Electrochemical and Photocatalytic Oxidative Coupling of Ketones via Silyl Bis-enol Ethers

Article abstract of DOI:10.1021/acs.joc.1c00384

Diastereoselective oxidative coupling of ketones through a silyl bis-enol ether intermediate by anodic and photocatalytic oxidation is reported. These methods provide several 1,4-diketones in good yields without the need for stoichiometric metal oxidants. The strategic use of a silicon tether enables the coupling of both aromatic and aliphatic ketones as well as the synthesis of quaternary centers. Cyclic voltammetry is used to gain insight into the oxidation events of the reaction.

Full text of DOI:10.1021/acs.joc.1c00384

pubs.acs.org/joc
Article
Electrochemical and Photocatalytic Oxidative Coupling of Ketones
via Silyl Bis-enol Ethers
Aidan C. Caravana, Benjamin Nagasing, Sandeep Dhanju, Rebekah G. Reynolds, Emily A. Weiss,
and Regan J. Thomson*
Cite This: J. Org. Chem. 2021, 86, 6600−6611
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Diastereoselective oxidative coupling of ketones
through a silyl bis-enol ether intermediate by anodic and
photocatalytic oxidation is reported. These methods provide
several 1,4-diketones in good yields without the need for
stoichiometric metal oxidants. The strategic use of a silicon tether
enables the coupling of both aromatic and aliphatic ketones as well
as the synthesis of quaternary centers. Cyclic voltammetry is used
to gain insight into the oxidation events of the reaction.
Anodic oxidative cyclizations have been studied in great
detail over the past 30 years.14−16 Reactions of this type usually
involve the oxidation of an electron-rich olefin to form a radical
cation that is subsequently trapped by a tethered nucleophile.
For instance, Moeller reported this method for the intra-
molecular oxidative coupling of aliphatic bis-enol ether 1,
which produced cyclized acetal product 2 in good yield
without resonance stabilization of the radical cation
intermediate (Figure 2a).17,18 This anodic coupling of
electron-rich alkenes,19−27 as well as the analogous trapping
of silyl enol ether radical cations with electron-rich aromatic
rings,28−37 have proven useful for the construction of carbon
frameworks. More recently, Meggers and co-workers reported
the synthesis of 1,4-diketones through the anodic oxidative
coupling of aromatic ketone 3 and a silyl enol ether (i.e., 4)
using the chiral rhodium complex, Rh1, as a Lewis acid catalyst
(Figure 2b).38 Diketone 5 was obtained in good yield with
high enantioselectivity; however, the scope of both coupling
partners was limited to substrates that stabilize the radical
cation intermediate with an aromatic group or through
extended conjugation. We proposed the use of a silicon tether
to increase yields and expand the substrate scope of anodic
oxidative coupling for the synthesis of 1,4-diketones. This
method enables fragment coupling of two substrates with the
benefits of the previously reported intramolecular reaction
mechanism, a result that could be especially advantageous in
electrochemical transformations because oxidation occurs in a
INTRODUCTION
■
The oxidative coupling of enolates is a powerful reaction for
chemical synthesis because it enables fragment coupling of
complex substrates while simultaneously creating vicinal
stereocenters and a functionally valuable 1,4-dicarbonyl
motif. Although the reaction was first reported over 80 years
ago, synthetically useful developments and applications in total
synthesis (Figure 1) have mainly been accomplished over the
last 20 years.1 For example, Baran and co-workers demon-
strated how intermolecular oxidative coupling of appropriately
chosen reaction partners enables convergency and stereo-
selectivity in their efficient synthesis of bursehernin (Figure
1a).2 Additionally, Overman and co-workers used an intra-
molecular oxidative coupling reaction in the construction of
the polycyclic framework of actinophyllic acid, a trans-
formation notable for its generation of a hindered bicyclic
ring system (Figure 1b).3 Our group has used oxidative
coupling as a major transformation in the total synthesis of
metacycloprodigiosin, in which the 1,4-diketone product was
the precursor of the fused pyrrole-macrocycle ring system
(Figure 1c).4 This example also demonstrates the strategic use
of a silicon tether, a concept first reported by Schmittel and co-
workers5−7 and further developed in our lab.8−12 The tether
enables the reaction to proceed intramolecularly, thereby
increasing yields and diastereoselectivities and facilitating the
selective cross-coupling of two different ketones. Traditionally,
metal complexes such as cerium(IV) ammonium nitrate
(CAN), as well as Fe(III) and Cu(II) reagents, have been
used as oxidants for these transformations; however, at least
two stoichiometric equivalents are typically necessary for the
reaction to go to completion. It would, therefore, be desirable
to develop photocatalytic- or electrochemical or routes to
oxidation in order to enhance the overall efficiency of these
reactions.13
Received: February 16, 2021
Published: April 21, 2021
https://doi.org/10.1021/acs.joc.1c00384
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 6600−6611
6600

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Figure 2. Previously reported (a) intramolecular and (b)
intermolecular anodic oxidative coupling reactions, (c) intermolecular
photocatalytic oxidative coupling, and (d) methods reported herein
for oxidative coupling of ketones through a silyl bis-enol ether
intermediate.
Figure 1. Representative examples of oxidative coupling reactions as
key transformations in natural product total synthesis. (a) The Baran
lab’s synthesis of burseherin. (b) The Overman lab’s synthesis of
actinophyllic acid. (c) The Thomson lab’s synthesis of metacyclo-
prodigiosin.
RESULTS AND DISCUSSION
■
Preliminary Investigations into Electrochemical and
Photocatalytic Oxidations. We began our electrochemical
studies with the oxidative dimerization of cyclohexanone via its
diisopropylsilyl bis-enol ether 8a (Table 1). As with previous
studies from our lab, the diisopropyl substituents offer
enhanced stability and improved levels of diastereoselectiv-
ity.8,11,12 In an undivided chamber, a 2.0 mA current was
applied to silyl bis-enol ether 8a in a 6:1 solution of acetonitrile
and propionitrile using an RVC anode, TBAPF6 as an
electrolyte, and 2,6-di-tert-butylpyridine (2,6-di-tBu-py) as a
proton scavenger (Table 1, entry 1). Although the product was
obtained in 57% yield, the reaction suffered from severe anode
passivation, as evidenced by a buildup of material on the anode
and a steadily increasing voltage necessary to maintain the 2.0
mA constant current. Several modifications of the reaction
conditions were attempted to reduce this issue, including
decreasing the current to 0.6 mA, using 2,6-lutidine as a base,
and using a platinum anode (Table 1, entries 2−4).
Unfortunately, these changes only led to lower yields and
persistent anode passivation. Interestingly, the addition of 5%
isopropanol (Table 1, entry 5) for the reduction of H+ to
hydrogen gas at the cathode helped keep a steady voltage
without increasing the F/mol needed for the reaction to go to
completion. However, this addition did not alleviate anode
passivation nor increase the yield of the diketone product.
Constant voltage (Table 1, entry 6) also did not increase the
reaction yield and caused the reaction to stop somewhat
prematurely due to the high resistance caused by anode
passivation. No product was observed using THF or DCM as a
double layer at the anode surface, favoring reactions with
nucleophiles in this double layer rather than the bulk
solution.39,40
Photocatalysis has also been used for the oxidation of silyl
enol ethers for several years. In the 1990s one-electron
oxidations of silyl enol ethers were reported using the
photocatalyst, 9,10-dicyanoanthracene, for overall redox
neutral cyclizations.41−45 In 2012, Akita and co-workers
reported a photocatalytic two-electron oxidative coupling
reaction using [Ru(bpy)3][PF6]2 as a catalyst and duroquinone
as a terminal oxidant.46 In this study, enamine 6 is coupled
with silyl enol ether 4 for the synthesis of 1,4-diketone 7
(Figure 2c). This reaction was successful for a variety of
substrates but was ineffective for the synthesis of quaternary
centers. Again, we wished to test the benefits of the silicon-
templated intramolecular method for the synthesis of 1,4-
diketones through photocatalytic oxidative coupling.
Herein we present an analysis of the oxidative coupling of
ketones via silyl bis-enol ether intermediates using three
methods: (1) stoichiometric, chemical oxidation using CAN;
(2) anodic oxidation using bulk electrolysis; and (3)
photocatalytic oxidation using a [Ru(bpz)3][PF6] photo-
catalysis (Figure 2d). We analyzed the efficiency and functional
group compatibility for a broad scope of silyl bis-enol ethers to
determine the most efficient method of oxidation for each
substrate. Cyclic voltammetry was also used to better
understand the potentials necessary for oxidative coupling to
occur in each substrate.
6601
https://doi.org/10.1021/acs.joc.1c00384
J. Org. Chem. 2021, 86, 6600−6611

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Table 1. Optimization of the Anodic Dimerization of
Cyclohexanone-Derived Silyl Bis-enol Ether 8a
Table 2. Optimization of Photocatalytic Reaction
Conditions in 6:1 ACN/EtCN with 4 Equiv of 2,6-Di-tert-
butyl Pyridine for 24 h
current
(mA)
yield
(%)
F/
entry
product
cat. (5%)
terminal oxidant
yield (%)
dr
entry
1
anode
RVC
base
solvent
mol
1
2
3
4
5
6
7
9a
9a
9a
9b
9b
9b
9b
Ir1
Ru1
Ru1
Ir1
Ru1
Ru1
Ru1
1,3-DNB
1,3-DNB
air
1,3-DNB
1,3-DNB
duroquinone
air
15
16
13
41
74
27
20
11:1
11:1
11:1
>20:1
>20:1
>20:1
>20:1
2.0
0.6
2.0
2.0
2.0
2,6-di-
tBu-py
2,6-di-
tBu-py
2,6-
lutidine
2,6-di-
tBu-py
2,6-di-
tBu-py
2,6-di-
tBu-py
2,6-di-
tBu-py
2,6-di-
tBu-py
ACN/EtCN (6:1)
57
41
47
52
47
54
0
2.6
3.0
2.6
2.7
2.6
2
3
RVC
RVC
Pt
ACN/EtCN (6:1)
ACN/EtCN (6:1)
ACN/EtCN (6:1)
4
5
RVC
RVC
RVC
RVC
RVC
RVC
ACN/EtCN (6:1),
5% iPrOH
a
6
N/A
(2.5 V)
ACN/EtCN (6:1)
THF
2.3
7
2.0
2.0
2.0
2.0
>3.0
>3.0
2.3
8
DCM
0
9
2,6-di-
tBu-py
2,6-di-
tBu-py
ACN/DME/EtCN
(10:5:3)
ACN/DME/EtCN
(10:5:3), 5%
iPrOH
62
65
10
2.3
(Table 2, entry 4), and the yield was improved to 74% using
the more oxidizing Ru1 as a catalyst (Table 2, entry 5).
Duroquinone proved to be an inefficient terminal oxidant,
giving 9b in only 27% yield (Table 2, entry 6), while using air
as a terminal oxidant gave several side products, most notably a
22% yield of 2-hydroxy-α-tetralone (Table 2, entry 7). The
conditions of entry 5 were the most efficient and were
therefore used when expanding the scope of the reaction.
With our best conditions for the electrochemical and
photochemical oxidation of 8a and 8b determined, we next
wished to explore the scope of the reactions and compare their
efficiency with the established chemical oxidation utilizing
cerium ammonium nitrate (Figure 3). The dimerization of α-
tetralone on a 0.1 mmol scale was most efficient with anodic
oxidation, which gave product 9b in 95% yield, surpassing the
77% yield obtained with stoichiometric CAN and the 74%
yield by photocatalytic oxidation. Yields for all three conditions
were slightly lower when conducted on a 1.0 mmol scale (69%
for CAN, 76% for anodic oxidation, and 59% yield for
photocatalytic conditions). The dimerization of tetrahydropyr-
an-(4)-one was successful by anodic oxidation, giving 1,4-
diketone 9c in 90% yield. Oxidation with CAN and Ru1 were
less effective for this substrate, giving 9c in 30% yield and trace
amounts, respectively.
These low yields were due to the low conversion of the silyl
bis-enol ether, which was the case for several of the
photocatalytic reactions below (see Figure 3). Interestingly,
minimal anode passivation was observed during the electro-
chemical synthesis of 9b and 9c, and dimethoxyethane was not
necessary to obtain the high yields.
The dimerization of enones was next examined for the
formation of 9d−9f. Diketones 9d and 9e were obtained in low
yields by anodic oxidation (39% and 36%, respectively), and
no desired product was formed through photocatalysis. The
main side products of the anodic oxidations were the
respective enone monomers from enol silane hydrolysis, and
in the case of the dimerization of carvone, 8% of the
aromatized monomer was isolated. On the other hand,
11
2.0
RVC
2,6-di-
tBu-py
DME
0
>3.0
a
For constant current conditions, reaction times ranged from 3.5 to 5
h depending on F/mol.
solvent (Table 1, entries 7 and 8). Finally, the addition of
dimethoxyethane (DME) to the reaction mixture prevented
anode passivation and gave a slight increase in yield (Table 1,
entry 9). These conditions were attempted based on the work
of Fuchigami and co-workers, who reported the use of DME to
prevent anode passivation in anodic fluorination reactions.47
The addition of 5% isopropanol further increased the yield to
65% (Table 1, entry 10), but the reaction was unsuccessful
when run with only DME as the solvent (Table 1, entry 11).
Acetonitrile likely plays a key role in stabilizing the radical
cation intermediate, as well as the positively charged silicon
tether after Si−O cleavage.6 The use of propionitrile as a
cosolvent was found to enhance the solubility of the silyl bis-
enol ether substrate in acetonitrile.
Photocatalytic oxidative coupling (Table 2) for the
formation of 9a was challenging due to the high oxidation
potential of 8a (ca. +1.45 V vs SCE, see Figure 5), and low
conversion of 8a was observed for these reactions.
Photocatalysts ([Ir(dF(CF3)ppy]2(dtbpy))PF6 (Ir1) and
[Ru(bpz)3][PF6]2 (Ru1) gave 9a in 15% and 16% yields,
respectively, using 1,3-dinitrobenzene (1,3-DNB) as a terminal
oxidant (Table 2, entries 1 and 2). Using air as a terminal
oxidant and Ru1 as a catalyst gave several side products and
only 13% of 9a (Table 2, entry 3). The low yields are not
surprising given that the M*/M− reduction potentials of Ir1
and Ru1 are +1.21 and +1.45 V vs SCE, respectively.48
Substrate 8b (silyl bis-enol ether of α-tetralone), however, has
a considerably lower oxidation potential than 8a (ca. +1.25 V
vs SCE, see Figure 5) and gave promising results. Diketone 9b
was formed in 41% yield with Ir1 and 1,3-dinitrobenzene
6602
https://doi.org/10.1021/acs.joc.1c00384
J. Org. Chem. 2021, 86, 6600−6611

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Figure 3. Oxidative coupling for the synthesis of 1,4-diketones using three methods on a 0.1 mmol scale: (a) CAN (2.0 equiv), NaHCO3, DMSO,
6:1 ACN/EtCN, −30 °C, 2−7 h; (b) 2.0 mA, RVC anode, graphite cathode, 2,6-di-tert-butylpyridine, 10:5:3 ACN/DME/EtCN, 5% iPrOH; (c)
[Ru(bpz)3][PF6]2 (5 mol %), 1,3-dinitrobenzene, 2,6-di-tert-butylpyridine, blue LEDs, 6:1 ACN/EtCN, 24 h. Footnote a indicates 6:1 ACN/EtCN
used as a solvent. Footnote b indicates minimal or no consumption of starting material observed. Footnote c indicates the low yield due to the
formation of multiple side products.
oxidation with CAN gave good yields of these compounds,
affording 71% of 9d and 84% of 9e. Alternatively, anodic
oxidation gave diketone 9f in 75% yield, comparable to the
77% obtained with CAN. No desired product was observed
under photocatalytic conditions. 1,4-Diketone 9g could only
be formed using anodic oxidation, for which it was obtained in
68% yield. Similarly, compound 9h was obtained in a low yield
using CAN, and no product was observed under photocatalytic
conditions. There was a small increase in yield to 29% with
anodic oxidation. The low yields observed with CAN and Ru1
are likely due to the high potentials required to form the
primary radical intermediate. This notion is supported by the
considerable increase in yields of the dimethyl-substituted
product, 9i. Notably, the chromanone dimer (9j) was formed
near a quantitative yield using stoichiometric CAN, while
anodic and photocatalytic oxidation were less efficient due to
the formation of side products. Anodic oxidation gave the
expected product 9j in 36% yield, along with 18% of the
chromanone monomer derived from silyl bis-enol ether
hydrolysis. Photocatalytic oxidation gave 34% of 9j; oxidation
to the α,β-unsaturated ketone monomer was also observed,
giving a 23% yield of the side product, chromeneone.
Lastly, we coupled various ketones with α-tetralone and 2-
methyl-1-tetralone to obtain unsymmetrical 1,4-diketones 9k−
9o. With these substrates, oxidation likely first occurs at the α-
tetralone-derived silyl enol ether, followed by an intramolecular
attack of the other enol silane partner. Compounds 9k−9n
were obtained in good yield with both CAN and electro-
chemical conditions. Photochemical oxidation also produced
high yields of the 1,4-diketones with the exception of
6603
https://doi.org/10.1021/acs.joc.1c00384
J. Org. Chem. 2021, 86, 6600−6611

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
compound 9l, which was obtained in only 12% yield. Notably,
9m was isolated in 60% and 78% yield by anodic and
photocatalytic oxidation, respectively, showing that these
methods can be used for the formation of quaternary centers.
Diketone 9o could be synthesized efficiently using CAN but
gave lower yields with photochemical and electrochemical
methods. The low yields were due to poor selectivity with a
significant amount of the α,β-unsaturated ketone, N-
carbomethoxy-4-oxo-1,2,3,4-tetrahydropyridine, isolated in
each reaction.
reduction potentials of CAN and excited state Ru1 to the
oxidative waves of the silyl bis-enol ether substrates (Figure 5).
While the waves were generally irreversible and therefore
formal oxidation potentials could not be obtained, the half-
peak potentials (the potential value at half the maximum
current) still provided reasonable estimates for comparing
relative values within our series of compounds.50 Figure 5
It was somewhat gratifying that oxidation with 5 mol % Mes-
Acr+ gave an increase in yield to compounds 9a, 9g, and 9l
(Figure 4), of which little or no product was formed using Ru1
as a catalyst, due to their high oxidation potentials relative to
the excited state of Ru1 (see Figure 5).
Figure 4. Oxidative coupling yields using Mes-Acr+ as a photocatalyst.
Mes-Acr+ is a strong oxidant in the excited state, with a
reduction potential of +2.18 V vs SCE49 vs (+1.45 V vs SCE)
for Ru1.48 These results indicate that low yields of these
compounds using Ru1 as a catalyst may be due to their high
oxidation potentials (vide infra). However, the Mes-Acr+
conditions were less efficient for compounds that were formed
in good yield using Ru1 due to the formation of side products
and slow catalyst turnover. For these reactions, oxygen was
used as the terminal oxidant. While oxygen is used as a
terminal oxidant in numerous photocatalytic studies involving
Mes-Acr+, the acridinium radical Mes-Acr• does not have
sufficient reducing power to reduce oxygen to superoxide, as
proposed in most studies.49 These reactions are typically one-
electron oxidations, so slow regeneration of Mes-Acr+ by
reduction of oxygen does not prevent the reactions from
occurring. However, our reaction is a two-electron oxidation,
and consequently, slow regeneration of the catalyst likely leads
to the one-electron oxidized substrate undergoing side
reactions or decomposition before the catalyst can be
regenerated and perform a second oxidation, resulting in low
reaction yields.
Figure 5. Cyclic voltammograms of substrates 8a−8o, recorded in 6:1
EtCN/MeCN with 100 mM TBAPF6 using a glassy carbon working
electrode, Pt wire counter electrode, and Ag wire pseudoreference
electrode (CVs were referenced by the addition of ferrocene or
decamethylferrocene and conversion to SCE). The listed percentages
are photocatalytic yields after illumination in the presence of
2+
Ru(bpz)3 (Ru1) under the conditions described in Figure 3. The
dotted and dashed lines indicate the oxidation potentials of CAN and
excited-state Ru(bpz)32+, respectively.
displays the voltammograms of each substrate in order of
approximate oxidation potential (when multiple waves were
present, the higher potential wave was used) with the
respective yields obtained by oxidation with catalytic Ru1.
Some of the substrates with low oxidation potentials showed
peaks above 2.0 V, which were assumed to be high energy
Cyclic Voltammetry of Silyl Bis-enol Ethers. To provide
insight into the variable yields obtained across different
methods, cyclic voltammetry was used to compare the
6604
https://doi.org/10.1021/acs.joc.1c00384
J. Org. Chem. 2021, 86, 6600−6611

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
processes unrelated to oxidative coupling. As expected,
photocatalytic yields generally decrease as the oxidation
potentials (and, specifically the second oxidation potential)
of the substrates increase. The sudden drop in yields beginning
at substrate 8a and above corresponds well to the substrate
oxidation wave reaching the M*/M− reduction potential of
catalyst Ru1, supporting a reductive quenching mechanism.
Generally, the first two oxidation peaks were overlapped
enough to appear as one broad peak, but discrete first and
second oxidation events are observed for substrates 8b, 8d, 8f,
and 8m. The trend in reaction yields suggests that these two
separate oxidation events are both necessary for formation of
the product. Several of the voltammograms, e.g., that for
substrate 8o, have excessive peak broadening, probably due to
several competing side reactions under anodic conditions.
These side reactions may also explain the low yield of 9j
compared to other substrates with similar oxidation potentials
of their corresponding silyl bis-enol ethers. Additionally, 8l
shows excessive broadening after the first peak (see Supporting
Information for individual voltammogram) making it difficult
to estimate the potential of the second oxidation event. This is
consistent with the broad peaks of 8e and suggests that the
carvone silyl enol ether may undergo several side reactions.
CAN is a surprisingly effective oxidant for the coupling of
α,β-unsaturated ketones (8d, 8e, 8f, and 8l), even though the
second oxidation potential of these substrates is slightly higher
than that of CAN. In contrast, little or no product is formed
from these substrates under photocatalytic conditions, even
though the Ru1 should have enough potential to drive this
reaction. The latter result could be due to the overpotential
typically required to drive electron transfer reactions at
reasonable rates or a difference in mechanism for coupling
with CAN versus Ru1. Additionally, Figure 5 indicates that
anodic oxidation can be an effective method to couple silyl bis-
enol ethers that cannot be oxidized efficiently by CAN. The
low yields of diketones 9c and 9g using stoichiometric CAN as
an oxidant (30% and 0%, respectively) can be explained by the
high oxidation potentials of the corresponding enol ethers
compared to CAN (+1.38 vs SCE).51 Alternatively, under
constant current conditions, the voltage will automatically
adjust to the potential necessary for oxidation, which gives
access to products 9c and 9g in 90% and 68% yields,
respectively. This electrochemical strategy could be especially
useful for the coupling of primary carbons, considering the
high potentials required to form primary radicals as well as
other silyl bis-enol ethers that require high potentials for
oxidative coupling.
catalysts and stoichiometric oxidants. Finally, we note that
clearly there is no universal “one size fits all” method that
works best for all substrates regardless of structure, but we
hope that the trends and conclusions presented herein may
prove useful for future synthetic efforts seeking to employ
these, or related, oxidative coupling reactions.
EXPERIMENTAL SECTION
■
General Experimental. All experiments were conducted under a
nitrogen atmosphere in flame-dried glassware. All reagents were used
as purchased. Reaction solvents were purchased as anhydrous or
purified by either a solvent purification column or distillation.
Purifications of products were performed by flash column
chromatography using silica gel (230−400 mesh) as a stationary
phase. Analytical thin-layer chromatography was performed on silica
gel precoated glass-backed plates, and the reactions were examined by
staining with potassium permanganate solution or anisaldehyde
solution. Electrochemical reactions were performed using an
Electrasyn 2.0 with Electrasyn accessories including vials and
electrodes. Cyclic voltammetry was performed using a Princeton
Applied Instruments VERSASTAT 3 potentiostat. A Bruker Avance
III, 500 MHz, instrument was used to record 1H and 13C NMR
spectra of all compounds. NMR data are reported as brs = broad
singlet, s = singlet, d = doublet, t = triplet, q = quartet, and m =
multiplet. Signals are detailed in ppm and coupling constants in hertz
(Hz). High-resolution mass spectra were recorded under electrospray
conditions with a time-of-flight (TOF) mass analyzer Bruker Impact-
II mass spectrometer. A Bruker Tensor 37 FTIR spectrometer was
used to obtain infrared spectra of compounds, and data were reported
in cm−1. Diastereomer ratios were determined using 1H NMR
spectroscopy of unpurified reaction mixtures.
General Procedures for the Synthesis of Silyl Bis-enol
Ethers and Compound Characterization Data. General
Procedure A: Synthesis of Symmetrical Silyl Bis-enol Ethers. A
solution of the desired ketone (1.0 equiv) in THF (0.5 M) was added
dropwise to a stirred solution of LDA at −78 °C (1.1 equiv, prepared
by adding n-BuLi [1.1 equiv] to a stirred solution of diisopropylamine
[1.2 equiv] in THF [0.16 M with respect to ketone] at −78 °C). The
reaction mixture was stirred for 30 min, and dichlorodiisopropylsilane
(0.5 equiv) was added, followed by triethylamine (0.5 equiv). The
reaction stirred at −78 °C for 1 h and an additional 2 h warming to
room temperature. The mixture was poured into pH 7 buffer and
extracted three times with pentane. The organic layers were
combined, dried over magnesium sulfate, filtered, and condensed
under reduced pressure. If necessary, the resulting oil was purified by
silica gel chromatography.
General Procedure B: Synthesis of Unsymmetrical Silyl Bis-Enol
Ethers. A solution of the ketone I (1.0 equiv) in THF (0.5 M) was
added dropwise to a stirred solution of LDA at −78 °C (1.1 equiv,
prepared by adding n-BuLi [1.1 equiv] to a stirred solution of
diisopropylamine [1.2 equiv] in THF [0.16 M with respect to ketone
I] at −78 °C). The reaction mixture was stirred for 30 min and was
cannulated dropwise over at least 1 h to a stirred solution of
dichlorodiisopropylsilane (1.0 equiv) in THF (0.25 M) at −78 °C.
After stirring for 45 min at −78 °C, a solution of the second enolate
(prepared with LDA from ketone II [1.0 equiv] in the same manner
described above) was cannulated to the reaction mixture over 40−60
min. The resulting solution stirred at −78 °C for 45 min and for an
additional 1−2 h warming to room temperature. The reaction mixture
was poured into pH 7 buffer and extracted three times with pentane.
The organic layers were combined, dried over magnesium sulfate,
filtered, and condensed under reduced pressure. If necessary, the
resulting oil was purified by silica gel chromatography. Note that the
formation of the silyl bis-enol ether is more successful when the more
hindered enone is added to the silane first.
CONCLUSIONS
■
Oxidative coupling of ketones through a silyl bis-enol ether
intermediate can be accomplished using anodic and photo-
catalytic oxidation methods. Aliphatic and aromatic dimers
were produced as well as several unsymmetrical 1,4-diketones.
These methods also showed the potential for the formation of
quaternary centers. Cyclic voltammetry of the silyl bis-enol
ether substrates revealed that photocatalytic yields are mainly
limited by the reduction potential of the photocatalyst, a
nontrivial result for this multielectron transformation that
guides the selection of photocatalysts for this class of reaction.
Additionally, these studies demonstrate that anodic oxidation
allows for the coupling of tethered silyl enol ethers with high
oxidation potentials, thereby providing access to 1,4-diketones
that cannot be efficiently synthesized with commonly used
Bis(cyclohexenyloxy)diisopropylsilane (8a). Compound 8a was
prepared from cyclohexanone (11.6 mmol) using general procedure
A. The crude product was purified by silica gel chromatography
eluting with 5% ethyl acetate in hexane, giving 8a as a colorless oil
6605
https://doi.org/10.1021/acs.joc.1c00384
J. Org. Chem. 2021, 86, 6600−6611

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1
(1.48 g, 83%): H NMR (500 MHz, CDCl3) δ 5.02 (tt, 2H, J = 4.0,
3408 (br), 2945, 2867, 1691, 1600, 1495, 1449, 1327, 1306, 1283,
1255, 1203, 1181, 1023, 961, 884, 826, 748, 680 cm−1; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C26H34O2Si 405.2244, found
405.2238.
1.4 Hz), 2.08 (m, 4H), 2.01 (m, 4H), 1.69−1.63 (m, 4H), 1.55−1.48
(m, 4H), 1.15−1.04 (m, 14H). The spectrum matches our previous
report.8
Bis((3,4-dihydronaphthalen-1-yl)oxy)diisopropylsilane (8b).
Compound 8b was prepared from α-tetralone (7.52 mmol) using
general procedure A. The crude product was purified by silica gel
chromatography eluting with 3% ethyl acetate in hexane, giving 8b as
a colorless oil (1.44 g, 94%): 1H NMR (500 MHz, CDCl3) δ 8.09 (d,
2H, J = 7.8 Hz), 7.49 (t, 2H, J = 7.32 Hz), 7.34 (t, 2H, J = 7.8 Hz),
7.3 (obs, 2H), 3.64 (dd, 2H, J = 13.18, 3.91 Hz), 3.24−3.17 (m, 2H),
3.00−2.96 (m, 2H), 2.13−2.09 (m, 2H), 2.04−1.96 (m, 2H). The
spectrum matches our previous report.8
(Z,Z)-Diisopropyldi(1-phenyl-1-propenyloxy)silane (8i). Com-
pound 8i was prepared from 1-phenyl-propan-1-one (2.26 mmol)
using general procedure A. The crude product was purified by silica
gel chromatography eluting with 2% ethyl acetate in hexane, giving 8i
as a colorless oil (0.365 g, 85%): 1H NMR (500 MHz, CDCl3) δ 7.51
(d, J = 7.2 Hz, 4H), 7.30−7.21 (m, 6H), 5.24 (q, J = 6.9 Hz, 2H),
1.81 (d, J = 7.0 Hz, 6H), 1.06−0.96 (m, 14H); 13C{1H} NMR (500
MHz, CDCl3) δ 149.7, 139.2, 128.0, 127.3, 125.5, 105.2, 17.0, 13.8,
11.8; FT-IR νmax (neat) 2946, 2867, 1653, 1493, 1464, 1445, 1382,
1318, 1265, 1119, 1056, 1029, 1001, 968, 914, 884, 869, 798, 761,
693, 640, 620 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C24H33O2Si, 381.2212, found 381.2244.
Bis((2H-chromen-4-yl)oxy)diisopropylsilane (8j). Compound 8j
was prepared from chromanone (1.35 mmol) using general procedure
A. The crude product was purified by silica gel chromatography
eluting with 2% ethyl acetate in hexane, giving 8j as a colorless oil
(0.217 g, 83%): 1H NMR (500 MHz, CDCl3) δ 7.41 (dd, J = 7.5,1.5
Hz, 2H), 7.37 (d, J = 1 Hz, 2H), 7.18−7.14 (m, 2H), 6.92 (t, J = 8.0
Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 5.14 (t, J = 3.5 Hz, 2H), 4.83 (d, J
= 4.0 Hz, 4H), 1.40 (spt, J = 6.5 Hz, 2H), 1.17 (d, J = 7.5 Hz, 12H);
13C{1H} NMR (500 MHz, CDCl3) δ 155.7, 145.0, 129.8, 122.3,
Bis(tetrahydro-4H-pyran-4-enyloxy)diisopropylsilane (8c). Com-
pound S8c was prepared from tetrahydro-4H-pyran-4-one (2.17
mmol) using general procedure A. The crude product was purified by
silica gel chromatography eluting with 8% ethyl acetate in hexane,
1
giving 8c as a colorless oil (0.212 g, 63%): H NMR (500 MHz,
CDCl3) δ 4.25 (ddt, 2H, J = 11.4, 7.2, 1.8 Hz), 4.11 (ddd, 2H, J =
15.6, 6.4, 1.7 Hz), 3.77 (td, 2H, J = 11.7, 3.0 Hz), 3.71 (t, 2H, J = 10.8
Hz), 2.79 (m, 2H), 2.65 (dddd, 2H, J = 19.2, 12.0, 7.3, 1.1 Hz), 2.42
(ddd, 2H, J = 14.9, 3.1, 1.9 Hz); 13C{1H} NMR (500 MHz, CDCl3) δ
205.7, 70.2, 68.0, 48.4, 42.3, 29.7; FT-IR νmax (neat) 2963, 2870,
1674, 1462, 1363, 1231, 1211, 1130, 1010, 885, 799, 772, 696 cm−1;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H29O4Si 313.1830,
found 313.1827.
121.6, 121.0, 115.6, 99.0, 65.7, 17.4, 12.4; FT-IR νmax (neat) 2946,
2867, 1649, 1605, 1486, 1452, 1349, 1221, 1153, 1133, 1100, 1065,
1010, 940, 878, 854, 798, 752, 702, 678 cm−1; HRMS (ESI-TOF) m/
z [M + H]+ calcd for C24H29O4Si 409.17925, found 409.1830.
(Cyclohexa-1,5-dienyloxy)(cyclohexenyloxy)diisopropylsilane
(8k). Compound 8k was prepared from α-tetralone (2.26 mmol) and
cyclohexanone (2.26 mmol) using general procedure B. The crude
product was purified by silica gel chromatography eluting with 2%
ethyl acetate in hexane, giving 8k as a colorless oil (0.365 g, 85%): 1H
NMR (500 MHz, CDCl3) δ 7.53 (d, 1H, J = 7.5 Hz), 7.22 (app t, 1H,
J = 7.3 Hz), 7.17 (app t, 1H, J = 7.3 Hz), 7.12 (d, 1H, J = 7.3 Hz),
5.41 (t, 1H, J = 4.6 Hz), 5.08 (s, 1H), 2.78 (t, 2H, J = 7.96), 2.36−
2.31 (m, 2H) 2.16−2.10 (m, 2H), 2.04−1.99 (m, 2H), 1.71−1.65 (m,
2H), 1.56−1.49 (m, 2H), 1.26 (sep, 2H, J = 7.4 Hz), 1.13 (d, 3H, J =
7.3), 1.12 (d, 3H, J = 7.3). The spectrum matches our previous
report.8
(R)-(3,4-Dihydronaphthalen-1-yloxy)diisopropyl(6-methyl-3-
(prop-1-en-2-yl)cyclohexa-1,5-dienyloxy)silane (8l). Compound 8l
was prepared from α-tetralone (10.0 mmol) and (R)-(−)-carvone
(10.0 mmol) using general procedure B. The product was obtained as
a yellow oil in 100% yield (4.09 g) with no need for further
purification: 1H NMR (500 MHz, CDCl3) δ 7.53 (dd, J = 7.6, 1.5 Hz,
1H), 7.24−7.09 (m, 3H), 5.63−5.58 (m, 1H), 5.41 (t, J = 4.7 Hz,
1H), 5.04 (d, J = 3.7 Hz, 1H), 4.77−4.44 (m, 1H), 4.69−4.67 (m,
1H), 3.01 (ddd, J = 12.4, 8.4, 3.7 Hz, 1H), 2.77 (t, J = 8.0 Hz, 2H),
2.36−2.29 (m, 2H), 2.24−2.07 (m, 2H), 1.83−1.80 (m, 3H), 1.69 (s,
3H), 1.38−1.27 (m, 2H), 1.17−1.11 (m, 12H). The spectrum
matches our previous report.8
Bis(cyclohexa-1,5-dienyloxy)diisopropylsilane (8d). Compound
8d was prepared from 2-cyclohexene-1-one (4.13 mmol) using
general procedure A. The crude product was purified by silica gel
chromatography eluting with 3% ethyl acetate in hexane, giving 8d as
1
a colorless oil (0.566 g, 90%): H NMR (500 MHz, CDCl3) 7.00−
6.97 (m, 2H), 6.05 (dd, 2H, J = 10.25, 2.44 Hz), 3.32 (dd, 2H, J =
13.18, 3.91 Hz), 2.58−2.50 (m, 2H), 2.44−2.39 (m, 2H), 1.95−1.91
(m, 2H), 1.86−1.78 (m, 2H). The spectrum matches our previous
report.8
Diisopropylbis((R)-6-methyl-3-(prop-1-en-2-yl)cyclohexa-1,5-
dienyloxy)silane (8e). Compound 8e was prepared from (R)-
(−)-carvone (5.11 mmol) using general procedure A. The crude
product was purified by silica gel chromatography eluting with 3%
ethyl acetate in hexane, giving 8e as a colorless oil (828 mg, 79%): 1H
NMR (500 MHz, CDCl3) δ 6.65 (d, 2H, J = 5.67), 4.85 (s, 2H), 4.80
(s, 2H), 3.47 (dt, 2H, J = 12.1, 6.1, 4.6 Hz), 2.49 (d, 2H, J = 12.6 Hz),
2.38−2.32 (m, 2H), 2.28−2.22 (m, 2H), 1.74 (s, 6H), 1.63 (s, 6H).
The spectrum matches our previous report.8
Bis(4,4-dimethylcyclohexa-1,5-dienyloxy)diisopropylsilane (8f).
Compound 8f was prepared from 4,4-dimethylcyclohexenone (10.0
mmol) using general procedure A. The product was obtained as a
yellow oil in 100% yield (1.83 g) with no need for further purification:
1H NMR (500 MHz, CDCl3) δ 5.66 (dd, J = 9.9, 2.1 Hz, 2H), 5.55
(dd, J = 9.9, 0.8 Hz, 2H), 4.93 (tdd, J = 4.6, 2.1, 0.8 Hz, 2H), 2.12 (d,
J = 4.6 Hz, 4H), 1.21−1.11 (m, 2H), 1.07 (d, J = 6.7 Hz, 12H), 1.01
(s, 12H). The spectrum matches our previous report.8
Diisopropylbis((1-phenylvinyl)oxy)silane (8g). Compound 8g was
prepared from acetophenone (10.0 mmol) using general procedure A.
The crude product was purified by silica gel chromatography eluting
with 0−20% DCM in hexane giving 8g as a colorless oil (0.996 g,
59%): 1H NMR (500 MHz, CDCl3) δ 7.73−7.66 (m, 4H), 7.41−7.30
(m, 6H), 5.00 (d, J = 2.0 Hz, 2H), 4.76 (d, J = 2.0 Hz, 2H), 1.48−
1.39 (m, 2H), 1.18 (d, J = 7.5 Hz, 12H); FT-IR νmax (neat) 2946,
2868, 1621, 1575, 1493, 1464, 1445, 1282, 1113, 1012, 884, 814, 770,
602 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C22H30O2Si
353.1931, found 353.1921.
Diisopropyl((2-methyl-3,4-dihydronaphthalen-1-yl)oxy)((1-
phenylvinyl)oxy)silane (8m). Compound 8m was prepared from 2-
methyl-1-tetralone (10.0 mmol) and acetophenone (10.0 mmol)
using general procedure B. The crude product was purified by silica
gel chromatography eluting with 0−10% DCM in hexane giving 8m as
1
a colorless oil (2.78 g, 71%): H NMR (500 MHz, CDCl3) δ 7.69−
7.64 (m, 2H), 7.56−7.51 (m, 1H), 7.37−7.29 (m, 3H), 7.17−7.09
(m, 3H), 4.99 (d, J = 2.0 Hz, 1H), 4.78 (d, J = 2.0 Hz, 1H), 2.76 (t, J
= 7.9 Hz, 2H), 2.28 (t, J = 7.9 Hz, 2H), 1.92 (s, 3H), 1.36−1.29 (m,
2H), 1.19−1.12 (m, 12H); 13C{1H} NMR (125 MHz, CDCl3) δ
155.1, 142.6, 137.4, 136.0, 134.2, 128.3, 128.2, 126.8, 126.4, 126.3,
125.3, 121.5, 116.8, 91.6, 29.6, 28.3, 17.7, 17.5, 17.4, 17.3, 13.3; FT-IR
νmax (neat) 2945, 2928, 2867, 2830, 1687, 1651, 1621, 1464, 1299,
1187, 1150, 1089, 1015, 917, 885, 811, 763, 733, 689 cm−1; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C25H34O2Si 393.2244, found
393.2234.
Diisopropylbis(((E)-4-phenylbuta-1,3-dien-2-yl)oxy)silane (8h).
Compound 8h was prepared from acetophenone (10.0 mmol)
using general procedure A. The crude product was purified by silica
gel chromatography eluting with 0−5% DCM in hexane giving 8h as a
1
colorless oil (0.810 g, 40%): H NMR (400 MHz, CDCl3) δ 7.46−
7.41 (m, 4H), 7.37−7.30 (m, 4H), 7.28−7.22 (m, 2H), 6.97 (d, J =
15.7 Hz, 2H), 6.62 (d, J = 15.7 Hz, 2H), 4.72 (s, 2H), 4.54 (s, 2H),
1.47−1.36 (m, 2H), 1.21 (d, J = 7.4 Hz, 12H); FT-IR νmax (neat)
6606
https://doi.org/10.1021/acs.joc.1c00384
J. Org. Chem. 2021, 86, 6600−6611

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
((3,6-Dihydro-2H-pyran-4-yl)oxy)((3,4-dihydronaphthalen-1-yl)-
oxy)diisopropylsilane (8n). Compound 8n was prepared from α-
tetralone (10.0 mmol) and tetrahydro-(4H)-pyran-4-one (10.0
mmol) using general procedure B. The crude product was purified
by silica gel chromatography eluting with 10−50% DCM in hexane
giving 8n as a colorless oil (2.30 g, 66%): 1H NMR (500 MHz,
CDCl3) δ 7.53−7.48 (m, 1H), 7.23−7.10 (m, 3H), 5.38 (t, J = 4.7
Hz, 1H), 5.08−5.04 (m, 1H), 4.13 (q, J = 2.6 Hz, 2H), 3.82 (t, J = 5.6
Hz, 2H), 2.77 (t, J = 8.0 Hz, 2H), 2.32 (dt, J = 8.0, 4.7 Hz, 2H),
2.27−2.22 (m, 2H), 1.32−1.22 (m, 2H), 1.16−1.09 (m, 12H);
13C{1H} NMR (125 MHz, CDCl3) δ 147.6, 147.3, 137.2, 133.2,
anhydrous acetonitrile, 2,6-di-tert-butylpyridine (0.4 mmol, 4.0
equiv), and 1,3-dinitrobenzene (2.2 mmol, 2.2 equiv). Nitrogen gas
saturated with acetonitrile was bubbled through the mixture for 15
min, and 5 mol % of the photocatalyst was added. The flask was
purged with N2 gas for an additional minute, and the reaction was
irradiated with a 450 nm LED about 1 in. from the flask. After 24 h,
the reaction was filtered through a silica plug with 50 mL of ethyl
acetate and condensed. The 1,4-diketone was further purified by silica
gel chromatography. If necessary, the column was flushed with
toluene to remove any 1,3-dinitrobenzene before eluting with an ethyl
acetate and hexane mixture to obtain the 1,4-diketone.
127.5, 127.2, 126.4, 121.8, 105.5, 103.1, 64.9, 64.8, 30.2, 28.2, 22.3,
17.6, 17.5, 12.6; FT-IR νmax (neat) 2943, 2866, 1675, 1639, 1464,
1360, 1339, 1211, 1186, 1130, 1094, 1012, 919, 884, 823, 765, 738,
697, 627 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C21H32O3Si 359.2037, found 359.2030.
General Procedure F: Oxidative Coupling with Stoichiometric
CAN. Cerium ammonium nitrate (2.2 equiv) and NaHCO3 (4.4
equiv) were dissolved in anhydrous acetonitrile (0.03 M with respect
to the silyl bis-enol ether), and DMSO (2.0 equiv) was added. The
mixture was cooled to −30 °C, and a solution of the silyl bis-enol
ether (1.0 equiv) in anhydrous propionitrile (0.2 M) was cannulated
to the reaction flask. The reaction was monitored by TLC and stirred
at −30 °C until completion, or no longer than 5 h. The reaction
mixture was diluted 1:1 with chloroform and washed with saturated
NaHCO3 aqueous solution. The aqueous layer was extracted three
times with chloroform, and all organic layers were combined, dried
(MgSO4), filtered, and condensed under reduced pressure. The
product was further purified by silica gel chromatography.
Methyl 4-((((3,4-Dihydronaphthalen-1-yl)oxy)diisopropylsilyl)-
oxy)-3,6-dihydropyridine-1(2H)-carboxylate (8o). Compound 8o
was prepared from α-tetralone (10.0 mmol) and 4-oxo-piperidine-1-
carboxylic acid methyl ester (10.0 mmol) using general procedure B.
The crude product was purified by silica gel chromatography eluting
with 40% ethyl acetate in hexane, giving 8o as a colorless oil (2.30 g,
66%): 1H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 7.5 Hz, 1H), 7.21
(td, J = 7.0, 1.0 Hz, 1H), 7.16 (td, J = 7.0, 1.5 Hz, 1H), 7.12 (d, J =
7.0 Hz, 1H), 5.35 (t, J = 4.5 Hz, 1H), 5.02 (brs, 1H), 3.90 (brs, 2H),
3.71 (s, 3H), 3.59 (brs, 2H), 2.76 (t, J = 8.0 Hz, 2H), 2.32 (td, J = 7.5,
4.5 Hz, 2H), 2.24 (brs, 2H), 1.27 (spt, J = 8.0 Hz, 2H), 1.11 (d, J =
7.5 Hz, 12H); 13C{1H} NMR (125 MHz, CDCl3), (peaks from
rotamer pairs are broad and reported in parentheses) δ (156.2,
155.9), (148.6, 148.1), 147.4, 137.1, 133.0, 127.5, 127.1, 126.3, 121.7,
105.3, (101.6, 101.1), 52.6, (42.1, 41.8), 40.8, (29.7, 29.5), 28.0,
222.2, 17.4, 12.5; FT-IR νmax (neat) 2945, 2866, 1704, 1639, 1447,
1409, 1360, 1339, 1241, 1201, 1183, 1139, 1115, 1094, 1045, 998,
941, 919, 883, 870, 823, 801, 765, 738, 696, 680 cm−1; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C23H34NO4Si 416.2257, found
416.2252.
(1RS,1′RS)-Bi(cyclohexane)-2,2′-dione (9a). Products were puri-
fied by silica gel chromatography eluting with 8% ethyl acetate in
hexane, giving a white solid. Using general procedure C, from 8a
(0.130 mmol), diketone 9a was obtained as an 11:1 mixture of
diastereomers (16.4 mg, 65%) after electricity consumption of 2.3 F/
mol. Using general procedure E, from 8a (0.10 mmol), diketone 9a
was obtained as a 10:1 mixture of diastereomers (3 mg, 16%). Using
general procedure F, from 8a (0.10 mmol), diketone 9a was obtained
1
as a 14:1 mixture of diastereomers (12.8 mg, 67%): H NMR (500
MHz, CDCl3) 2.91 (m, 2H), 2.44−2.26 (m, 4H), 2.12−2.04 (m,
4H), 1.91−1.84 (m, 2H), 1.76−1.57 (m, 4H), 1.37−1.25 (m, 2H).
The spectrum matches our previous report.8
(2RS,2′RS)-3,3′,4,4′-Tetrahydro-2,2′-binaphthyl-1,1-(2H,2′H)-
dione (9b). Products were purified by silica gel chromatography
eluting with 7% ethyl acetate in hexane, giving 9b as a white solid.
Using general procedure D, from 8b (0.10 mmol), diketone 9b was
obtained as a single diastereomer (28 mg, 95%) after electricity
consumption of 2.1 F/mol. Using general procedure E, from 8b (0.10
mmol), diketone 9b was obtained as a single diastereomer (22 mg,
77%). Using general procedure F, from 8b (0.10 mmol), diketone 9b
was obtained as a single diastereomer (21.5 mg, 74%). Compound 9b
was also prepared on a 1.0 mmol scale. Using general procedure C,
from 8b (1.0 mmol), diketone 9b was obtained as a single
diastereomer (221 mg, 76%) after electricity consumption of 2.5 F/
mol (33.5 h). Using general procedure E, from 8b (1.0 mmol),
diketone 9b was obtained as a single diastereomer (172 mg, 59%).
Using general procedure F, from 8b (1.0 mmol), diketone 9b was
General Oxidative Coupling Procedures and Character-
ization of 1,4-Diketones. General Procedure C: Electrochemical
Oxidative Coupling. In a flame-dried 5 mL ElectrSyn vial equipped
with a stir bar, 194 mg (0.5 mmol) of tetrabutylammonium
hexafluorophosphate (TBAPF6) was dissolved in 2.6 mL of anhydrous
acetonitrile, and 1.3 mL of anhydrous dimethoxyethane was added.
The silyl bis-enol ether substrate (0.13 mmol, 1.0 equiv) was added
with 0.8 mL (0.16 M) of anhydrous propionitrile, followed by 120 μL
of 2,6-di-tert-butylpyridine (0.52 mmol, 4.0 equiv) and 0.26 mL of
anhydrous isopropanol. The mixture was purged with N2 gas for 5
min. Using an RVC working electrode and a graphite counter
electrode, a 2.0 mA current was applied to the mixture, and the
reaction was monitored by TLC. When all of the starting material had
reacted, TBAPF6 was removed by filtering the reaction mixture
through a silica plug with 50−70 mL of 10%−50% ethyl acetate in
hexane. After condensation, the crude product was further purified by
silica gel chromatography.
General Procedure D: Electrochemical Oxidative Coupling. In a
flame-dried 5 mL vial equipped with a stir bar, 148 mg of TBAPF6 was
dissolved in 3.3 mL of anhydrous acetonitrile. The silyl bis-enol ether
substrate (0.10 mmol) was added with 0.5 mL of anhydrous
propionitrile, and 0.090 mL (0.40 mmol) of 2,6-di-tert-butylpyridine
was added. The cap was equipped with an RVC working electrode
and a graphite counter electrode and screwed onto the vial. The
mixture was purged with N2 gas for 5 min. A 2.0 mA current was
applied to the mixture, and the reaction was monitored by TLC.
When all of the starting material had reacted, TBAPF6 was removed
by filtering the reaction mixture through a silica plug with 50−70 mL
of 10%−50% ethyl acetate in hexane. After condensation, the crude
product was further purified by silica gel chromatography.
1
obtained as a single diastereomer (200 mg, 69%): H NMR (500
MHz, CDCl3) 8.09 (d, 2H, J = 7.8 Hz), 7.49 (t, 2H, J = 7.32 Hz),
7.34 (t, 2H, J = 7.8 Hz), 7.3 (obs, 2H), 3.64 (dd, 2H, J = 13.18, 3.91
Hz), 3.24−3.17 (m, 2H), 3.00−2.96 (m, 2H), 2.13−2.09 (m, 2H),
2.04−1.96 (m, 2H). The spectrum matches our previous report.8
(3RS,3′RS)-Octahydro-4H,4′H-[3,3′-bipyran]-4,4′-dione (9c).
Products were purified by silica gel chromatography eluting with
40% ethyl acetate in hexane, giving a white solid. Using general
procedure D, from S8c (0.10 mmol), diketone 9c was obtained as a
14:1 mixture of diastereomers (18 mg, 90%) after electricity
consumption of 2.3 F/mol. Using general procedure E, from 8c
1
(0.10 mmol), diketone 9c was observed in trace quantities by H
NMR. Using general procedure F, from 8c (0.16 mmol), diketone 9c
1
was obtained as a 14:1 mixture of diastereomers (11 mg, 35%): H
NMR (500 MHz, CDCl3) 4.25 (ddt, 2H, J = 11.4, 7.2, 1.8 Hz), 4.11
(ddd, 2H, J = 15.6, 6.4, 1.7 Hz), 3.77 (td, 2H, J = 11.7, 3.0 Hz), 3.71
(t, 2H, J = 10.8 Hz), 2.79 (m, 2H), 2.65 (dddd, 2H, J = 19.2, 12.0,
7.3, 1.1 Hz), 2.42 (ddd, 2H, J = 14.9, 3.1, 1.9 Hz), 13C{1H} NMR
(500 MHz, CDCl3) 205.7, 70.2, 68.0, 48.4, 42.3, 29.7; FT-IR νmax
General Procedure E: Photocatalytic Oxidative Coupling. The
silyl bis-enol ether substrate (0.10 mmol, 1.0 equiv) was dissolved in
0.15 mL of anhydrous propionitrile in a flame-dried 5 mL flask
equipped with a stir bar. To this solution were added 1 mL of
6607
https://doi.org/10.1021/acs.joc.1c00384
J. Org. Chem. 2021, 86, 6600−6611

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(neat) 3370 (br), 2917, 2898, 2873, 2849, 1699, 1254, 1208, 1147,
1105, 1083, 978, 818, 619 cm−1; HRMS (ESI-TOF) m/z [M + Na]+
calcd for C10H14O4Na 221.0798, found 221.0789.
7.43 (m, 4H), 4.02−3.93 (m, 2H), 1.29 (d, J = 6.9 Hz, 6H). The
spectrum matches previously reported data.54
[3,3′-Bichroman]-4,4′-dione (9j). Products were purified by silica
gel chromatography eluting with 15% ethyl acetate in hexane, giving a
white solid. Using general procedure C, from 8j (0.13 mmol),
diketone 9j was obtained as a 10:1 mixture of diastereomers (14 mg,
36%) after electricity consumption of 2.2 F/mol. Using general
procedure E, from 8j (0.10 mmol), diketone 9j was obtained as a 10:1
mixture of diastereomers (11.2 mg, 38%). Using general procedure F,
from 8j (0.10 mmol), diketone 9j was obtained as a 14:1 mixture of
(1RS,1′RS)-1,1′-Bi(cyclohex-3-ene)-2,2′-dione (9d). Products were
purified by silica gel chromatography eluting with 15% ethyl acetate in
hexane, giving 9d as a white solid. Using general procedure C, from
8d (0.13 mmol), diketone 9d was obtained as a 5:1 mixture of
diastereomers 10 mg, 39%) after electricity consumption of 2.0 F/
mol. Using general procedure E, 8d (0.10 mmol) yielded no desired
product. Using general procedure F, from 8d (0.20 mmol), diketone
9d was obtained as a 3:1 mixture of diastereomers (27 mg, 71%): 1H
NMR (500 MHz, CDCl3) 7.00−6.97 (m, 2H), 6.05 (dd, 2H, J =
10.25, 2.44 Hz), 3.32 (dd, 2H, J = 13.18, 3.91 Hz), 2.58−2.50 (m,
2H), 2.44−2.39 (m, 2H), 1.95−1.91 (m, 2H), 1.86−1.78 (m, 2H).
The spectrum matches our previous report.8
1
diastereomers (29 mg, 97%): H NMR (500 MHz, CDCl3)δ 7.91
(dd, J = 7.9, 1.6 Hz, 2H), 7.58−7.41 (m, 2H), 7.04 (t, J = 7.8 Hz,
2H), 6.98 (d, J = 8.4 Hz, 2H), 4.66 (t, J = 11.7 Hz, 2H), 4.53 (dd, J =
20.2, 5.0 Hz, 2H), 3.54−3.26 (m, 2H). The spectrum matches
previously reported data.55
(1R,1′R,6R,6′R)-3,3′-Dimethyl-6,6′-di(prop-1-en-2-yl)-1,1′-bi-
(cyclohex-3-ene)-2,2′-dione (9e). Products were purified by silica gel
chromatography eluting with 10% ethyl acetate in hexane, giving 9e as
a white solid. Using general procedure C, from 8e (0.13 mmol),
diketone 9e was obtained as a single diastereomer (14 mg, 36%) after
electricity consumption of 2.0 F/mol. Using general procedure E, 8e
(0.10 mmol) yielded no desired product. Using general procedure F,
from 8e (0.56 mmol), diketone 9e was obtained as a single
(R,S)-2-((R,S)-2-oxocyclohexyl)-3,4-dihydronaphthalen-1(2H)-
one (9k). Products were purified by silica gel chromatography eluting
with 15% ethyl acetate in hexane, giving 9k as a white solid. Using
general procedure C, from 8k (0.13 mmol), diketone 9k was obtained
as a single diastereomer (24 mg, 76%) after electricity consumption of
2.1 F/mol. Using general procedure E, from 8k (0.10 mmol),
diketone 9k was obtained as a single diastereomer (13 mg, 54%).
Using general procedure F, from 8k (0.10 mmol), diketone 9k was
1
1
diastereomer (236 mg, 84%): H NMR (500 MHz, CDCl3) δ 6.65
obtained as a single diastereomer (19.8 mg, 82%): H NMR (500
(d, 2H, J = 5.67), 4.85 (s, 2H), 4.80 (s, 2H), 3.47 (dt, 2H, J = 12.1,
6.1, 4.6 Hz), 2.49 (d, 2H, J = 12.6 Hz), 2.38−2.32 (m, 2H), 2.28−
2.22 (m, 2H), 1.74 (s, 6H), 1.63 (s, 6H). The spectrum matches our
previous report.8
MHz, CDCl3) δ 8.04 (d, 1H, J = 7.8 Hz), 7.47 (td, 1H, J = 7.5, 1.5
Hz), 7.31 (t, 1H, J = 7.1 Hz), 7.25 (d, 1H, J = 7.8 Hz), 3.36 (dq, 1H, J
= 13.2, 2.4 Hz), 3.21 (dt, 1H, J = Hz), 3.18−3.13 (m, 1H), 2.97 (dt,
1H, J = Hz), 2.50−2.36 (m, 2H), 2.21−2.09 (m, 2H), 2.02 (m, 1H),
1.96−1.85 (m, 2H), 1.80 (qt, 1H, J = Hz), 1.69 (qdd, 1H, J = 12.8,
4.7, 3.4 Hz), 1.54 (qd, 1H, J = 9.2, 5.4 Hz). The spectrum matches
our previous report.8
(R)-2-((1R,6R)-3-Methyl-2-oxo-6-(prop-1-en-2-yl)cyclohex-3-
enyl)-3,4-dihydronaphthalen-1(2H)-one (9l). Products were purified
by silica gel chromatography eluting with 10% ethyl acetate in hexane,
giving 9l as a colorless oil. Using general procedure C, from S8l (0.13
mmol), diketone 9l was obtained as a 7:1 mixture of diastereomers
(29 mg, 75%) after electricity consumption of 2.1 F/mol. Using
general procedure E, from 8l (0.10 mmol), diketone 9l was obtained
as a 7:1 mixture of diastereomers (3.5 mg, 12%). Using general
procedure F, from 8l (0.10 mmol), diketone 9l was obtained as a 7:1
mixture of diastereomers (20.6 mg, 75%): 1H NMR (500 MHz,
CDCl3) δ 7.98 (dd, J = 7.9, 1.5 Hz, 1H), 7.42 (td, J = 7.4, 1.5 Hz,
1H), 7.30−7.23 (m, 1H), 7.21 (d, J = 7.6 Hz, 1H), 6.72 (d, J = 5.9
Hz, 1H), 4.85 (s, 1H), 4.79−4.76 (m, 1H), 3.41 (td, J = 12.3, 4.8 Hz,
1H), 3.06−2.89 (m, 2H), 2.84 (ddd, J = 13.5, 4.6, 1.5 Hz, 1H), 2.73−
2.57 (m, 2H), 2.48−2.40 (m, 1H), 2.36−2.27 (m, 1H), 1.97−1.91
(m, 1H), 1.79−1.76 (m, 3H), 1.72 (s, 3H). The spectrum matches
our previous report.8
2-Methyl-2-(2-oxo-2-phenylethyl)-3,4-dihydronaphthalen-
1(2H)-one (9m). Products were purified by silica gel chromatography
eluting with 8% ethyl acetate in hexane, giving 9m as a colorless oil.
Using general procedure C, from 8m (0.13 mmol), diketone 9m was
obtained in 60% yield (13 mg) after electricity consumption of 2.9 F/
mol. Using general procedure E, from 8m (0.10 mmol), diketone 9m
was obtained in 78% yield (22 mg). Using general procedure F, from
8m (0.10 mmol), diketone 9m was obtained in 88% yield (25 mg):
1H NMR (500 MHz, CDCl3) δ 8.11 (dd, J = 7.9, 1.5 Hz, 1H), 7.99−
7.92 (m, 2H), 7.59−7.51 (m, 1H), 7.51−7.40 (m, 3H), 7.36−7.30
(m, 1H), 7.29−7.21 (m, 1H), 3.72 (d, J = 17.5 Hz, 1H), 3.21 (d, J =
17.5 Hz, 1H), 3.18−3.10 (m, 1H), 2.90 (ddd, J = 17.1, 4.9, 3.5 Hz,
1H), 2.64 (td, J = 13.0, 4.9 Hz, 1H), 1.86 (ddd, J = 13.0, 4.9, 3.5 Hz,
1H), 1.34 (s, 3H). The spectrum matches our previous report.9
(RS)-3-((RS)-1-Oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-
tetrahydro-4H-pyran-4-one (9n). Products were purified by silica gel
chromatography eluting with 20% ethyl acetate in hexane, giving 9n as
a yellow oil. Using general procedure C, from 8n (0.13 mmol),
diketone 9n was obtained as a single diastereomer (22 mg, 69%) after
electricity consumption of 2.25 F/mol. Using general procedure E,
from 8n (0.10 mmol), diketone 9n was obtained as a single
diastereomer (16 mg, 64%). Using general procedure F, from 8n
(1RS,1′RS)-5,5,5′5′-Tetramethyl-1,1′-bi(cyclohex-3-ene)-
2,2′dione (9f). Products were purified by silica gel chromatography
eluting with 10% ethyl acetate in hexane, giving 9f as a white solid.
Using general procedure C, from 8f (0.13 mmol), diketone 9f was
obtained as a single diastereomer (24 mg, 75%) after electricity
consumption of 2.1 F/mol. Using general procedure E, 8f (0.10
mmol) yielded no desired product. Using general procedure F, from
8f (0.10 mmol), diketone 9f was obtained as a single diastereomer (19
mg, 77%): 1H NMR (500 MHz, CDCl3) δ 6.57 (dd, J = 10.0, 2.2 Hz,
2H), 5.79 (d, J = 10.0 Hz, 2H), 3.47−3.34 (m, 2H), 1.70 (dd, J =
13.4, 12.7 Hz, 2H), 1.58 (ddd, J = 12.7, 4.3, 2.2 Hz, 2H), 1.22 (s,
6H), 1.09 (s, 6H). The spectrum matches our previous report.8
1,4-Diphenylbutane-1,4-dione (9g). Products were purified by
silica gel chromatography eluting with 10% ethyl acetate in hexane,
giving 9g as a colorless oil. Using general procedure C, from 8g (0.13
mmol), diketone 9g was obtained in 68% yield (21 mg) after
electricity consumption of 2.25 F/mol. Using general procedure E, 8g
(0.10 mmol) yielded no desired product. Using general procedure F,
1
8g (0.10 mmol) yielded no desired product: H NMR (500 MHz,
CDCl3) δ 8.10−8.00 (m, 4H), 7.62−7.55 (m, 2H), 7.51−7.46 (m,
4H), 3.47 (s, 4H). The spectrum matches previously reported data.52
(1E,7E)-1,8-Diphenylocta-1,7-diene-3,6-dione (9h). Products
were purified by silica gel chromatography eluting with 10% ethyl
acetate in hexane, giving 9h as a colorless oil. Using general procedure
C, from 8h (0.13 mmol), diketone 9h was obtained in 29% yield (11
mg) after electricity consumption of 2.5 F/mol. Using general
procedure E, 8h (0.10 mmol) yielded no desired product. Using
general procedure F, from 8h (0.10 mmol), diketone 9h was obtained
1
in 18% yield (21 mg): H NMR (500 MHz, CDCl3) δ 7.63 (d, J =
16.3 Hz, 2H), 7.60−7.53 (m, 4H), 7.42−7.38 (m, 6H), 6.80 (d, J =
16.3 Hz, 2H), 3.10 (s, 4H). The spectrum matches previously
reported data.53
(2RS,3RS)-2,3-Dimethyl-1,4-diphenylbutane-1,4-dione (9i). Prod-
ucts were purified by silica gel chromatography eluting with 40% ethyl
acetate in hexane, giving a white solid. Using general procedure C,
from 8i (0.13 mmol), diketone 9i was obtained as a 4:1 mixture of
diastereomers (22 mg, 64%) after electricity consumption of 2.0 F/
mol. Using general procedure E, from 8i (0.10 mmol), diketone 9i
was obtained as a 3:1 mixture of diastereomers (17 mg, 65%). Using
general procedure F, from 8i (0.10 mmol), diketone 9i was obtained
1
as an 2:1 mixture of diastereomers (19 mg, 71%): H NMR (500
MHz, CDCl3) δ 7.99 (d, J = 7.0 Hz, 4H), 7.56−7.52 (m, 2H), 7.48−
6608
https://doi.org/10.1021/acs.joc.1c00384
J. Org. Chem. 2021, 86, 6600−6611

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(0.10 mmol), diketone 9n was obtained as a single diastereomer (22
mg, 92%): H NMR (500 MHz, CDCl3) δ 8.02 (dd, J = 7.8, 1.5 Hz,
Authors
1
Aidan C. Caravana − Department of Chemistry, Northwestern
University, Evanston, Illinois 60208, United States;
orcid.org/0000-0002-9519-6709
Benjamin Nagasing − Department of Chemistry,
Northwestern University, Evanston, Illinois 60208, United
States
Sandeep Dhanju − Department of Chemistry, Northwestern
University, Evanston, Illinois 60208, United States;
orcid.org/0000-0002-0920-0784
Rebekah G. Reynolds − Department of Chemistry,
Northwestern University, Evanston, Illinois 60208, United
States
1H), 7.47 (td, J = 7.7, 1.5 Hz, 1H), 7.35−7.27 (m, 1H), 7.24 (d, J =
7.7 Hz, 1H), 4.31−4.25 (m, 1H), 4.21 (ddd, J = 10.9, 6.7, 1.8 Hz,
1H), 3.82−3.73 (m, 2H), 3.37−3.30 (m, 1H), 3.16−3.07 (m, 1H),
3.04 (ddd, J = 13.8, 4.4, 3.0 Hz, 1H), 2.97 (td, J = 16.6, 3.4 Hz, 1H),
2.77−2.67 (m, 1H), 2.45 (ddd, J = 14.9, 3.0, 1.8 Hz, 1H), 2.18−2.11
(m, 1H), 2.08−1.98 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ
206.9, 198.1, 144.0, 133.6, 132.5, 128.9, 127.6, 126.8, 70.1, 68.3, 51.5,
45.5, 42.6, 29.9, 27.2; FT-IR νmax (neat) 2952, 2866, 1677, 1597,
1481, 1456, 1372, 1290, 1261, 1224, 1203, 1094, 1017, 978, 873, 799,
759, 731, 673 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C15H16O3Na 267.0992, found 267.0988.
Methyl (RS)-4-Oxo-3-((RS)-1-oxo-1,2,3,4-tetrahydronaphthalen-
2-yl)piperidine-1-carboxylate (9o). Products were purified by silica
gel chromatography eluting with 50% diethyl ether in pentane, giving
9o as a white solid. Using general procedure C, from 8o (0.13 mmol),
diketone 9o was obtained as a single diastereomer (9 mg, 22%). Using
general procedure E, from 8o (0.10 mmol), diketone 9o was obtained
as a single diastereomer (9.1 mg, 30%). Using general procedure F,
from 8o (0.60 mmol), diketone 9o was obtained as a single
diastereomer (145 mg, 80%): 1H NMR (500 MHz, CDCl3) δ 8.02 (d,
J = 7.8 Hz, 1H), 7.47 (t, J = 7.4 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H),
7.23 (d, J = 7.7 Hz, 1H), 4.28 (brs, 2H), 3.76 (s, 3H), 3.38 (brs, 2H),
3.23−2.88 (m, 4H), 2.63−2.49 (m, 2H), 2.63−2.48 (m, 2H), 2.24−
2.02 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 207.5, 197.9,
155.8, 143.9, 133.5, 132.4, 128.7, 127.5, 126.7, 117.7, 55.7, 53.0,
(50.7,49.9), (46.4, 45.6), 43.2, 40.8, 29.7, (27.6, 27.1); FT-IR νmax
(neat) 2931, 2866, 1689, 1676, 1597, 1480, 1450, 1416, 1374, 1353,
1310, 1278, 1265, 1226, 1114, 987, 952, 755, 732 cm−1; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C17H20NO4 302.1364, found
302.1362.
Emily A. Weiss − Department of Chemistry, Northwestern
University, Evanston, Illinois 60208, United States;
orcid.org/0000-0001-5834-463X
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00384
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge support from the National
Institutes of Health (NIHGMS 1R01GM124089) and from
the Air Force Office of Scientific Research (FA9550-20-1-
0364).
Cyclic Voltammetry of Substrates 8a−8o. Cyclic voltammetry
was performed using a Princeton Applied Instruments VERSASTAT
3 potentiostat. All samples were dissolved in distilled, anhydrous 6:1
MeCN/EtCN with 100 mM tetrabutylammonium hexafluorophos-
phate (TBAPF6) supporting electrolyte and degassed with N2 before
measurement. A three-electrode setup was used, with glassy carbon as
the working electrode, a platinum wire as the counter electrode, and a
silver wire as a pseudoreference electrode. The voltammograms were
collected at a scan rate of 50 mV/s and internally referenced to
ferrocene or decamethylferrocene, which was dissolved in the analyte
solutions, and then referenced to SCE based on the potential of the
ferrocene or decamethylferrocene couple.
REFERENCES
■
(1) Guo, F.; Clift, M. D.; Thomson, R. J. Oxidative Coupling of
Enolates, Enol Silanes, and Enamines: Methods and Natural Product
Synthesis. Eur. J. Org. Chem. 2012, 2012, 4881−4896.
(2) Martin, C. L.; Overman, L. E.; Rohde, J. M. Total Synthesis of
( )-Actinophyllic Acid. J. Am. Chem. Soc. 2008, 130, 7568−7569.
(3) Baran, P. S.; DeMartino, M. P. Intermolecular Oxidative Enolate
Heterocoupling. Angew. Chem., Int. Ed. 2006, 45, 7083−7086.
(4) Clift, M. J.; Thomson, R. J. Development of a Merged Conjugate
Addition:Oxidative Coupling Sequence. Application to the Enantio-
selective Total Synthesis of Metacycloprodigiosin and Prodigiosin R1.
J. Am. Chem. Soc. 2009, 131, 14579−14583.
(5) Schmittel, M.; Burghart, A.; Malisch, W.; Reising, J.; Sollner, R.
Diastereoselective Enolate Coupling through Redox Umpolung in
Silicon and Titanium Bisenolates: A Novel Concept Based on
Intramolecularization of Carbon-Carbon Bond Formation. J. Org.
Chem. 1998, 63, 396−400.
(6) Schmittel, M.; Haeuseler, A. One-Electron Oxidation of Metal
Enolates and Metal Phenolates. J. Organomet. Chem. 2002, 661, 169−
179.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00384.
Experimental procedures, NMR spectra, and cyclic
voltammograms (PDF)
(7) Schmittel, M.; Burghart, A.; Werner, H.; Laubender, M.; Söllner,
R. Probing M-O Bond Cleavage in Silicon and Titanium Bisenolate
Radical Cations. J. Org. Chem. 1999, 64, 3077−3085.
(8) Avetta, C. T.; Konkol, L. C.; Taylor, C. N.; Dugan, K. C.; Stern,
C. L.; Thomson, R. J. Diastereoselective Oxidative Carbon-Carbon
Bond Formation Via Silyl Bis-Enol Ethers. Org. Lett. 2008, 10, 5621−
5624.
(9) Clift, M. D.; Taylor, C. N.; Thomson, R. J. Oxidative Carbon-
Carbon Bond Formation Via Silyl Bis-Enol Ethers: Controlled Cross-
Coupling for the Synthesis of Quaternary Centers. Org. Lett. 2007, 9,
4667−4669.
(10) Konkol, L. C.; Jones, B. T.; Thomson, R. J. Oxidative Carbon-
Carbon Bond Formation Via Allyldimethylsilyl Enol Ethers. Org. Lett.
2009, 11, 5550−5553.
(11) Robinson, E. E.; Thomson, R. J. A Strategy for the Convergent
and Stereoselective Assembly of Polycyclic Molecules. J. Am. Chem.
Soc. 2018, 140, 1956−1965.
Accession Codes
CCDC 2060656−2060657 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Regan J. Thomson − Department of Chemistry, Northwestern
University, Evanston, Illinois 60208, United States;
orcid.org/0000-0001-5546-4038; Email: r-thomson@
northwestern.edu
6609
https://doi.org/10.1021/acs.joc.1c00384
J. Org. Chem. 2021, 86, 6600−6611

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(12) Jones, B. T.; Avetta, C. T.; Thomson, R. J. Total Synthesis of
Propolisbenzofuran B. Chemical Science 2014, 5, 1794−1798.
(13) Do, H. Q.; Tran-Vu, H.; Daugulis, O. Copper-Catalyzed
Homo-Dimerization of Nitronates and Enolates under Oxygen
Atmosphere. Organometallics 2012, 31, 7816−7818.
(35) Sperry, J. B.; Wright, D. L. The Gem-Dialkyl Effect in Electron
Transfer Reactions- Rapid Synthesis of Seven-Membered Rings
through an Electrochemical Annulation. J. Am. Chem. Soc. 2005,
127, 8034−8035.
(36) Miller, A. K.; Hughes, C. C.; Kennedy-Smith, J. J.; Gradl, S. N.;
Trauner, D. Total Synthesis - Total Synthesis of (−)-Heptemerone B
and (−)-Guanacastepene E. J. Am. Chem. Soc. 2006, 128, 17057−
17062.
(37) Redden, A.; Moeller, K. D. Anodic Coupling Reactions-
Exploring the Generality of Curtin−Hammett Controlled Reactions.
Org. Lett. 2011, 13, 1678−1681.
(38) Huang, X.; Zhang, Q.; Lin, J.; Harms, K.; Meggers, E.
Electricity-Driven Asymmetric Lewis Acid Catalysis. Nat. Catal. 2019,
2, 34−40.
(39) Moeller, K.; Tang, F.; Chen, C. Electrochemistry and
Umpolung Reactions: New Tools for Solving Synthetic Challenges
of Structure and Location. Synthesis 2007, 2007, 3411−3420.
(40) Frey, D. A.; Krishna Reddy, S. H.; Moeller, K. D.
Intramolecular Anodic Olefin Coupling Reactions- the Use of
Allylsilane Coupling Partners with Allylic Alkoxy Groups. J. Org.
Chem. 1999, 64, 2805−2813.
(41) Hintz, S.; Mattay, J.; van Eldik, R.; Fu, W.-F. Regio- and
Stereoselective Cyclization Reactions of Unsaturated Silyl Enol Ethers
by Photoinduced Electron Transfer. Eur. J. Org. Chem. 1998, 8,
1583−1596.
(42) Heidbreder, A.; Mattay, J. Pet-Oxidative Cyclization of
Unsaturated Enol Silyl Ethers. Tetrahedron Lett. 1992, 33, 1973−
1976.
(43) Hintz, S.; Fröhfich, R.; Mattay, J. Pet-Oxidative Cyelization of
Unsaturated Silyl Enol Ethers. Regioselective Control by Solvent
Effects. Tetrahedron Lett. 1996, 37, 7349−7352.
(44) Snider, B. B.; Kwon, T. Oxidative Cyclization of ∂,E- and E,Z-
Unsaturated Enol Silyl Ethers and Unsaturated Siloxycyclopropanes. J.
Org. Chem. 1992, 57, 2399−2410.
(45) Snider, B. B.; Kwon, T. Oxidative Cyclization of ∂,E- and E,Z-
Unsaturated Enol Silyl Ethers. J. Org. Chem. 1990, 55, 4786−4788.
(46) Yasu, Y.; Koike, T.; Akita, M. Sunlight-Driven Synthesis of
Gamma-Diketones Via Oxidative Coupling of Enamines with Silyl
Enol Ethers Catalyzed by [Ru(Bpy)3]2+. Chem. Commun. 2012, 48,
5355−7.
(47) Shaaban, M. R.; Ishii, H.; Fuchigami, T. Electrolytic Partial
Fluorination of Organic Compounds. 42.1 Marked Solvent Effects on
Regioselective Anodic Monofluorination of 4-Oxo-2-Pyrimidyl
Sulfides. J. Org. Chem. 2000, 65, 8685−8689.
(48) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. Visible Light
Photoredox Catalysis with Transition Metal Complexes: Applications
in Organic Synthesis. Chem. Rev. 2013, 113, 5322−5363.
(49) Romero, N. A.; Nicewicz, D. A. Organic Photoredox Catalysis.
Chem. Rev. 2016, 116, 10075−166.
(50) Nicewicz, D.; Roth, H.; Romero, N. Experimental and
Calculated Electrochemical Potentials of Common Organic Molecules
for Applications to Single-Electron Redox Chemistry. Synlett 2016,
27, 714−723.
(51) Nair, V.; Deepthi, A. Cerium(Iv) Ammonium Nitratea Versatile
Single-Electron Oxidant. Chem. Rev. 2007, 107, 1862−1891.
(52) Xu, W. L.; Hu, W.; Zhao, W. M.; Wang, M.; Chen, J.; Zhou, L.
Copper(I)/Ddq-Mediated Double-Dehydrogenative Diels-Alder Re-
action of Aryl Butenes with 1,4-Diketones and Indolones. Org. Lett.
2020, 22, 7169−7174.
(14) Moeller, K. D. Synthetic Applications of Anodic Electro-
chemistry. Tetrahedron 2000, 56, 9527−9554.
(15) Yan, M.; Kawamata, Y.; Baran, P. S. Synthetic Organic
Electrochemical Methods since 2000: On the Verge of a Renaissance.
Chem. Rev. 2017, 117, 13230−13319.
(16) Moeller, K. D. Using Physical Organic Chemistry to Shape the
Course of Electrochemical Reactions. Chem. Rev. 2018, 118, 4817−
4833.
(17) Moeller, K. D.; Tinao, L. V. Intramolecular Anodic Olefin
Coupling Reactions: The Use of Bis Enol Ether Substrates. J. Am.
Chem. Soc. 1992, 114, 1033−1041.
(18) Reddy, S. H. K.; Moeller, K. D. Intramolecular Anodic Olefin
Coupling Reactions: The Construction of Bridged Bicyclic Ring
Skeletons. Tetrahedron Lett. 1998, 39, 8027−8030.
(19) Reddy, S. H. K.; Chiba, K.; Sun, Y.; Moeller, K. D. Anodic
Oxidations of Electron-Rich Olefins Radical Cation Based Approaches
to the Synthesis of Bridged Bicyclic Ring Skeletons. Tetrahedron 2001,
57, 5183−5197.
(20) Tang, F.; Moeller, K. D. Intramolecular Anodic Olefin
Coupling Reactions- the Effect of Polarization on Carbon−Carbon
Bond Formation. J. Am. Chem. Soc. 2007, 129, 12414−12415.
(21) Tang, F.; Moeller, K. D. Anodic Oxidations and Polarity:
Exploring the Chemistry of Olefinic Radical Cations. Tetrahedron
2009, 65, 10863−10875.
(22) Hudson, C. M.; Moeller, K. D. Intramolecular Anodic Olefin
Coupling Reactions and the Use of Vinylsilanes. J. Am. Chem. Soc.
1994, 116, 3347−3356.
(23) Redden, A.; Perkins, R. J.; Moeller, K. D. Oxidative Cyclization
Reactions: Controlling the Course of a Radical Cation-Derived
Reaction with the Use of a Second Nucleophile. Angew. Chem., Int. Ed.
2013, 52, 12865−8.
(24) Moeller, K. D.; Marzabadi, M. R.; New, D. G.; Chiang, M. Y.;
Keith, S. Oxidative Organic Electrochemistry: A Novel Intramolecular
Coupling of Electron-Rich Olefins. J. Am. Chem. Soc. 1990, 112,
6123−6124.
(25) Sun, Y.; Moeller, K. D. Anodic Olefin Coupling Reactions
Involving Ketene Dithioacetals Evidence for a Radical-Type
Cyclization. Tetrahedron Lett. 2002, 43, 7159−7161.
(26) Huang, Y.-T.; Moeller, K. D. Anodic Cyclization Reactions:
Probing the Chemistry of N,O-Ketene Acetal Derived Radical
Cations. Tetrahedron 2006, 62, 6536−6550.
(27) Huang, Y.-T.; Moeller, K. D. Anodic Coupling Reactions- the
Use of N,O-Ketene Acetal Coupling Partners. Org. Lett. 2004, 6,
4199−4202.
(28) Wright, D. L.; Whitehead, C. R.; Sessions, E. H.; Ghiviriga, I.;
Frey, D. A. Studies on Inducers of Nerve Growth Factor- Synthesis of
the Cyathin Core. Org. Lett. 1999, 1, 1535−1538.
(29) Hughes, C. C.; Miller, A. K.; Trauner, D. An Electrochemical
Approach to the Guanacastepenes. Org. Lett. 2005, 7, 3425−3428.
(30) Mihelcic, J.; Moeller, K. D. Anodic Cyclization Reactions- the
Total Synthesis of Alliacol A. J. Am. Chem. Soc. 2003, 125, 36−37.
(31) Whitehead, C. R.; Sessions, E. H.; Ghiviriga, I.; Wright, D. L.
Two-Step Electrochemical Annulation for the Assembly of Polycyclic
Systems. Org. Lett. 2002, 4, 3763−3765.
(32) Sperry, J. B.; Whitehead, C. R.; Ghiviriga, I.; Walczak, R. M.;
Wright, D. L. Electrooxidative Coupling of Furans and Silyl Enol
Ethers- Application to the Synthesis of Annulated Furans. J. Org.
Chem. 2004, 69, 3726−3734.
(53) Wiesler, S.; Bau, M. A.; Niepel, T.; Younas, S. L.; Luu, H.-T.;
Streuff, J. Synthesis of A,Ω-Bis-Enones by the Double Addition of
Alkenyl Grignard Reagents to Diacid Weinreb Amides. Eur. J. Org.
Chem. 2019, 2019, 6246−6260.
(54) Jagtap, P. R.; Cisarova, I.; Jahn, U. Bioinspired Total Synthesis
of Tetrahydrofuran Lignans by Tandem Nucleophilic Addition/
Redox Isomerization/Oxidative Coupling and Cycloetherification
Reactions as Key Steps. Org. Biomol. Chem. 2018, 16, 750−755.
(55) Zhao, M.; Liu, J. L.; Liu, H. F.; Chen, J.; Zhou, L. Construction
of Bisbenzopyrone Via N-Heterocyclic Carbene Catalyzed Intra-
(33) Sperry, J. B.; Wright, D. L. Synthesis of the Hamigeran Skeleton
through an Electro-Oxidative Coupling Reaction. Tetrahedron Lett.
2005, 46, 411−414.
(34) Sperry, J. B.; Ghiviriga, I.; Wright, D. L. Electrochemical
Annulation of Five-Membered Rings through Dearomatization of
Furans and Thiophenes. Chem. Commun. 2006, 194−6.
6610
https://doi.org/10.1021/acs.joc.1c00384
J. Org. Chem. 2021, 86, 6600−6611

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
molecular Hydroacylation-Stetter Reaction Cascade. Org. Lett. 2018,
20, 2676−2679.
6611
https://doi.org/10.1021/acs.joc.1c00384
J. Org. Chem. 2021, 86, 6600−6611