Electrochemical Arylation of Aldehydes, Ketones, and Alcohols: from Cathodic Reduction to Convergent Paired Electrolysis

Article abstract of DOI:10.1002/anie.202015230

Arylation of carbonyls, one of the most common approaches toward alcohols, has received tremendous attention, 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 α-arylation of benzylic alcohols.

Full text of DOI:10.1002/anie.202015230

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 7275–7282
International Edition: doi.org/10.1002/anie.202015230
German Edition: doi.org/10.1002/ange.202015230
Electrochemistry
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
aldehydes and ketones using iridium catalysts (Scheme 1c).[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 2b).[7] Moreover, to further exploit the capabilities
of electrochemistry, we considered whether convergent
paired electrolysis could enable a direct a-arylation of
alcohols (Scheme 2b). This neutral-redox reaction can serve
as an attractive synthetic route to higher value alcohols
starting from benzylic alcohols.[8] MacMillan unveiled a pho-
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 1a).
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 1b). 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)
À
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 2a).[9] Nevertheless, to the best of our
knowledge, electrochemical a-arylation of alcohols has not
previously been reported.
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)
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-
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.
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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 1a): 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
Figure 1. Challenges in electrochemical redox neutral reactions and
recent progress.
approach (Figure 1b).[11b] An elegantly designed microfluidic Results and Discussion
device has been reported by Jensen and co-workers in a range
of redox-neutral reactions (Figure 1c).[11c] A novel strategy
employing nickel catalysis was developed by Hu in a direct
To better explore paired electrolysis, the reductive
arylation of benzaldehyde (2a) with 1,4-dicyanobenzene
(1a) 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
nBu4NBF4 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).
arylation of benzylic C H bonds (Figure 1d).[11d] Despite this
À
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 1e). 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.
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Table 1: Optimization of electrochemically reductive arylation of ben-
zaldehyde.[a]
Entry
Variations from standard conditions
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
none
CH3CN as solvent
DMA as solvent
99
trace
89
78
81
trace
trace
71
56
87
nBu4NBF4 instead of nBu4NOAc
nBu4NClO4 instead of nBu4NOAc
nBu4NBr instead of nBu4NOAc
nBu4NI instead of Bu4NOAc
n
C(+)-Pt(À) instead of C(+)-Ni(À)
C(+)-C(À) instead of C(+)-Ni(À)
No valeraldehyde
[a] Reaction condition: graphite anode, nickel cathode, 1 mmol 1a,
2 mmol 2a, 1 mmol valeraldehyde, 1 mmol nBu4NOAc, 10 mL DMSO,
constant current=16 mA, 6 h, 3.6 FmolÀ1, 508C. [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 (3a–3j) afford superior product
yields than electron-withdrawing groups (3k–3l). Aside from
the commonly studied functional groups (3a–3l), a range of
relatively sensitive groups, such as ester (OAc, 3m), amide
(NHAc, 3n), amine (NMe2, 3o), thioether (SMe, 3p) and
borate (BPin, 3q) 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 (3r–3t). The reaction conditions are also
compatible with multiply-substituted aldehydes (3u–3w).
Additionally, aromatic fused rings (3x–3z) and heterocycles
(3aa–3ac) proved to be amenable to the electrochemical
transformation. Paraformaldehyde led to an inferior yield
(3ad). With regards to the scope of substrate 1, 4-cyanopyr-
idine (3ae), methyl 4-cyanobenzoate (3af) and 4-(methyl-
sulfonyl)benzonitrile (3ag) could all be successfully em-
ployed, albeit with diminished yields of products. Strongly
electron-deficient aldehydes failed in the reaction as listed
below (Scheme 3).
To further explore the generality of the reductive
arylation approach, a broad range of ketones were examined
in the reaction (Scheme 4). To our delight, a variety of
acetophenone derivatives with different electronic properties
and substitution patterns can serve as competent substrates
(5a–5l). We also found that other aryl methyl ketones,
bearing naphthalene, benzodioxole, and furan were suitable
substrates (5m–5p). Moreover, the R group in substrate 4
need not be simply -Me and can be replaced with other alkyl
chains or rings to furnish the corresponding products with
good to moderate yields (5q–5t). Notably, cyclopropyl ketone
was transformed to the desired product without observation
Scheme 3. Substrate scope of electroreductive arylation of aldehydes.
[a] Reaction condition: graphite anode, nickel cathode, 1 mmol 1,
2 mmol 2, 1 mmol valeraldehyde, 1 mmol nBu4NOAc, 10 mL DMSO,
constant current=16 mA, 6 h, 3.6 FmolÀ1, 508C. Yield of isolated
product 3. [b] 3 mmol paraformaldehyde was used as substrate in the
absence of valeraldehyde.
of any ring-cleavage product (5t). This result suggests that
ketone substrates are unlikely to generate a radical inter-
mediate to initiate the reductive arylation. In addition, it was
found that benzocyclo-ketones with different ring sizes were
readily arylated (5u–5z). It is particularly noteworthy that
this novel protocol can be easily applied in the late-stage
diversification of pharmaceutical intermediate 4-(3,4-Di-
chlorophenyl)-1-tetralone (4y), spice Tonalid (4aa) and
medicine Adapalene derived substrate (4ab). Sterically
hindered ketone and electron-rich diaryl ketone were also
found to be suitable substrates, albeit giving corresponding
products 5ac and 5ad with poor yields.
Given the successful implementation of electroreductive
arylation of aldehydes and ketones, we posited that alcohols
could be used directly as an arylation partner under a con-
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Scheme 5. Optimization of electrochemical redox neutral arylation of
benzylic alcohol.
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 FmolÀ1, 508C. Yield of isolated product 5. [b]
0.5 mmol scale, 808C.
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 FmolÀ1, 508C. Yield of isolated
product 7. [b] 0.5 mmol scale.
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 (7a–7z) with acceptable yields. It
should be noted that the arylation is compatible with para-
CF3 (7l) and ortho-chloro (7r) substituents, in sharp contrast
with the reaction of aldehydes alone (failed substrates in
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 (7aa–7ac). Other
aryl nitriles showed inferior activity in the transformation
(7ad–7ae). This approach also provided a site-selective access
to mono-arylation products (7af–7ag) for those substrates
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À
which contain multiple reactive C H bonds. The synthetic
utility of the protocol was further demonstrated by the
derivatization of Adapalene (7ah).
cathodic peak at À2.11 V and anodic peak at À1.73 V.
Subsequently, benzaldehyde 2a and acetophenone 4a were
subjected to the same CV experiment (Figure 2, curves c and
d). It was found that both substrates 2a and 4a were much
harder to reduce than 1,4-dicyanobenzene with reductive
peaks at À2.43 V (curve c) and À2.88 V (curve d), respec-
tively. Moreover, the CV of mixed 1a and 2a (curve e) only
showed a couple of reversible redox peaks with shifted
positions, which was assigned to 1a. The peak arising from
benzaldehyde (2a) was not detected on the CV. The decrease
of anodic peak of curve e (comparing with curve b) verified
that radical anion generating from 1a was intercepted by 2a.
We thus conclude that the reductive arylation reaction should
be initiated by the reduction of 1,4-dicyanobenzene 1a, 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 À2.06 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 5t (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 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
n
of 1,4-dicyanobenzene 1a was recorded in 0.1 M Bu4NOAc
(DMSO) at a 100 mVsÀ1 scan rate. As shown below (Figure 2,
curve b), two reversible redox peaks were detected, with
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 3a). In contrast,
no significant cathodic peak was observed for benzyl alcohol
6a (Figure 3a). 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 3b). 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.
Scheme 7. Large-scale electrochemical arylation.
To further investigate the reaction mechanism, the
arylation of benzylic alcohol (6a) was conducted in a divided
cell (Scheme 8a). As expected, no desired product 7a was
detected, while benzaldehyde was observed in the anode
chamber (Scheme 8a). 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-6a)
(Scheme 8b). The ratio of H/D in the product (7a) indicates
a primary KIE (kH/kD = 2/1) is present in the reaction,
À
suggesting benzylic C H cleavage as a plausible rate-deter-
mining step (Scheme 8b). 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
n
Figure 2. Cyclic voltammograms of substrates in 0.1 M Bu4NOAc
(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 mVsÀ1 scan rate: a) background; b) 1,4-dicyanobenzene (1a)
(0.025 M); c) benzaldehyde (2a) (0.025 M); d) acetophenone (4a)
(0.025 M); e) mixture of 1a (0.025 M) and 2a (0.025 M); f) 4-(trifluor-
omethyl)benzaldehyde (0.025 M).
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Scheme 8. Mechanistic experiments.
Figure 3. a) Cyclic voltammograms of substrates (0.025 M) in 0.1 M
nBu4NOAc (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 mVsÀ1 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 mVsÀ1 scan rate.
were chosen as radical trap in the arylation of aldehyde (2a)
and benzylic alcohol (6a; Scheme 8c). The radical scavengers
had only a negligible effect on the reductive arylation of
aldehyde 2a, 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 (6a), 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 (6a) 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,
Figure 4. Proposed mechanism for redox-neutral arylation of benzylic
alcohol.
intermediate IV undergoes elimination of CNÀ to generate
the desired product 7a, and toxic CNÀ 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 7a
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 1a 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 8c).
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[3] For reviews of reductive addition of carbonyls, see: a) H. Iida,
Conclusion
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2017, 50, 2371 –2380; d) M. Holmes, L. A. Schwartz, M. J.
Krische, Chem. Rev. 2018, 118, 6026 –6052.
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.
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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.
[8] For redox-neutral reaction of alcohols, see: a) J. M. Ketcham, I.
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Keywords: arylation of alcohols ·cathodic reduction ·
convergent paired electrolysis ·reductive arylation of carbonyls
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Manuscript received: November 14, 2020
Revised manuscript received: December 16, 2020
Accepted manuscript online: December 29, 2020
Version of record online: February 24, 2021
7282
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