Electrochemical α-Arylation of Ketones via Anodic Oxidation of in Situ Generated Silyl Enol Ethers

Article abstract of DOI:10.1021/acs.joc.1c01224

An electrochemical procedure for the α-arylation of ketones has been developed. The method is based on the generation and one-pot anodic oxidation of silyl enol ethers in the presence of the arene. This strategy avoids isolation of the silyl enol intermediate and the utilization of external supporting electrolytes. Intermolecular arylations, which had not been reported so far, are possible when electron-rich arenes are utilized as coupling partners. The method has been demonstrated for a wide variety of aryl ketones and activated arenes, with moderate to good yields (up to 69%) obtained. Mechanistic insights and a theoretical rationale that explains the ketone α-arylation versus dimerization selectivity are also presented.

Full text of DOI:10.1021/acs.joc.1c01224

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Article
Electrochemical α‑Arylation of Ketones via Anodic Oxidation of In
Situ Generated Silyl Enol Ethers
Wolfgang Jud, Florian Sommer, C. Oliver Kappe, and David Cantillo*
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ABSTRACT: An electrochemical procedure for the α-arylation of
ketones has been developed. The method is based on the
generation and one-pot anodic oxidation of silyl enol ethers in
the presence of the arene. This strategy avoids isolation of the silyl
enol intermediate and the utilization of external supporting
electrolytes. Intermolecular arylations, which had not been
reported so far, are possible when electron-rich arenes are utilized
as coupling partners. The method has been demonstrated for a wide variety of aryl ketones and activated arenes, with moderate to
good yields (up to 69%) obtained. Mechanistic insights and a theoretical rationale that explains the ketone α-arylation versus
dimerization selectivity are also presented.
In all anodic arylation methods cited above, the silyl enol ether
was prepared, isolated, and utilized in the electrochemical step in
a pure form. An external supporting electrolyte (LiClO4 was
utilized in all cases7−11) was added to aid the electrolysis by
increasing the conductivity of the solution. Moreover, not
surprisingly, all examples of electrochemical coupling of silyl
enol ethers with arenes published to date comprised intra-
molecular reactions (Figure 1a).14 Intermolecular couplings are
likely tampered by the expected dimerization of the carbonyl
species, which can readily take place by a reaction of the radical
cation resulting from anodic oxidation of the silyl enol ether with
another unreacted molecule of the enol intermediate.15
We envisioned that one-pot electrolysis of a ketone silylation
reaction mixture, which includes a silylating agent and a base as
reagents, would not require the addition of external supporting
electrolytes to confer conductivity to the solution (Figure 1b).
Such a strategy would avoid purification of the silyl enol ether
and the use of additional salts for the electrochemical step,
rendering a more convenient and sustainable methodology.
Moreover, we wondered whether intermolecular electro-
chemical couplings of silyl enol ether and arenes, not reported
thus far, were also possible and questioned what accounts for the
reaction selectivity in this type of electrochemically induced C−
C coupling reaction.
INTRODUCTION
■
The α-arylation of ketones constitutes a useful and powerful
class of C−C bond-forming reactions. Many α-aryl carbonyl-
containing compounds feature interesting pharmacological and
biological properties, including several approved active
pharmaceutical ingredients such as fluindione or anisindione.
Over the past two decades, metal-catalyzed α-arylations using
aryl halides have been extensively investigated and utilized,1
stemming from the pioneering work of Buchwald,2 Hartwig,3
and Miura.4 More recently, novel methodologies that circum-
vent the need for aryl halides have been developed, based on the
activation of either the carbonyl α-position or the arene.5 In this
context, oxidative umpolung of silyl enol ethers and enolates,
typically using hypervalent iodine reagents, has emerged as an
interesting methodology.6 In such umpolung strategies,
electron-rich nucleophilic enol ethers and enolates are trans-
formed into electrophiles, thus promoting the coupling with the
electron-rich aromatic ring. Not surprisingly, electrochemical
umpolung of silyl enol ethers to achieve carbonyl α-arylation has
also been described (Figure 1a).7−11 For instance, Moeller and
co-workers reported electrochemical procedures for the intra-
molecular coupling of silyl enol ethers and furans, as
intermediate steps in the synthesis of Alliacol A and the
Arteannuin skeleton.7,8 An analogous procedure, also involving
oxidative coupling of enol ethers and furans, was described by
the group of Trauner for the generation of the guanacastepene
core.9 Intramolecular coupling of silyl enol ethers with
substituted electron-rich phenyl derivatives has also been
demonstrated by Sperry and White (Figure 1a, bottom).11
These examples illustrate organic electrochemistry as a powerful
strategy for the generation of reactivity via umpolung of
functional groups,12 in addition to an enabling potentially
sustainable method of organic synthesis.13
Herein, we describe an electrochemical procedure for the α-
arylation of ketones based on the in situ generation and anodic
Special Issue: Electrochemistry in Synthetic Organic
Chemistry
Received: May 25, 2021
© XXXX The Authors. Published by
American Chemical Society
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A

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a convenient strategy for the preparation of α-aryl ketones 8.
However, unreacted 7, with also a marked nucleophilic
character, can readily react with the cation radical, providing
dimer 9. A potential strategy to selectively form the target
compound 8, apart from performing the arylation in an
intramolecular fashion,7−11 would be the utilization of
electron-rich arenes. Activated aromatics could be able to trap
the cation radical, selectively avoiding the formation of 9.
However, electron-rich aromatics can also be oxidized, typically
producing the corresponding biaryls 10.16 To test this
hypothesis, the coupling of acetophenone (5a) with 1,3,5-
trimethoxybenzene (TMB) (6a) was initially evaluated as a
model reaction (Table 1). First, the conditions for the in situ
generation of the corresponding silyl enol ether 7a were
screened (see Experimental Section). A combination of
trimethylsilyl triflate (TMSOTf) as a silylating agent and 2,6-
lutidine as a base in THF as solvent provided satisfactory results.
Importantly, 2,6-lutidine is sufficiently stable to anodic oxidation
and can withstand the electrolysis of the silyl enol ether. Other
organic bases typically used for silylation, such as iPr2EtN or
Et3N, are oxidatively labile and were therefore not considered.
Generation of silyl enol ethers 7 using this system produces 2,6-
lutidinium triflate as a byproduct. This salt, which is also
relatively electrochemically inert, served as a supporting
electrolyte for the subsequent electrolysis.
Electrochemical α-arylation experiments were carried out
using an IKA ElectraSyn 2.0 reactor in an undivided 5 mL cell. In
a typical experiment, acetophenone (5a), TMB (6a), and 2,6-
lutidine were placed into the vial. Then, TMSOTf was added
under stirring, and the cell was capped with the vial head
equipped with the electrodes. The mixture was stirred for 30 min
at room temperature to permit silyl enol ether generation, and
then a protic cosolvent was added. The electrolysis under
constant current was then initiated. Optimal reaction conditions
(Table 1, entry 1) included a 0.5 M concentration of substrate
5a, 2 equiv of arene 6a, and a current of 10 mA (6.7 mA/cm2).
Figure 1. (a) Previous examples of the synthesis of α-aryl ketones via
electrochemical oxidation of silyl enol ethers and intramolecular
cyclization and (b) proposed one-pot strategy for intramolecular
electrochemical ketone α-arylation.
oxidation of silyl enol ethers. Intermolecular couplings have
been achieved in the presence of electro-rich aromatic
compounds. Mechanistic insights and a theoretical rationale
that interprets the intermolecular reaction selectivity are also
presented.
1
The reaction outcome was monitored by H NMR using
trichloroethylene as an internal standard. Gratifyingly, NMR
analysis of the crude mixture revealed the formation of the target
α-aryl ketone 8a and confirmed the generation of a ketone dimer
as the main side product of the reaction (see Figure S1).
Impervious graphite was found to be an excellent material for
this transformation, superior to standard graphite (Table 1,
entry 1 vs entry 2). This is probably due to the fact that
impervious graphite is nonporous, and therefore it does not
absorb reaction solution (graphite was thoroughly washed with
THF in an attempt to recover all the material). Other electrode
material combinations, including stainless steel and platinum as
the cathode material or platinum as the anode, did not improve
the results (entries 3−6). A combination of glassy carbon and
nickel (entry 7) provided a similar yield as impervious graphite/
nickel. However, the latter was selected as optimal material due
to its lower cost. Several protic solvents were evaluated as
additives to facilitate proton reduction at the cathode. Water
(entry 1) performed significantly better than alcohols such as
MeOH, iPrOH, or hexafluoroisopropanol (HFIP) (entries 8−
10). The amount of water also played an important role in the
reaction efficiency. Thus, excessive amounts of water (entry 11
vs 12) reduced the yield by more than 20%. Notably, the current
efficiency of the anodic oxidation proved to be relatively high, as
high conversion and 70% yield was obtained with 2 F/mol,
which corresponds to the theoretical amount of charge needed
(entry 13). An analogous yield was achieved with 2.2 F/mol,
RESULTS AND DISCUSSION
■
Anodic oxidation of silyl enol ethers 7 (Figure 2) generates the
corresponding cation radical. In principle, this reactive species
can be trapped by a nucleophile, such as an arene (6), providing
Figure 2. Expected reactivity from the anodic oxidation of silyl enol
ethers in the presence of arenes.
B
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Table 1. Optimization of the Electrochemical α-Arylation of Ketones via In Situ Generated Silyl Enol Ethers
a
b
entry
variation from the above
none
yield [%]
1
2
3
4
5
6
69(62)
46
56
61
47
(+)graphite /(−)Ni
(+)graphite/(−)steel
(+)graphite /(−)Pt
(+)impervious graphite/(−)Pt
(+)Pt/(−)Pt
23
7
8
9
(+)glassy carbon/(−)Ni
MeOH instead of H2O
iPrOH instead of H2O
HFIP instead of H2O
THF/H2O 80:1
THF/H2O 20:1
2 F/mol
2.5 F/mol
2 equiv base
70
44
39
53
66
42
70
54
10
11
12
13
14
15
16
17
59
62
66
1.5 equiv base, 3 equiv 6a
1 M concentration of 5a
a
Conditions: 1.5 mmol 5a, 2 mL of solvent (the total volume of the reaction solution was ca. 3 mL); a 5 mL IKA ElectraSyn 2.0 vial was used. The
b
reaction mixture was stirred at rt for 30 min and then electrolyzed under constant current. Determined by 1H NMR using trichloroethylene as an
internal standard. Isolated yield shown in parentheses. CIG = impervious graphite.
which was selected as optimal for the methodology to make it
suitable for less reactive systems. Further increase of the charge
(entry 14) led to product degradation. Variation of the excess
amount of arene or 2,6-luditine did not improve the results
(entries 15 and 16). Notably, the electrochemical procedure was
also compatible with higher substrate concentration (1 M 5a)
(entry 17), although a slightly lower yield was achieved.
Purification of the reaction mixture by column chromatography
permitted isolation of 8a (62%). Importantly, dimer 9a (see
Figure 2) could also be isolated and characterized, thus
confirming the identity of the main side product of the reaction.
With the optimal reaction conditions in hand, the scope of the
electrochemical α-arylation was investigated (Figure 3). Both
the suitability of a wide variety of aryl ketones (Figure 3a) and
electron-rich arenes (Figure 3b) were evaluated. All reactions
were carried out under the same conditions to provide a better
understanding of the substituent effects. The presence of
halogens (8b−d) in the acetophenone derivative did not have a
significant effect on the reaction outcome. A stronger electron-
withdrawing group such as a nitrile (8e) considerably reduced
the yield. In this case, low conversion of the starting material was
observed, along with a notable proportion of arene dimerization.
This effect could be ascribed to a higher oxidation potential of
the silyl enol ether due to the electron-withdrawing effect of the
4-CN group. Interestingly, an electron-rich acetophenone
derivative also provided a relatively low yield (8h). In this
case, aryl−aryl oligomerization may also occur with the activated
aromatic ring of the silyl enol ether. Notably, the method was
compatible with ketones bearing a sulfur-containing heterocycle
(8i) but not a pyridine derivative (8j). An aliphatic ketone was
also evaluated under the optimal electrolysis conditions.
Cyclohexanone did not provide the corresponding α-aryl
derivative 8k. Instead, partial α-carbonyl desaturation most
likely ensued.17 It is expected that a similar effect would be
observed for aryl ketones bearing hydrogens in β-position (e.g.,
aryl ethyl ketones).
We next turned our attention to the range of arenes that can
be utilized for this transformation (Figure 3b). As anticipated,
only electron-rich arenes were suitable for the anodic α-
arylation. Indeed, most examples contained one or two alkoxy
substituents. Additional substituents such as alkyl (8o) and
halogen (8p−r) were well tolerated. Coupling of the
naphthalene ring was also successful (8s-t) as well as 2-
methylthiophene (8u). Most compounds could be isolated in
moderate yields by column chromatography. In some cases (8l,
8t, and 8u), purification was difficult, and only NMR yields are
reported. As stated above, for the model reaction (8a), variable
amounts of the dimer formation were observed in many
examples and predominated in cases in which low yield was
observed. For example, with compound 8l (13% yield), a 24%
NMR yield for the dimer was observed. 1,3-Dialkoxy arenes
(8m−8r) typically resulted in notable amounts of silyl enol
1
dimerization, amounting to 20−35% by H NMR analysis.
Generation of α-aryl ketone 8u also proceeds with concomitant
ketone dimerization (25%). It should be noted that many more
arenes were evaluated under the optimal electrolysis conditions
and failed to produce the α-aryl ketones. It was expected that
electron-poor aromatics would not be sufficiently reactive to
trap the cation radical developed by anodic oxidation of the silyl
enol ether 5, in which case formation of the dimer 9 would ensue
(see Figure 2). However, to our surprise, activated arenes such as
1,2,3-trimethoxybenzene or 1,2,4-trimethoxybenezene failed to
react. NMR monitoring of the crude reaction mixtures revealed
that some electron-rich arenes tended to dimerize, generating
biaryl side products 10 while most of the acetophenone (5a)
remained unreacted. On the other hand, ketone dimerization to
9 instead of α-arylation was observed in some cases. We
hypothesized that aromatic rings with a very high electron
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Figure 3. Scope of the electrochemical α-arylation of ketones. (a) Scope of ketones. (b) Scope of arenes. 1H NMR yields using trichloroethylene as a
standard, and isolated yields (in parentheses) are shown.
density could oxidize at a lower potential than the silyl enol ether
group, thus forming biaryl dimers 10, while arenes with
insufficient electron density would lack sufficient nucleophilicity
to trap the cation radical 7•+.
Details in the Experimental Section). This method has shown a
good correlation between experimental and theoretical values
for the ionization and redox potentials of arenes and
heteroarenes in solution.22 Interestingly, when the IP and the
quadrupole moment of all arene molecules were plotted (Figure
4), all reactants which had worked followed a similar trend.
Successful examples featured an IP in the range 140−147 kcal/
mol and a quadrupole in the range from −9 DÅ to −15 DÅ. The
IP value had a major impact on the observed arene reactivity.
Indeed, all arenes with a value below 140 kcal/mol (Figure 4)
had been experimentally observed to fail as α-arylation coupling
partners, typically giving low conversion of acetophenone 5a and
biaryls 10 as the main side product. This can therefore be
ascribed to a lower oxidation potential for the arene compared to
the silyl enol ether. On the other hand, arenes with a higher IP
To shed light into the observed reactivity and provide a
theoretical rationale, the ionization potentials (IP) of all arenes
tested for the reaction were calculated using density functional
theory (DFT). The IP of a molecule is a measure of both its
oxidation potential18 and its nucleophilicity.19 Moreover, the
quadrupole moments of the arenes were also computed. The
quadrupole moments of aromatics have classically been
associated with their tendency of aggregate via π-stacking,20
which may also influence their adsorption behavior in the
presence of graphite material.21 DFT calculations were carried
out at the M06-2X/def2-TZVPP level (see Computational
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Figure 4. Graphic representation of ionization potentials (IP) and quadrupole moments of all arenes evaluated, and additionally 1-hexene, calculated at
the M06-2X/def2-TZVPP level.
(e.g., biphenyl, 1-bromonathlene, etc.) failed to trap the cation
radical 7•+ resulting from the anodic oxidation of the enol ether,
which thus ensued dimerization to 9, due to the lack of
nucleophilicity of the arene. In this context, an aliphatic alkene
(1-hexene) was also tested with the same results.
The effect of the quadrupole moment proved to be more
complex. Importantly, aromatic compounds that should have
worked according to their IP value (2-methylfuran, 2-
naphthylacetonitrile) failed to provide α-aryl ketones. Their
computed quadrupole moment was less negative, which may
point to a lower tendency to aggregate in solution or adsorb on
the anode surface. It should be emphasized that the computa-
tional data presented a very good fit with the experimental
results. Thus, this computational methodology could serve as a
predictive tool to evaluate whether a nucleophile is suitable for
Figure 5. Cyclic voltammograms of acetophenone (5a), 1,3,5-
trapping anodically generated cation radical intermediates. Yet,
the calculated molecular properties failed to explain why the
ketone α-arylation with mesitylene, benzofuran, and benzothio-
phene did not work.
trimethoxybenzene (6a), and intermediate 7a. Footnote a represents
7a was generated in situ from 5a, TMSOTf, and 2,6-lutidine in a
separate vial, and an aliquot of the reaction mixture was diluted in the
voltammetry cell.
Cyclic voltammetry of the reaction components (Figure 5)
confirmed that acetophenone (5a) presents a relatively high
oxidation potential, while upon transformation into the
corresponding silyl enol ether 7a, the molecule can be oxidized
with ease (Ep/2 = +0.98 V vs Fc/Fc+). To carry out this
voltammogram, 7a was generated in a separate vial from 5a,
TMSOTf, and 2,6-lutidine and then diluted into a cyclic
voltammetry cell containing solvent and supporting electrolyte.
1,3,5-Trimethoxybenzene (6a) was oxidized at a higher
oxidation potential (Ep/2 = +1.20 V vs Fc/Fc+), thus explaining
that, during the study of the model reaction, no arene oxidation
was observed. Both reactants showed irreversible oxidation
peaks, pointing to rapid chemical reactions of the cation radicals
generated.
With this information in hand, a mechanism for the
electrochemical α-arylation of ketones from in situ generated
silyl enol ether was proposed (Figure 6). Ketone 5 reacts with
TMSOTf in the presence of 2,6-lutidine, generating oxidizable
silyl enol ether 7 and 2,6-lutidinium triflate [(Lut-H)+(OTf)−]
as a byproduct, thus also producing a salt that can act as a
supporting electrolyte. One-electron anodic oxidation of 7
generates the corresponding cation radical 7•+, which can be
trapped either by the arene 6 or by another molecule of 7. In the
latter case, a second oxidation event and hydrolysis release dimer
9. Trapping of 7•+ by 6 generates radical intermediate 11, which,
upon a second 1-electron oxidation to 12 and hydrolysis with the
release of protons, produces α-aryl ketone 8. Both the formation
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ionization potentials (IP) and quadrupole moments of all arenes
evaluated have been calculated using DFT methods. The
calculations have shown a good fit with the experimental
observations due to their close relation to important parameters
such as oxidation potential or nucleophilicity, which play a key
role in the arene reactivity.
EXPERIMENTAL SECTION
■
General. 1H NMR spectra were recorded on a 300 MHz instrument.
13C NMR spectra were recorded on the same instrument at 75 MHz.
Chemical shifts (δ) are expressed in ppm downfield from TMS as an
internal standard. The letters s, d, t, q, and m are used to indicate singlet,
doublet, triplet, quadruplet, and multiplet, respectively. Flash
chromatography purifications were carried out on an automated flash
chromatography system using cartridges packed with KP-SIL, 60 Å
(32−63 μm particle size). All chemicals, including ketones 5 and arenes
6, were obtained from standard commercial vendors and were used
without any further purification. All electrochemical reactions were
carried out in an IKA ElectraSyn 2.0 using IKA Electra-Syn 2.0
undivided cells (5 mL vials) equipped with standard IKA ElectraSyn 2.0
electrodes, unless stated otherwise. All electrodes were polished with
sandpaper (3000 frit) before each electrolysis experiment.
Cyclic Voltammetry. Cyclic voltammograms were recorded in a
glass cell with a Rodeostat open source potentiostat (IO Rodeo Inc.). A
glassy carbon disk (a 2 mm diameter rod with a PTFE shroud) was used
as the working electrode and a platinum wire as the counter electrode. A
silver wire was utilized as a quasi reference electrode, using ferrocene as
a reference. The electrolyte consisted of 10 mM of analyte and 0.1 M
Et4NBF4 in MeCN. Samples were degassed prior to analysis.
Computational Details. All calculations were carried out with the
Gaussian 09 package.25 The M06-2X density functional method26 in
conjunction with the def2-TZVP(-f) basis set was selected for all
geometry optimizations and frequency analysis. The geometries were
optimized with the inclusion of solvation effects. For this purpose, the
SMD solvation method27 was employed using tetrahydrofuran as a
solvent. The def2-TZVPP basis set was used to obtain single point
energies. Ground states were characterized by no imaginary frequency.
All of the presented relative energies are free energies at 298.15 K.
Ionization potentials were calculated as the difference between the
neutral arenes and the corresponding cation radicals.
Screening of Reaction Conditions for the Generation of the
Silyl Enol Ether Intermediate 7a. In situ generation of 7a was
evaluated using TMSCl or TMSOTf as a silylating agent, MeCN or
THF as a solvent, and 2,6-lutidine pr iPr2EtN as the base. For this set of
experiments, acetophenone (5a) (1 mmol) and the base (1.5 mmol)
were placed in a vial and dissolved in the corresponding solvent (2 mL).
Then, the silylating agent (1.2 mmol) was added under stirring. The
reaction mixture was monitored by GC-FID. TMSCl failed to generate
7a in the presence of the mild bases utilized at room temperature. In
contrast, TMSOTf was successful in all cases. Conversion to 7a was
nearly quantitative in THF, both with 2,6-lutidine and iPr2EtN as the
base (96% and 99%, respectively). 2,6-Lutidine was ultimately selected
due to its higher stability to anodic oxidation.
Figure 6. Proposed mechanism for the electrochemical α-arylation of
ketones via in situ generated silyl enol ethers.
of 8 and 9 involve the exchange of 2 electrons with the anode and
the release of 2 protons. At the same time, 2 protons are reduced
at the cathode producing H2 gas as a byproduct. If an arene 6
with a low oxidation potential is present (lower than the
oxidation potential of 7), 6 is oxidized at the anode instead of 5,
resulting in the corresponding biaryl side product, or even more
complex trimers or oligomers.23 The mechanism of this type of
aryl−aryl anodic coupling has been published elsewhere.24 In an
additional experiment, the electrochemical reaction was carried
out under the optimal conditions but in the absence of arene 6.
1H NMR analysis of the reaction mixture showed that ketone
dimer 9a had been formed in 53% yield.
CONCLUSIONS
■
In summary, we have described an electrochemical procedure
for the α-arylation of ketones, based on the generation and
anodic oxidation of silyl enol ethers in the presence of an arene.
The one-pot strategy avoids isolation of the silyl enol
intermediate and, importantly, exploits the formation of a salt
byproduct during the silylation to increase the conductivity of
the reaction mixture. Thus, the addition of supporting
electrolytes could be avoided. Only intramolecular arylations
based on the anodic oxidation of silyl enol ethers had been
previously reported. Herein, intermolecular anodic arylation
reactions have been shown to work when electron-rich arenes
are utilized. The method simply consists of the addition of
TMSOTf and 2,6-lutidine to a THF solution containing the
ketone and the arene and, after a few minutes, to permit the
formation of silyl enol ether, electrolysis under constant current
in an undivided cell with inexpensive impervious graphite and
nickel electrodes. Moderate to good yields have been obtained
for a variety of aryl ketones. Only electron-rich arenes have been
found to be suitable for this transformation. Less activated
aromatics were not sufficiently nucleophilic to trap the cation
radical intermediate, thus provoking ketone dimerization
instead of α-arylation. However, some electron-rich arenes
also failed in the reaction due to the formation of biaryl side
products. This effect has been ascribed to anodic oxidation of
the arene instead of the target enol ether. To explain the reaction
selectivity and provide a predictive computational tool, the
Optimization of the Electrochemical α-Arylation of Ketones
(Table 1). To a 5 mL IKA ElectraSyn 2.0 vial were placed the
corresponding amounts of 1,3,5-trimethoxybenzene (6a), 2 mL of
THF, acetophenone (5a), and 2,6-lutidine. Then, trimethylsilyl triflate
(TMSOTf) was added under stirring. The vial was capped, and the
reaction solution was stirred at room temperature for an additional 30
min. The corresponding amount of the protic cosolvent was then
added, and the electrolysis was initiated under constant current. After
the desired amount of charge had been passed, 2 mL of MeOH was
added, and the solution was gently warmed to quench any remaining
silyl enol ether species. The solvent was evaporated under reduced
pressure. Then, 1 equiv of trichloroethylene was added to the
concentrated reaction mixture and analyzed by 1H NMR.
General Procedure for the Electrochemical α-Arylation of
Ketones (Optimized Conditions). All reactions were performed in
an IKA ElectraSyn 2.0 using an IKA Ni electrode as a cathode and
F
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impervious graphite as an anode. A 5 mL IKA ElectraSyn 2.0 vial was
equipped with a stir bar and charged with 2 mL of THF, 1 mmol of
ketone 5, 174 μL (1.5 equiv) of 2,6-lutidine, and 2 equiv of the
corresponding arene. Then, 217 μL (1.2 equiv) of trimethylsilyl
trifluoromethanesulfonate (TMSOTf) was added, and the reaction
mixture was stirred at room temperature for 30 min. Then, 50 μL water
was added, and the electrolysis was initiated with a constant current of
10 mA (ca. 6.7 mA/cm2) and a 600 rpm stirring speed. After 2.2 F/mol
of charge had been passed, the reaction mixture was evaporated under
reduced pressure, and the residue was purified by flash column
chromatography using petroleum ether/ethyl acetate as an eluent.
1-Phenyl-2-(2,4,6-trimethoxyphenyl)ethan-1-one (8a). Following
the general procedure with acetophenone (5a) and 1,3,5-trimethox-
ybenzene (6a) as starting materials, the title compound was obtained as
a white solid (177 mg, 62% yield): mp = 104−106 °C (lit.28 90−91 °C);
1H NMR (300 MHz, CDCl3) δ 8.09−7.99 (m, 2H), 7.59−7.49 (m,
1H), 7.49−7.41 (m, 2H), 6.16 (s, 2H), 4.25 (s, 2H), 3.82 (s, 3H), 3.74
(s, 6H). 13C{1H} NMR (75 MHz, CDCl3) δ 198.5, 160.5, 159.0, 137.6,
132.6, 128.5, 128.3, 104.8, 90.8, 55.8, 55.5, 33.8; HRMS (ESI) m/z [M
+ H]+ calcd for C17H19O4 287.1278, found 287.1275.
1-(4-Chlorophenyl)-2-(2,4,6-trimethoxyphenyl)ethan-1-one (8b).
Following the general procedure with 4′-chloroacetophenone (5b) and
1,3,5-trimethoxybenzene (6a) as starting materials, the title compound
was obtained as a white solid (192 mg, 60% yield): mp = 122−124 °C;
1H NMR (300 MHz, CDCl3) δ 8.00−7.89 (m, 2H), 7.43−7.37 (m,
2H), 6.15 (s, 2H), 4.19 (s, 2H), 3.81 (s, 3H), 3.74 (s, 6H). 13C{1H}
NMR (75 MHz, CDCl3) δ 197.5, 160.6, 158.9, 138.9, 135.8, 129.7,
128.7, 104.4, 90.7, 55.8, 55.5, 33.8; HRMS (ESI) m/z [M + H]+ calcd
for C17H18ClO4 321.0888, found 321.0885.
1-(p-Tolyl)-2-(2,4,6-trimethoxyphenyl)ethan-1-one (8g). Follow-
ing the general procedure with 4′-methylacetophenone (5g) and 1,3,5-
trimethoxybenzene (6a) as starting materials, the title compound was
obtained as white solid (155 mg, 52% yield): mp = 103−105 °C; 1H
NMR (300 MHz, CDCl3) δ 7.96 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.0 Hz,
2H), 6.18 (s, 2H), 4.25 (s, 2H), 3.84 (s, 3H), 3.76 (s, 6H), 2.43 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 198.1, 160.4, 159.0, 143.2, 135.0,
129.1, 128.4, 104.9, 90.7, 55.8, 55.5, 33.6, 21.7; HRMS (ESI) m/z [M +
H]+ calcd for C18H21O4 301.1434, found 301.1433.
1-(4-Methoxyphenyl)-2-(2,4,6-trimethoxyphenyl)ethan-1-one
(8h). Following the general procedure with 4′-methoxyacetophenone
(5h) and 1,3,5-trimethoxybenzene (6a) as starting materials, the title
compound was obtained as a white solid (93 mg, 29% yield): mp =
1
132−134 °C; H NMR (300 MHz, CDCl3) δ 8.06−7.99 (m, 2H),
7.00−6.87 (m, 2H), 6.16 (s, 2H), 4.20 (s, 2H), 3.86 (s, 3H), 3.81 (s,
3H), 3.74 (s, 6H); 13C{1H} NMR (75 MHz, CDCl3) δ 197.0, 163.1,
160.4, 159.0, 130.5, 113.6, 105.0, 90.8, 55.8, 55.5, 55.5, 33.4; HRMS
(ESI) m/z [M + H]+ calcd for C18H21O5 317.1384, found 317.1384.
1-(Thiophen-2-yl)-2-(2,4,6-trimethoxyphenyl)ethan-1-one (8i).
Following the general procedure with 2-acetylthiophene (5i) and
1,3,5-trimethoxybenzene (6a) as starting materials, the title compound
was obtained as a white solid (114 mg, 39% yield): mp = 107−109 °C;
1H NMR (300 MHz, CDCl3) δ 7.78 (dd, J = 3.8, 1.1 Hz, 1H), 7.57 (dd,
J = 4.9, 1.2 Hz, 1H), 7.10 (dd, J = 5.0, 3.8 Hz, 1H), 6.16 (s, 2H), 4.18 (s,
2H), 3.82 (s, 3H), 3.75 (s, 6H); 13C{1H} NMR (75 MHz, CDCl3) δ
191.4, 160.6, 159.1, 144.4, 132.8, 131.7, 127.9, 104.4, 90.7, 55.9, 55.5,
34.4; HRMS (ESI) m/z [M + H]+ calcd for C15H17O4S 293.0842,
found 293.0843.
2-(2,4-Dimethoxyphenyl)-1-phenylethan-1-one (8m). Following
the general procedure with acetophenone (5a) and 1,3-dimethox-
ybenzene (6m) as starting materials, the title compound was obtained
as a colorless oil (43 mg, 17% yield): 1H NMR (300 MHz, CDCl3) δ
8.07−8.02 (m, 2H), 7.60−7.50 (m, 1H), 7.50−7.42 (m, 2H), 7.12−
7.05 (m, 1H), 6.48−6.45 (m, 2H), 4.21 (s, 2H), 3.80 (s, 3H), 3.77 (s,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ 198.4, 160.2, 158.2, 137.1,
132.9, 131.3, 128.6, 128.5, 116.1, 104.4, 98.8, 55.5, 55.4, 39.4; MS-EI
m/z 256 (7%), 151 (100%), 121 (39%), 105 (25%), 91 (26%), 77
(58%). These data are in agreement with those reported previously in
the literature.30
1-(4-Bromophenyl)-2-(2,4,6-trimethoxyphenyl)ethan-1-one (8c).
Following the general procedure with 4′-bromoacetophenone (5c) and
1,3,5-trimethoxybenzene (6a) as starting materials, the title compound
was obtained as a white solid (226 mg, 61% yield): mp = 109−111 °C;
1H NMR (300 MHz, CDCl3) δ 7.90−7.84 (m, 2H), 7.59−7.53 (m,
2H), 6.15 (s, 2H), 4.18 (s, 2H), 3.81 (s, 3H), 3.74 (s, 6H); 13C{1H}
NMR (75 MHz, CDCl3) δ 197.7, 160.6, 158.9, 136.2, 131.7, 129.9,
127.6, 104.4, 90.7, 55.8, 55.5, 33.8; HRMS (ESI) m/z [M + H]+ calcd
for C17H18BrO4 365.0383, found 365.0383.
2-(3,5-Diethoxyphenyl)-1-phenylethan-1-one (8n). Following the
general procedure with acetophenone (5a) and 1,3-diethoxybenzene
(6n) as starting materials, the title compound was obtained as a
colorless oil (79 mg, 28% yield): 1H NMR (300 MHz, CDCl3) δ 8.10−
7.99 (m, 2H), 7.58−7.49 (m, 1H), 7.49−7.41 (m, 2H), 7.08 (d, J = 8.7
Hz, 1H), 6.48−6.39 (m, 2H), 4.19 (s, 2H), 3.99 (dq, J = 8.7, 7.0 Hz,
4H), 1.40 (t, J = 7.0 Hz, 3H), 1.29 (t, J = 7.0 Hz, 3H); 13C{1H} NMR
(75 MHz, CDCl3) δ 198.8, 159.4, 157.4, 137.3, 132.9, 131.3, 128.6,
128.5, 116.3, 104.9, 100.0, 63.7, 63.6, 39.4, 15.0, 14.8; HRMS (ESI) m/
z [M + H]+ calcd for C18H21O3 285.1485; found 285.1487.
1-(4-Fluorophenyl)-2-(2,4,6-trimethoxyphenyl)ethan-1-one (8d).
Following the general procedure with 4′-fluoroacetophenone (5d) and
1,3,5-trimethoxybenzene (6a) as starting materials, the title compound
was obtained as a white solid (163 mg, 54% yield): mp = 101−103 °C;
1H NMR (300 MHz, CDCl3) δ 8.11−7.98 (m, 2H), 7.15−7.06 (m,
2H), 6.16 (s, 2H), 4.20 (s, 2H), 3.82 (s, 3H), 3.74 (s, 6H). 13C{1H}
NMR (75 MHz, CDCl3) δ 197.0, 165.5 (d, J = 253.4 Hz), 160.5, 158.9,
133.9, 130.8, 115.5 (d, J = 21.7 Hz), 104.5, 90.7, 55.8, 55.5, 33.7. 19F
NMR (282 MHz, CDCl3) δ −106.46 (ddd, J = 14.0, 8.5, 5.5 Hz);
HRMS (ESI) m/z [M + H]+ calcd for C17H18FO4 305.1184, found
305.1187.
4-(2-(2,4,6-Trimethoxyphenyl)acetyl)benzonitrile (8e). Following
the general procedure with 2′,4′,6′-trimethoxyacetophenone (5e) and
1,3,5-trimethoxybenzene (6a) as starting materials, the title compound
was obtained as a colorless oil (65 mg, 21% yield): 1H NMR (300 MHz,
CDCl3) δ 8.08−8.03 (m, 2H), 7.74−7.70 (m, 2H), 6.14 (s, 2H), 4.20
(s, 2H), 3.81 (s, 3H), 3.74 (s, 6H); 13C{1H} NMR (75 MHz, CDCl3) δ
197.7, 160.7, 158.8, 140.6, 132.4, 128.6, 118.3, 115.8, 103.8, 90.7, 55.8,
55.5, 34.3; HRMS (ESI) m/z [M + H]+ calcd for C18H18NO4 312.1230,
found 312.1231.
2-(2,4-Dimethoxy-6-methylphenyl)-1-phenylethan-1-one (8o).
Following the general procedure with acetophenone (5a) and 1,3-
dimethoxy-5-methylbenzene (6o) as starting materials the title
compound was obtained as a white solid (111 mg, 41% yield): mp =
1
108−110 °C; H NMR (300 MHz, CDCl3) δ 8.12−8.02 (m, 2H),
7.62−7.53 (m, 1H), 7.52−7.43 (m, 2H), 6.38 (dd, J = 12.4, 2.3 Hz,
2H), 4.29 (s, 2H), 3.80 (s, 3H), 3.72 (s, 3H), 2.22 (s, 3H); 13C{1H}
NMR (75 MHz, chloroform-d) δ 198.1, 159.4, 158.5, 139.2, 137.4,
132.9, 128.6, 128.3, 115.0, 106.8, 96.3, 55.7, 55.4, 36.3, 20.4; HRMS
(ESI) m/z [M + H]+ calcd for C17H19O3 271.1329, found 271.1330.
2-(2-Fluoro-4,6-dimethoxyphenyl)-1-phenylethan-1-one (Major)
and 2-(4-Fluoro-2,6-dimethoxyphenyl)-1-phenylethan-1-one
(Minor) (8p). Following the general procedure with acetophenone
(5a) and 1-fluoro-3,5-dimethoxybenzene (6p) as starting materials, the
title compound was obtained as a white solid as a 10:1 mixture of
isomers (94 mg, 34% yield, 75% purity according to NMR): 1H NMR
(300 MHz, CDCl3) δ 8.08−8.01 (m, 2H), 7.62−7.53 (m, 1H), 7.52−
7.43 (m, 2H), 6.35−6.22 (m, 2H), 4.25 (s, 2H), 3.79 (s, 3H), 3.74 (s,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ 196.8, 163.9, 160.7, 160.5,
160.3, 159.3, 159.1, 137.0, 133.0, 128.6, 128.3, 103.7, 103.5, 94.6, 94.5,
93.3, 92.9, 55.9, 55.6, 33.0, 33.0; 19F NMR (282 MHz, CDCl3) δ
1-(o-Tolyl)-2-(2,4,6-trimethoxyphenyl)ethan-1-one (8f). Follow-
ing the general procedure with 2′-methylacetophenone (5f) and 1,3,5-
trimethoxybenzene (6a) as starting materials, the title compound was
1
obtained as a colorless oil (93 mg, 31% yield): H NMR (300 MHz,
CDCl3) δ 7.71 (dd, J = 8.0, 1.5 Hz, 1H), 7.36−7.27 (m, 1H), 7.26−7.16
(m, 2H), 6.14 (s, 2H), 4.13 (s, 2H), 3.80 (s, 3H), 3.77 (s, 6H), 2.47 (s,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ 203.4, 160.4, 158.9, 139.0,
137.6, 131.6, 130.6, 128.1, 125.4, 105.0, 90.7, 55.8, 55.4, 36.7, 20.8;
HRMS (ESI) m/z [M + H]+ calcd for C18H21O4 301.1434, found
301.1435.
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Article
−111.69 (t, J = 10.8 Hz, minor), −115.14 (d, J = 9.9 Hz, major); HRMS
(ESI) m/z [M + H]+ calcd for C16H16FO3 275.1078, found 275.1079.
2-(2-Chloro-4,6-dimethoxyphenyl)-1-phenylethan-1-one (8q).
Following the general procedure with acetophenone (5a) and 1-
chloro-3,5-dimethoxybenzene (6q) as starting materials, the title
compound was obtained as a white solid (119 mg, 41% yield, 75%
purity according to NMR): 1H NMR (300 MHz, CDCl3) δ 8.09−8.02
(m, 2H), 7.64−7.52 (m, 1H), 7.54−7.43 (m, 2H), 6.59 (d, J = 2.4 Hz,
1H), 6.40 (d, J = 2.4 Hz, 1H), 4.42 (s, 2H), 3.80 (s, 3H), 3.73 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 196.8, 159.8, 159.2, 137.2, 135.8,
133.0, 128.7, 128.3, 115.2, 105.7, 97.7, 55.9, 55.7, 37.1; HRMS (ESI)
m/z [M + H]+ calcd for C16H16ClO3 [M + H]+ 291.0782, found
291.0784.
Florian Sommer − Institute of Chemistry, University of Graz,
8010 Graz, Austria; Center for Continuous Flow Synthesis and
Processing (CCFLOW), Research Center Pharmaceutical
Engineering GmbH (RCPE), 8010 Graz, Austria
C. Oliver Kappe − Institute of Chemistry, University of Graz,
8010 Graz, Austria; Center for Continuous Flow Synthesis and
Processing (CCFLOW), Research Center Pharmaceutical
Engineering GmbH (RCPE), 8010 Graz, Austria;
orcid.org/0000-0003-2983-6007
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01224
2-(2-Bromo-4,6-dimethoxyphenyl)-1-phenylethan-1-one (8r).
Following the general procedure with acetophenone (5a) and 1-
bromo-3,5-dimethoxybenzene (6r) as starting materials, the title
compound was obtained as a white solid (129 mg, 38% yield, 73%
purity according to NMR): 1H NMR (300 MHz, CDCl3) δ 8.10−8.01
(m, 2H), 7.63−7.54 (m, 1H), 7.54−7.43 (m, 2H), 6.76 (d, J = 2.4 Hz,
1H), 6.43 (d, J = 2.4 Hz, 1H), 4.46 (s, 2H), 3.80 (s, 3H), 3.72 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 196.7, 160.0, 159.1, 137.2, 133.1,
128.7, 128.3, 126.3, 117.1, 108.8, 98.3, 56.0, 55.7, 39.8; HRMS (ESI)
m/z [M + H]+ calcd for C16H16BrO3 335.0277, found 335.0278.
2-(Naphthalen-1-yl)-1-phenylethan-1-one (8s). Following the
general procedure with acetophenone (5a) and naphthalene (6r) as
starting materials, the title compound was obtained as a white solid (65
mg, 26% yield): mp = 101−103 °C (lit.29 106−106 °C); 1H NMR (300
MHz, CDCl3) δ 8.14−8.03 (m, 2H), 7.93−7.86 (m, 2H), 7.81 (d, J =
8.1 Hz, 1H), 7.64−7.56 (m, 1H), 7.54−7.46 (m, 4H), 7.45−7.41 (m,
1H), 7.37 (d, J = 6.0 Hz, 1H), 4.75 (s, 2H); 13C{1H} NMR (75 MHz,
CDCl3) δ 197.7, 136.8, 134.0, 133.4, 132.4, 131.5, 128.9, 128.8, 128.6,
128.1, 128.0, 126.4, 125.9, 125.6, 124.0, 43.2; HRMS (ESI) m/z [M +
H]+ calcd for C18H15O 247.1117, found 247.1116.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The CCFLOW project (Austrian Research Promotion Agency
FFG no. 862766) is funded through the Austrian COMET
Program by the Austrian Federal Ministry for Climate
Protection, Environment, Energy, Mobility, Innovation, and
Technology (BMK), the Austrian Federal Ministry of Digital,
and Economic Affairs (BMDW) and by the State of Styria
(Styrian Funding Agency SFG).
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■
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01224.
■
sı
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Copies of 1H and 13C NMR spectra, Cartesian
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AUTHOR INFORMATION
Corresponding Author
■
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David Cantillo − Institute of Chemistry, University of Graz,
8010 Graz, Austria; Center for Continuous Flow Synthesis and
Processing (CCFLOW), Research Center Pharmaceutical
Engineering GmbH (RCPE), 8010 Graz, Austria;
orcid.org/0000-0001-7604-8711; Email: david.cantillo@
uni-graz.at
Authors
Wolfgang Jud − Institute of Chemistry, University of Graz, 8010
Graz, Austria; Center for Continuous Flow Synthesis and
Processing (CCFLOW), Research Center Pharmaceutical
Engineering GmbH (RCPE), 8010 Graz, Austria
H
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