledge, electrochemical a-arylation of alcohols has not
previously been reported.
The past decade has witnessed great progress in the
development of redox neutral reactions particularly in the
field of organic photochemistry.[10] In contrast, most synthetic
electrochemistry reported to date only involves a single half-

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Scheme 2. Photocatalyzed C@H arylation and electrochemical aryla-

tion.

electrode reaction (anodic oxidation, cathodic reduction).[6]

Electrochemical redox neutral reactions (that is, convergent
paired electrolysis), in which both electrode reactions have
been fully utilized, is under-developed,[11] although it is more
energy-efficient and synthetically useful. There are two major
challenges associated with convergent paired electrolysis
(Figure 1 a): a) both of the half-electrode reactions should
generate reactive intermediates efficiently; specifically, the
poorly developed cathodic reduction is the bottle neck for
paired electrolysis and,[7e, 12] b) the reactive species which are
generated in situ should react rapidly with one another to
outcompete both undesired side reactions and decomposition
pathways. Consequently, great effort has been devoted to
addressing these issues. Recently, a significant breakthrough
in the field has been achieved by the groups of Ye, Jensen and
Hu independently.[11b,c,d] Ye disclosed a TEMPO-mediated
arylation of a-amines in a convergent paired electrolysis
approach (Figure 1 b).[11b] An elegantly designed microfluidic
device has been reported by Jensen and co-workers in a range
of redox-neutral reactions (Figure 1 c).[11c] A novel strategy
employing nickel catalysis was developed by Hu in a direct
arylation of benzylic C@H bonds (Figure 1 d).[11d] Despite this
exciting recent progress, electrochemical redox-neutral a-
arylation of alcohols still remains to be explored as cathodic
reductive arylation is less developed. Herein, we described an
electrochemical a-arylation of alcohols based on the study of
electroreductive arylation of aldehydes and ketones (Fig-
ure 1 e). This approach allows a general and scalable access to
secondary and tertiary alcohols (97 examples) starting from
commercially available carbonyl compounds or benzylic
alcohols. An excellent functional group (including ester,
amide, amine, thioether, borate) tolerance, mild conditions
(metal catalyst- and external reductant-free), good scalability
(> 10 gram-scale) and site-selectivity make this protocol more
appealing when compared with more conventional synthetic
methods.
Figure 1. Challenges in electrochemical redox neutral reactions and
recent progress.
Results and Discussion
To better explore paired electrolysis, the reductive
arylation of benzaldehyde (2 a) with 1,4-dicyanobenzene
(1 a) was first studied. The reaction was carried out in an
undivided cell equipped with a graphite anode and nickel
cathode under constant current electrolysis. As shown in
Table 1, nearly quantitative yield (99 %) was observed when
the reaction was conducted employing dimethyl sulfoxide
(DMSO) as solvent with nBu4NOAc as electrolyte and
valeraldehyde as an additive (entry 1, Table 1). Valeraldehyde
additive acts as a scavenger for the toxic cyanide ion in the
reaction,[9] and also afforded a slight benefit in the reaction
performance (entry 1 vs. entry 10). A screen of solvents
revealed that CH3CN completely shut down the reaction
(entry 2), while DMA only marginally affected the yield
(entry 3). Use of a halide electrolyte failed to afford any
detectable levels of arylation product (entries 6,7), and
n
Bu4NBF4 and nBu4NClO4 both resulted in noticeable de-
creases in overall reaction yields (entries 4,5). Replacing the
nickel cathode with either a platinum or a graphite cathode
caused a significant detrimental effect on the efficiency of the
reaction (entries 8,9).

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Tabelle 1: Optimization of electrochemically reductive arylation of

benzaldehyde.[a]

Entry Variations from standard conditions Yield [%][b]

1 none 99
2 CH3CN as solvent trace
3 DMA as solvent 89
n
4 Bu4NBF4 instead of nBu4NOAc 78
n
5 Bu4NClO4 instead of nBu4NOAc 81
n
6 Bu4NBr instead of nBu4NOAc trace
n
7 Bu4NI instead of nBu4NOAc trace
8 C(++)-Pt(@) instead of C(+
+)-Ni(@) 71
9 C(++)-C(@) instead of C(+
+)-Ni(@) 56
10 No valeraldehyde 87
[a] Reaction condition: graphite anode, nickel cathode, 1 mmol 1 a,
2 mmol 2 a, 1 mmol valeraldehyde, 1 mmol nBu4NOAc, 10 mL DMSO,
constant current = 16 mA, 6 h, 3.6 Fmol@1, 50 8C. [b] Isolated yield.

With an optimized set of conditions in hand, the substrate

scope of the arylation of aldehydes was evaluated (Scheme 3).
The electronic effect of aryl-substitution was studied with
a variety of para-substituted benzaldehydes. It was found that
electron-donating groups (3 a–3 j) afford superior product
yields than electron-withdrawing groups (3 k–3 l). Aside from
the commonly studied functional groups (3 a–3 l), a range of
relatively sensitive groups, such as ester (OAc, 3 m), amide
(NHAc, 3 n), amine (NMe2, 3 o), thioether (SMe, 3 p) and
borate (BPin, 3 q) were also tolerated; these groups are
inaccessible using previous conventional approaches.[5] Meta-
and ortho-substituted aldehydes also proceeded smoothly in
the reaction affording the desired products, albeit in more
moderate yields (3 r–3 t). The reaction conditions are also
compatible with multiply-substituted aldehydes (3 u–3 w). Scheme 3. Substrate scope of electroreductive arylation of aldehydes.
Additionally, aromatic fused rings (3 x–3 z) and heterocycles [a] Reaction condition: graphite anode, nickel cathode, 1 mmol 1,
(3 aa–3 ac) proved to be amenable to the electrochemical 2 mmol 2, 1 mmol valeraldehyde, 1 mmol nBu4NOAc, 10 mL DMSO,
constant current = 16 mA, 6 h, 3.6 Fmol@1, 50 8C. Yield of isolated
transformation. Paraformaldehyde led to an inferior yield
product 3. [b] 3 mmol paraformaldehyde was used as substrate in the
(3 ad). With regards to the scope of substrate 1, 4-cyanopyr- absence of valeraldehyde.
idine (3 ae), methyl 4-cyanobenzoate (3 af) and 4-(methyl-
sulfonyl)benzonitrile (3 ag) could all be successfully em-
ployed, albeit with diminished yields of products. Strongly of any ring-cleavage product (5 t). This result suggests that
electron-deficient aldehydes failed in the reaction as listed ketone substrates are unlikely to generate a radical inter-
below (Scheme 3). mediate to initiate the reductive arylation. In addition, it was
To further explore the generality of the reductive found that benzocyclo-ketones with different ring sizes were
arylation approach, a broad range of ketones were examined readily arylated (5 u–5 z). It is particularly noteworthy that
in the reaction (Scheme 4). To our delight, a variety of this novel protocol can be easily applied in the late-stage
acetophenone derivatives with different electronic properties diversification of pharmaceutical intermediate 4-(3,4-Di-
and substitution patterns can serve as competent substrates chlorophenyl)-1-tetralone (4 y), spice Tonalid (4 aa) and
(5 a–5 l). We also found that other aryl methyl ketones, medicine Adapalene derived substrate (4 ab). Sterically
bearing naphthalene, benzodioxole, and furan were suitable hindered ketone and electron-rich diaryl ketone were also
substrates (5 m–5 p). Moreover, the R group in substrate 4 found to be suitable substrates, albeit giving corresponding
need not be simply -Me and can be replaced with other alkyl products 5 ac and 5 ad with poor yields.
chains or rings to furnish the corresponding products with Given the successful implementation of electroreductive
good to moderate yields (5 q–5 t). Notably, cyclopropyl ketone arylation of aldehydes and ketones, we posited that alcohols
was transformed to the desired product without observation could be used directly as an arylation partner under a con-

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Scheme 4. Substrate scope of electroreductive arylation of ketones. [a]
Reaction condition: graphite anode, nickel cathode, 1 mmol 1, 2 mmol
4, 1 mmol valeraldehyde, 1 mmol nBu4NOAc, 10 mL DMSO, constant
current = 16 mA, 6 h, 3.6 Fmol@1, 50 8C. Yield of isolated product 5. [b]
0.5 mmol scale, 80 8C.
vergent paired electrolysis approach. After an exhaustive
screening of reaction solvents (for details see Supporting
Information), we were pleased to find that the mixed solvent
CH3CN/EtOAc (3:7) enabled a satifactory yield (71 %) of
arylation product (Scheme 5).
Having identified the optimal conditions of electrochem-
ical arylation of benzylic alcohol, we next examined the
structural diversity of substrates. As summarized in Scheme 6,
a series of benzylic alcohols underwent the arylation effi-
ciently to form the products (7 a–7 z) with acceptable yields. It
should be noted that the arylation is compatible with para-
CF3 (7 l) and ortho-chloro (7 r) substituents, in sharp contrast
with the reaction of aldehydes alone (failed substrates in
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Scheme 5. Optimization of electrochemical redox neutral arylation of
benzylic alcohol.
Scheme 6. Substrate scope of direct arylation of alcohols. [a] Reaction
condition: graphite anode, nickel cathode, 1 mmol 1, 2 mmol 6,
1 mmol valeraldehyde, 1 mmol nBu4NOAc, CH3CN/EtOAc (3/7 mL),
constant current = 16 mA, 6 h, 3.6 Fmol@1, 50 8C. Yield of isolated
product 7. [b] 0.5 mmol scale.
Scheme 3). This observation suggested that different reaction
pathways may be involved in the arylation of benzylic alcohol
and aldehyde. Secondary alcohols could also couple with
terephthalonitrile, albeit with a lower yields (7 aa–7 ac). Other
aryl nitriles showed inferior activity in the transformation
(7 ad–7 ae). This approach also provided a site-selective access
to mono-arylation products (7 af–7 ag) for those substrates
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which contain multiple reactive C@H bonds. The synthetic
utility of the protocol was further demonstrated by the
derivatization of Adapalene (7 ah).
The newly developed protocol is performed with inex-
pensive graphite and nickel electrodes in an undivided cell
under constant current electrolysis. These mild conditions laid
open the possibility of large-scale electrosynthesis. Employing
higher concentrations of substrates and larger electrode areas,
both arylation of benzaldehyde and benzyl alcohol were
readily amenable to scale up affording the desired product
in 94 % (19.7 g) and 64 % yield (13.4 g), respectively
(Scheme 7). Thus, establishing that this electrochemical
approach provides the potential for practical access to high
value alcohols.
In an effort to gain insight into the reaction mechanism,
a series of cyclic voltammetric (CV) experiments were carried
out. Initially, the electrochemical behavior of substrates in
reductive arylation was explored. The cyclic voltammogram
of 1,4-dicyanobenzene 1 a was recorded in 0.1 M nBu4NOAc
(DMSO) at a 100 mV s@1 scan rate. As shown below (Figure 2,
curve b), two reversible redox peaks were detected, with
Scheme 7. Large-scale electrochemical arylation.
Figure 2. Cyclic voltammograms of substrates in 0.1 M nBu4NOAc
(DMSO), using a glassy carbon working electrode and Pt wire and Ag/
AgNO3 (0.1 M in CH3CN) as counter and reference electrodes at
a 100 mVs@1 scan rate: a) background; b) 1,4-dicyanobenzene (1 a)
(0.025 M); c) benzaldehyde (2 a) (0.025 M); d) acetophenone (4 a)
(0.025 M); e) mixture of 1 a (0.025 M) and 2 a (0.025 M); f) 4-(trifluor-
omethyl)benzaldehyde (0.025 M).
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cathodic peak at @2.11 V and anodic peak at @1.73 V.
Subsequently, benzaldehyde 2 a and acetophenone 4 a were
subjected to the same CV experiment (Figure 2, curves c and
d). It was found that both substrates 2 a and 4 a were much
harder to reduce than 1,4-dicyanobenzene with reductive
peaks at @2.43 V (curve c) and @2.88 V (curve d), respec-
tively. Moreover, the CV of mixed 1 a and 2 a (curve e) only
showed a couple of reversible redox peaks with shifted
positions, which was assigned to 1 a. The peak arising from
benzaldehyde (2 a) was not detected on the CV. The decrease
of anodic peak of curve e (comparing with curve b) verified
that radical anion generating from 1 a was intercepted by 2 a.
We thus conclude that the reductive arylation reaction should
be initiated by the reduction of 1,4-dicyanobenzene 1 a, rather
than the reduction of aldehydes or ketones. To provide
further support for this assumption, a CV experiment of an
unsuccessful substrate 4-(trifluoromethyl)benz-aldehyde was
performed (Figure 2, curve f). A cathodic peak was observed
at @2.06 V, which was less negative than 1,4-dicyanobenzene.
In other words, a more readily reducible aldehyde was
unfavorable for the reductive arylation. Additionally, this
conclusion was further supported by the retention of the
cyclopropyl ring in product 5 t (in Scheme 4) which argues
against generation of a ketone-based radical species. The
study of anodic process in the reductive arylation shows that
oxidation of DMSO occurs over the surface of anode (for
details see Supporting Information).
The anodic and cathodic processes in redox-neutral a-
arylation of alcohols were subsequently investigated (Fig-
ure 3). A similar set of reversible redox peaks arising from
1,4-dicyanobenzene were recorded (Figure 3 a). In contrast,
no significant cathodic peak was observed for benzyl alcohol
6 a (Figure 3 a). This result suggests that 1,4-dicyanobenzene
is the active substrate at the cathode surface. In stark contrast,
completely different electrochemical behavior was observed
in the anodic process, and benzyl alcohol was found to be an
active substrate at the anode surface with an observed peak at
2.19 V (Figure 3 b). As a result, we propose that the redox-
neutral a-arylation of alcohols proceeds through a convergent
paired electrolysis, involving anodic oxidation of benzyl
alcohol and cathodic reduction of 1,4-dicyanobenzene.
To further investigate the reaction mechanism, the
arylation of benzylic alcohol (6 a) was conducted in a divided
cell (Scheme 8 a). As expected, no desired product 7 a was
detected, while benzaldehyde was observed in the anode
chamber (Scheme 8 a). This demonstrated that both electrode
reactions were essential for the electrochemical arylation.
Next, the presence of a kinetic isotope effect (KIE) was
demonstrated by employing deuterated alcohol (D-6 a)
(Scheme 8 b). The ratio of H/D in the product (7 a) indicates
a primary KIE (kH/kD = 2/1) is present in the reaction,
suggesting benzylic C@H cleavage as a plausible rate-deter-
mining step (Scheme 8 b). To identify the reaction pathway,
a suitable radical scavenger may be selected and employed in
the reaction. TEMPO as one of most common scavengers but
cannot be employed as it is more susceptible to undergoing
oxidation and reduction processes than the substrates in the
reaction. More redox stable reagents, 1,1-diphenylethylene,
butylated hydroxytoluene (BHT), P(OEt)3 and allyl sulfone
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Figure 3. a) Cyclic voltammograms of substrates (0.025 M) in 0.1 M
n
Bu4NOAc (CH3CN/EtOAc = 3/7), using a glassy carbon working
electrode and Pt wire and Ag/AgNO3 (0.1 M in CH3CN) as counter
and reference electrodes at a 100 mVs@1 scan rate. b) Cyclic voltammo-
grams of substrates (0.025 M) in 0.1 M LiClO4 (CH3CN), using a glassy
carbon working electrode and Pt wire and Ag/AgNO3 (0.1 M in
CH3CN) as counter and reference electrodes at a 100 mVs@1 scan rate.
were chosen as radical trap in the arylation of aldehyde (2 a)
and benzylic alcohol (6 a; Scheme 8 c). The radical scavengers
had only a negligible effect on the reductive arylation of
aldehyde 2 a, suggesting a non-radical pathway in the trans-
formation. By contrast, a significant diminishing of the yield
was observed upon introduction of radical scavengers to the
redox neutral arylation of benzylic alcohol (6 a), although the
reaction still afforded the product in trace to 29 % yield.
These observations suggest that this reaction might proceed
via multiple, distinct, mechanistic pathways (for more control
experiments, see the Supporting Information).
On the basis of the above experimental observations and
a previously reported mechanistic study,[11b, 13] a plausible
mechanism was proposed for the redox-neutral arylation of
benzylic alcohol and is depicted in Figure 4. Initially, benzylic
alcohol (6 a) undergoes a single-electron transfer (SET)
process to afford a cation radical II at the anode surface.
Subsequently, a rate-determining deprotonation of intermedi-
ate II produces a benzylic radical III, which could further
proceed through two possible pathways (path a and path b) to
deliver the final product. In path a, benzylic radical III
couples with a cathodically generated anion radical I to
produce intermediate IV. In the presence of valeraldehyde,
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Scheme 8. Mechanistic experiments.
Figure 4. Proposed mechanism for redox-neutral arylation of benzylic
alcohol.
intermediate IV undergoes elimination of CN@ to generate
the desired product 7 a, and toxic CN@ is converted to
cyanohydrin. In path b, benzylic radical III loses both an
electron and proton to generate benzaldehyde. Benzaldehyde
subsequently acts as an electrophile which can be intercepted
by nucleophilic anion radical I yielding intermediate V. A
single-electron reduction of V results in the generation of
intermediate IV, which finally transforms into the product 7 a
via a similar elimination process to path a. As shown in path b,
the nucleophilic addition between benzaldehyde and anion
radical I arising from substrate 1 a is the key step toward the
arylation product. This reaction process is regarded as the
most pausible pathway involved in the reductive arylation of
aldehyde in agreement with both CV studies (Figure 2) and
radical scavenger experiments (Scheme 8 c).
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Conclusion
We have developed electrochemical approaches to the
direct arylation of carbonyls and alcohols through less-
explored cathodic reduction and convergent paired electrol-
ysis. This novel electrochemical protocol provides mild access
to a broad range of arylated products bearing reactive
functional groups, which are inaccessible to conventional
methods, with metal catalyst- and external reductant-free
conditions. Moreover, this approach enables a large-scale
electrosynthesis of high value alcohols starting from carbonyls
or benzylic alcohols. Taken together, these features make the
present electrochemical method a highly appealing alterna-
tive to existing approaches. Two plausible reaction pathways
have been proposed to rationalize the mechanistic observa-
tions in the electrochemical arylation.
Acknowledgements
We are grateful to the National Natural Science Foundation
of China (21702113, 22071102 and 91956110), the Thousand
Talents Plan of Central Plains, the Key Scientific Research
Projects of Higher Education Institutions in Henan Province
(20A150029), the National Science Foundation (CHE-
1554906) and Robert A. Welch Foundation (D-1361) for
their financial support.
Conflict of interest
The authors declare no conflict of interest.
Stichwçrter: arylation of alcohols · cathodic reduction ·
convergent paired electrolysis · reductive arylation of carbonyls
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Manuskript erhalten: 14. November 2020
Ver-nderte Fassung erhalten: 16. Dezember 2020
Akzeptierte Fassung online: 29. Dezember 2020
Endggltige Fassung online: 24. Februar 2021
Angew. Chem. 2021, 133, 7351 – 7358