Anodic Cyclizations, Seven-Membered Rings, and the Choice of Radical Cation vs. Radical Pathways

Article abstract of DOI:10.1002/cjoc.201900132

While many steps in an oxidative cyclization reaction can be important, it is the cyclization step itself that plays the central role. If this step does not proceed well, then optimization of the rest of the sequence is futile. We report here that the key

Full text of DOI:10.1002/cjoc.201900132

Accepted Article
Title: Anodic Cyclizations, Seven-Membered Rings, and the Choice of Radical Cation
vs. Radical Pathways
Authors: Robert J. Perkins, Ruozhu Feng, Qingquan Lu, and Kevin D. Moeller*
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Anodic Cyclizations, Seven-Membered Rings, and the Choice of Radical
Cation vs. Radical Pathways
Robert J. Perkins, Ruozhu Feng, Qingquan Lu, and Kevin D. Moeller*
a Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
While many steps in an oxidative cyclization reaction can be important, it is the cyclization step itself that plays the central role. If this step does not
proceed well, then optimization of the rest of the sequence is futile. We report here that the key to the cyclization is channeling the reaction down the
correct pathway. Some reactions require the use of an radical pathway and some require the use of a radical cation pathway. An example of each is
provided along with a strategy for accessing both pathways using a common intermediate.
overall process. If this step in the mechanism does not proceed
well, then there is no chance for a successful reaction outcome.
Background and Originality Content
Electroorganic synthesis offers
a number of unique
The key to this first step being successful is providing the very
reactive intermediates generated at the anode with a productive
reaction pathway. Radical cation intermediates like 1 are not
stable. If the anticipated cyclization reaction is too slow, then the
reaction will quickly lead to undesired products from elimination
and/or polymerization reactions.
These observations have led to two approaches to
channeling oxidative cyclizations down a productive reaction
pathway; one that takes advantage of the radical cation
intermediate and a second that immediately traps the radical
cation and channels the reaction down an radical pathway (Figure
1).
opportunities for the construction of complex molecules.1 These
opportunities range from a chance to conduct chemical reactions
in more sustainable ways, to unique transformations that combine
electrochemical methods with the development of new catalysts,
to new umpolung reactions that allow for existing functional
groups to be used in new ways. As part of this later group, we have
been particularly interested in anodic transformations that allow
for electron-rich olefins to be trapped by nucleophiles (Scheme
1).2 The reactions proceed through a highly reactive
Scheme 1. Mechanistic model for the anodic olefin coupling reaction
Figure 1 Two possible pathways for a radical cation initiated oxidative
cyclization.
The work highlighted below provides the backdrop needed for
determining which of the two pathways one might want to choose
when designing an oxidative cyclization and the methodology
needed to access either pathway within a given synthetic scheme.
radical cation intermediate (1), and they can be used to make
fused, bridge, and spirocyclic ring skeletons, tetrasubstituted
carbons, and a variety of heterocycles.3
While a number of issues can arise during an oxidative
cyclization reaction ranging from the need to rapidly remove a
second electron following the cyclization and elimination reactions
leading to overoxidation of the product,2 the initial cyclization
from 1 to 2 always plays the central role in the success of the
Results and Discussion
The need for the two reaction pathways can be seen by
considering the two failed anodic cyclization reactions Two
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Robert J. Perkins et al.
Report
examples of such a situation are shown in Scheme 2. In the first of
these reactions, an enol ether was oxidized to form a radical cation
that was then to be trapped by an allylsilane to simultaneously
form a six-membered ring and a quaternary carbon. However, the
cyclization was too slow and the reaction led to both elimination
products derived from the radical cation prior to the cyclization
and polymerization.4 None of the desired cyclization product was
observed. In the second reaction, it was hoped that the oxidative
could still undergo the desired cyclization. The result was an
radical reaction that led to the desired cyclized product in good
yield. Clearly, the oxidative cyclization reaction was compatible
with the use of an allylsilane trapping group and the combined
formation of a six-membered ring and a quaternary carbon if the
reaction was channeled down a productive “oxidative cyclization
type” pathway.
The observation made in Scheme 3 suggested that perhaps
all of the previously problematic anodic cyclizations might benefit
cyclization would afford
a
seven-membered ring product.5
However, once again the cyclization was too slow and the reaction
led to the same types of elimination and polymerization products
along with only 9% of the desired reaction.
from a similar radical type approach. This suggestion was
particularly intriguing in connection with the failed
seven-membered ring forming reaction shown in Scheme 2,
equation 2.
Scheme 2. Unsuccessful cyclization reactions
The formation of a seven-membered ring from the
oxidative coupling of an enol ether and a furan was being
investigated as part of a larger effort to target the synthesis of
artemisolide (Scheme 4).7,8 One of the goals of this effort was to
illustrate the synthetic utility of an anodic cyclization controlled by
the Curtin-Hammett Principle.9 The key was to be an initial
oxidation of the dithioketal in 17 that would occur preferentially to
the less electron-rich enol ether and furan groups needed for the
cyclization. An intramolecular electron transfer from the enol
ether to the radical cation of the dithioketal would lead to the
reversible generation of the enol ether radical cation needed for
the cyclization. The cyclization would then drain the equilibrium
toward the desired product 16. The result would be a product
functionalized at every carbon necessary for achieving the final
total synthesis.
In these situations, one can either accelerate the desired
cyclization or slow down the undesired side reactions. Both
approaches can work well. For example (Scheme 3, equation 1),
the generation of a six-membered ring and a quaternary carbon
can be accomplished with the use of a more reactive trapping
group like a second enol ether.4 Of course, this changes the nature
of product leading to a bisacetal, and in turn a new synthetic
challenge of having to differentiate the two ends of the cyclization.
An alternative approach that slowed the elimination and
polymerization reactions originating from the radical cation might
circumvent this added complexity. For example, the second
Scheme 4. Retrosynthesis of artemisolide.
Scheme 3. Alternatives to six-membered ring and quaternary carbon
formation.
Three previous studies (Scheme 5) led to this proposed
strategy. The first was an anodic olefin coupling reaction between
an enol ether radical cation and a furan ring that demonstrated
that the base reaction was compatible with the formation of a
seven-membered ring.10 In the chemistry that supported this
finding, the
Scheme 5. Preliminary studies
approach illustrated in Scheme 3 trapped the initial enol ether
derived radical cation intermediate with an alcohol nucleophile to
generate a radical intermediate.6 The radical intermediate could
no longer undergo proton elimination-derived side reactions but
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The reaction did lead to a low yield of the desired cyclic product
26. However, the major product observed (27) arose from
oxidation of the furan ring. The two products were unstable and
could not be isolated in decent yields. So, the crude reaction was
analyzed by proton NMR and the yields for the two products
obtained with the use of coumarin as an internal standard.
Changes in the electrolyte, solvent, nature of the base, etc. either
led to no change in the reaction, a drop in current efficiency
(recovered starting material), or in the cases where
tetraethylammonium tosylate was used as the electrolyte the
generation of elimination products from the enol ether radical
cation.
In these reactions, the formation of a furan oxidation product
(27) was puzzling. As pointed out above, previous studies had
clearly demonstrated that an enol ether will oxidize in the
presence of a furan ring even when it is less electron-rich than the
enol ether in substrate 25.10 In addition, the oxidation leading to
radical cation 8 in Scheme 2b had not led to any furan oxidation
product. Finally, the reaction to form a six-membered ring
originating from the oxidation of substrate 28 (Scheme 6, equation
b) led nicely to the desired product without any evidence for the
furan oxidation.6 This last reaction ruled out any suggestion of an
initial proton induced cyclization of the enol ether in the substrate
to form the cyclic ketal prior to the oxidation. Such a side reaction
would not depend on the size of the ring being generated.
Furthermore, the ratio of the two products generated in the
attempt to make a seven membered ring did not depend on the
pH of the reaction, another observation that was inconsistent with
decomposition of the enol ether prior to the oxidation.
chain between the enol ether and the furan was extended to a
point where no coupling between the two groups could occur. In
that example, the enol ether was oxidized and the furan was
recovered intact, a clear indication that the initial oxidation
occurred at the enol ether. In the second study, the proposed
Curtin-Hammett controlled cyclization was used for the generation
of a six-membered ring. Clearly, the initial oxidation of the
dithioketal followed by electron-transfer from the enol ether
worked well, and the reaction proceeded as planned when the
cyclization was fast enough. The third example from the work of
Sperry and Wright (Scheme 5c) provided a note of caution.11 In
their efforts, they demonstrated that the formation of a seven
membered ring only occurred when a methyl group was placed on
the allylic carbon of the enol ether. This was required to accelerate
the reaction. A similar observation was made by the Trauner group
in their synthesis of guanacastepene.12 When this methyl group
was not present, the reaction led to no cyclized product. In our
hands, the substrate without the methyl group led to the enol
ether radical cation derived elimination and polymerization types
of products typical of a slow cyclization. We hoped that in
substrate 17 (Scheme 4) the ketal would provide
a rate
acceleration that was sufficient to favor the cyclization and avoid
these issues without the inclusion of a methyl group that would
not be compatible with the synthesis of artemisolide.
As shown in Scheme 2, equation 2, this was clearly not the
case. In comparison with the successful cyclization shown in
Scheme 5a, it appeared that in radical cation 7 the optimized
overlap between the proton on the allylic carbon and the enol
ether derived radical cation accelerated the rate of the elimination
reaction relative to the cyclization. The presence of the dithioketal
was not sufficient to overcome this problem.
In light of these observations, it seems more likely that the
desired radical for the radical cyclization led to a hydrogen atom
abstraction as shown in Scheme 7. This H-atom abstraction
With the inability to use this approach to accelerate the
cyclization, we turned our attention toward slowing the
elimination reaction. It was against this backdrop that substrate 25
(Scheme 6a) was synthesized and submitted to the anodic
oxidation reaction. We hoped to use the successful strategy
employed to make 14 to once again avoid the elimination of a
proton from the radical cation intermediate and in so doing buy
time for the desired cyclization. The two methyl groups were
added to the enol ether in order to improve the solubility of the
substrate. The attempt was partially successful.
Scheme 7. H-atom abstraction mechanism.
Scheme 6. The radical pathway.
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Robert J. Perkins et al.
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abstraction and the resulting furan oxidation.
followed by a second oxidation, methanol trapping, and then
methanolysis of the resulting diene ether would lead to the
oxidized furan product 27 in a manner consistent with previous
observations about the selectivity of the oxidation and stability of
the enol ether. In this mechanism, the trapping of oxonium 34
would occur in a kinetic 1,2-type manner. Alternatively, radical 33
could undergo an intermolecular hydrogen abstraction followed by
oxidation of the resulting furan to form 27. While this possibility
For comparison, none of the desired product was isolated
from the reaction forced down the oxidative cyclization pathway
(substrate 39). While there was some evidence for cyclization in
the proton NMR of the crude reaction product, the reaction was
very messy, the current efficiency of the reaction was poor, and
the major product generated was the product derived from a
hydrogen atom abstraction reaction.
Of the two reaction pathways, it was clear that the
would require
a
4
electron oxidation and the competitive
reaction channeled down the radical cation pathway (substrate 36)
held the best chance for success because the use of the radical
cation intermediate did avoid the H-atom abstraction reaction. At
this point, we do not know if this observation is an inherent
property of the radical cation or if the more electron-poor radical
cation simply favors a reaction with the more electron-rich furan
ring. As mentioned earlier, no previous anodic olefin coupling
reactions involving a radical cation has led to a H-atom abstraction.
However, each of those reactions involved coupling to an
electron-rich olefin. Either say, the conclusion reached indicate
that one cannot simply channel a reaction down an radical
pathway to overcome a slow radical cation based cyclization.
While for the specific examples shown there is still work to do to
either accelerate the cyclization to avoid the competitive
elimination from the radical cation or block that elimination, the
use of a radical cation based pathway holds the best chance for a
successful seven-membered ring cyclization.
At the same time, it is also clear that in situations such as
the one shown in Scheme 3 the best course of action is the use of
the radical pathway. With this in mind, it is important to take note
that both families of substrates are made from the same starting
materials. The silyl enol ether substrates are typically made by a
cuprate addition to an enone followed by trapping of the enolate
with a silylating agent.11,12 As illustrated in Scheme 9, the ene diol
substrates can be made from the same cuprate and enone starting
material by first converting the enone into a cyclic acetal.14 In
using the same overall synthetic sequence to produce both types
of substrate, both the radical cation and radical pathways can be
accessed within a given synthetic sequence.
oxidation of radical 33 at the anode is expected to be fast, the low
mass balance of the reaction makes it impossible to rule this
pathway. Either way, the occurrence of the intramolecular H-atom
abstraction should not have been a surprise.13 However, it caught
us off guard because of the success of the cyclization shown in
Scheme 5, equation 1. In fact, no other anodic olefin coupling
reaction conducted to date has led to a similar competitive
H-atom abstraction. Could it be that radical cation intermediates
do not abstract H-atoms?
Either way, it was clear that a different approach to solving
the seven-membered ring problem was needed. This refocused
our efforts on a method to accelerate the cyclization reaction
relative to the unwanted side reactions and led to the design of
two new substrates (Scheme 8). In these substrates, a phenyl ring
was
Scheme 8. Radical cation vs. radical pathways and seven-membered rings.
Scheme 9. Substrate synthesis.
inserted as a conformational constraint into the tether between
the two coupling partners in order to accelerate the cyclization
reaction. The phenyl ring might also accelerate the hydrogen atom
abstraction and the elimination of a proton from alpha to the enol
ether radical cation. However, it was hoped that the presence of
the phenyl ring would accelerate the cyclization in a manner that
overcame either of those side reactions. The two substrates gave
us an opportunity to determine whether it was better to push the
reaction down a radical-cation pathway (Scheme 8a) or an radical
pathway (Scheme 8b).
The cyclization reaction originating from the oxidation of 36
was partially successful and led to a low yield of the desired
product. The reaction appeared to lead to the types of
polymerization products that have previously been associated
with the elimination of a proton from the carbon alpha to the enol
ether radical cation. No evidence was obtained for the H-atom
Conclusions
While the optimization of an anodic cyclization reaction can
involve a series of steps including a need to accelerate a second
oxidation step or avoid eliminations from a cyclized product that
lead to overoxidation,2 all of the reactions require the initial
cyclization to proceed well. The success of that step is dependent
on the proper choice of the reactive intermediate involved. There
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are times like the formation of six membered rings and quaternary
carbons where channeling the reaction down an radical pathway
and away from a radical cation based cyclization is essential.6
There are also times, seven-membered ring formation, that the
use of the radical cation intermediate is essential. The key to
identifying which processes is best appears to be the possibility of
an intramolecular H-atom transfer. When an intramolecular
H-atom abstraction can occur, the use of a radical cation
intermediate is essential. While this is important to know for the
design of the oxidative cyclization, the need to choose between
the reactive intermediates does not require a change to a larger
synthetic strategy that takes advantage of the desired umpolung
reaction. Both the radical and radical cation pathways can be
accessed using the same overall synthetic approach. The
requirement for one intermediate over the other only influences
the manner in which the step forming the oxidation substrate is
performed. Hence, both pathways are equally viable.
solution. The aqueous layer was extracted with ether, and the
organic washes were dried over Na2SO4 and concentrated in
vacuo.
The crude tosylate was then taken up in acetone (5.5 mL) and LiBr
added (0.26 g). The reaction was refluxed for 4 hr, then cooled to
0⁰C. Water was added, the layers separated, and the aqueous
layer extracted with ether. The organic washes were dried over
Na2SO4 and concentrated in vacuo. The crude bromide was
purified via silica gel chromatography (eluting with 10:1
hexanes:ether) to give bromide product (1.9938 g, 10.6 mmol) in
63% yield over 2 steps. The spectral data for this bromide
matched that previously reported.
To make a stock solution of the Grignard reagent: To dried
magnesium powder (1.3 g) under argon in dry THF (5 mL) was
added bromide (0.9444 g, 5.0 mmol) in THF (2 mL) dropwise over
1 hr. The reaction was stirred another hour, diluted with THF (3
mL), and stirred another hour. The grey solution was then
cannulated off the excess magnesium into a separate flask. The
Grignard stock solution was titrated using a menthol with a small
amount of 1,10-phenanthroline in THF until a slight pink color
persisted. These stock solutions typically yielded a 0.3-0.4 M
Grignard solution.
Experimental
(2,3-dimethyl-1,4-dioxaspiro[4.4]non-6-ene: To
a solution of
2-cyclopenten-1-one (1.0 mL, 12.0 mmol) in CH2Cl2 (10 mL) was
added Na2SO4 (0.36 g). A solution of cis-epoxybutane (3.1 mL, 36
mmol) in CH2Cl2 (10 mL) was added dropwise very slowly
overnight via syring pump. Triethylamine (1.5 mL) was then
added, and the reaction was diluted with ether. The solution was
washed with saturated aqueous NaHCO3 and brine, dried over
Na2SO4, and concentrated in vacuo. The crude epoxide was
purified via chromatography on basic alumina (eluting with 5:1
hexanes:ether) to give ketal product as a colorless liquid (1.622 g,
7.0 mmol) in 58% yield. 1H NMR (300 MHz, CDCl3) 6.08 (dt, J =
5.7 Hz, 1H), 5.72 (dt, J = 5.7 Hz, 1H), 3.70-3.57, (m, 4H), 2.75-2.37
(m, 2H), 2.12-2.07 (m, 2H), 1.28 (d, J = 2.1 Hz, 3H), 1.26 (d, J = 2.1
Hz, 3H). 13C NMR (125 MHz, CDCl3) 136.3, 131.7, 119.3, 78.6,
78.2, 35.5, 29.4, 16.9, 16.6; IR (neat, KBr) 2997, 2931, 2878, 2250,
1457 cm-1; ESI HRMS m/z (M+Na)+ calcd 177.0881, obsd 177.0886.
3-({3-[3-(furan-3-yl)propyl]cyclopent-1-en-1-yl}oxy)butan-2-ol: A
solution of 0.3-0.4 M in THF stock Grignard solution (3.0 mL) and
HMPA (0.46 mL, 2.6 mmol) was sonicated for 10 minutes. The
mixture was cooled to -20⁰C and freshly purified CuI (0.12 g, 0.63
mmol) was added. The solution was stirred at -20⁰C for 30 min.
A solution of 2,3-dimethyl-1,4-dioxaspiro[4.4]non-6-ene (0.0872 g,
0.57 mmol) in THF (0.3 mL) was then added, followed by dropwise
addition of BF3-Et2O (0.07 mL, 0.57 mmol) at -20⁰C. The reaction
was stirred at -20⁰C for 3 hr. 2,6-lutidine (0.15 mL, 1.3 mmol)
was then added at -20⁰C. The reaction mixture was warmed to
room temperature, quenched with cold saturated aqueous
NaHCO3, and diluted with ether. The layers were separated and
the organic layer washed twice with saturated aqueous NaHCO3.
The aqueous layer was then extracted once with ether. The
combined organic layers were washed with 0.1 M EDTA solution at
pH 8 until the washes no longer showed any blue/green coloration.
The organic layer was then washed with water and brine, dried
over Na2SO4, and concentrated in vacuo. The crude enol ether
was purified via silica gel chromatography (packed with 1.5% NEt3,
eluting with 5:1 hexanes:ether) to give enol ether product (0.0997
g, 0.38 mmol) as a colorless to pale yellow oil in 67% yield, along
with some amount of 2,6-lutidine mixed in. 1H NMR (300 MHz,
CDCl3) 7.34 (s, 1H), 7.21 (s, 1H), 6.26 (s, 1H), 4.45 (s with fine
coupling, 1H), 3.79 (septet, J = 6 Hz, 1H), 3.69 (septet of d, J = 6, 3
Hz, 1H), 2.74-2.59 (m, 1H), 2.46-2.22 (m, 4H), 2.10-1.96 (m, 1H),
1.66-1.46 (m, 2H), 1.46-1.23 (m, 3H), 1.21-1.14 (m, 6H) 13C NMR
Grignard reagent stock solution:
The furanyl alcohol was synthesized according to the procedure
given in Mihelcic, J.; Moeller, K.D. J Am. Chem. Soc. 2004, 126,
9106.
To the alcohol (2.1346 g, 16.8 mmol) in CH2Cl2 (85 mL) was added
DMAP (2.67 g, 21.8 mmol) followed by tosyl chloride (3.94 g, 20.7
mmol) and the reaction stirred overnight. The reaction mixture
was diluted with ether and washed with saturated aqueous NH4Cl
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Robert J. Perkins et al.
Report
(75 MHz, CDCl3) 142.6, 138.7, 125.2, 111.0, 110.0, 99.43, 99.39,
79.4, 70.5, 70.4, 42.1, 42.0, 37.2, 37.1, 31.79, 31.76, 28.1, 27.9,
25.0, 18.3, 15.1, 15.0 ; IR (neat, KBr) 3434, 2975, 2924, 2858, 1642
cm-1
1.30-1.18 (m, 6H); 13C NMR ( 75 MHz, CDCl3) 145.6, 123.6, 107.8,
106.9, 78.3, 76.6, 54.2, 53.7, 44.5, 38.0, 37.8, 37.6, 37.3, 35.8, 35.6,
30.5, 29.7, 26.6, 25.8, 17.2, 17.0, 16.9; IR (neat, KBr) 2966, 2929,
2867, 1740, 1673 cm-1; ESI HRMS m/z (M+Na)+ calcd 349.1985,
obsd 349.1982.
General Procedure for the Electrolyses:
In a flame-dried three-neck round bottom flask, the substrate was
dissolved in an anhydrous 20% MeOH/CH2Cl2 solution (0.025 M,
1.0 equiv.) with 2,6-lutidine (10.0 equiv.) and LiClO4 (0.1 M)
electrolyte. The reaction flask was equipped with a reticulated
vitreous carbon anode (100 PPI) and a carbon rod cathode. The
reaction was cooled to -78⁰C. A constant current of 8.0 mA was
passed through the solution. Upon completion (as monitored by
TLC), the solution was allowed to warm to room temperature,
diluted with ether and then washed with water and brine. The
organic layer was dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was chromatographed through a silica gel
column (using Sorbtech Premium Rf silica gel, slurry packed using
(2-Bromophenyl)(furan-3-yl)methanol: To a solution of 3-bromo
furan (5.23 g, 36 mmol, 1.1 eq) in THF (40 mL) at -78 oC was added
n-BuLi (14.2 mL of a 1.6 M solution in hexane, 1.2 eq) in a
dropwise fashion. After 30min, 2-bromobenzaldehyde (3.66 mL,
32 mmol) in 15 mL THF was added in dropwise. The reaction
mixture was allowed to warm to room temperature and then
stirred overnight. The reaction was then quenched with a
saturated aqueous solution of NH4Cl and most of THF solvent
removed under reduced pressure. The residue was diluted with
water and DCM, and the aqueous layer extracted with three times
with dichloromethane (DCM). The combined organic layer was
dried over MgSO4, filtered, and concentrated in vacuo. The crude
product was chromatographed through silica gel using 20% ethyl
acetate in hexane as eluent to give 7.0 g of product (87% yield).
The NMR data matched the previously published data (Hartman,
G. D.; Halczenko, W.; Phillips, B. T.; J. Org. Chem. 1986, 51, 142).
3-(2-Bromobenzyl)furan:
1% triethylamine in hexane/ether).
Crude 1H NMR for the electrolysis of susbstrate 25 with coumarin
as an internal standard – Shown above. (In this case, the
suspected cyclized product could not be isolated in its pure form.
Its identity was confirmed by conversion to the corresponding
furan derivative. The proton NMR for the furan product is included
To a solution of NaI (5.55 g, 37 mmol, 4.5 eq) in acetonitrile (100
mL) at 0 oC, was added TMSCl (4.73 mL, 37 mmol, 4.5 eq) in a
dropwise fashion. The reaction was stirred at 0 oC for 15min
before adding 57 (2.08 g, 8.2 mmol, 1 eq) in 50 mL of CH3CN
in the supporting information along with
a more easily
characterized analog missing the methyls on the cyclic ketal.):
o
Spectral data for the hydrogen atom abstraction byproduct.
dropwise over 1h at 0 C. The reaction was then quenched with
NaOH (2M). The resulting aqueous layer was extracted two times
with Et2O. The combined organic layer was dried over MgSO4,
filtered, and concentrated in vacuo. The crude product was
chromatographed through silica gel with hexane as eluent to give
2.0 g of product (85% yield). The NMR data again matched the
previously reported data (Hartman, G. D.; Halczenko, W.; Phillips, B.
T.; J. Org. Chem. 1986, 51, 142).
7-(3-(2,5-dimethoxy-2,5-dihydrofuran-3-yl)propyl)-2,3-dimethyl-1
,4 dioxaspiro[4.4]nonane: 1H NMR (300 MHz, CDCl3) 5.64 (s,
1H), 5.53 (s, 1H), 5.41 (s, 1H), 3.62-3.49 (m, 2H), 3.41 (s, 3H), 3.38
(s, 3H), 2.44 (t, J = 7.4 Hz, 1H), 2.28-1.68 (m, 6H), 1.64-1.30 (m, 6H),
A procedure for making phenyl bromide Grignard:
Mg ribbon (4 g, freshly sanded, freshly cut) was placed in 50 mL
flask. The flask was flame dried and then cooled to room
temperature. THF (12 mL) was added to the flask and the mixture
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Chin. J. Chem.
sonicated for 15 min. The starting bromide (8.5 mmol) was
dissolved in 8 mL of THF. The subsequent additions were made
using a Sage Instruments Syringe Pump (Model number 341B). In
stage one, 2 mL of the bromide solution was added to the flask
with the syringe pump at a rate of 8 mL/min. A heat gun was then
used to initiate a reflux. In a second stage, the remaining 6 mL of
bromide solution was added to the flask at a rate of 2 mL/min
while the reaction was heated with a hot plate. In the third stage
of the reaction, the result mixture was refluxed for 5h. A dark red
solution was obtained.
pylsilane: A Grignard solution (10 mL, 0.2 M) was freshly made
using the procedure reported above. To this solution at 0 oC was
added CuI (200 mg, 0.5 eq) and HMPA (0.68 mL, 2 eq). The
mixture was then stirred at 0 oC for 10 min before the temperature
was allowed to slowly climb to room temperature and the reaction
stirred for an additional 30 min. The reaction was cooled to -78 oC,
and then cyclopent-2-en-1-one (164 mg, 2 mmol) in 3 mL of THF
was added to the mixture followed by the addition of TIPSOTf
(1.62 mL, 3 eq). The reaction was stirred for 1h before the addition
of trimethylamine (1.6 mL, 3 eq). The resulting reaction mixture
was allowed to warm to room temperature, 2,6-lutidine (0.21 mL)
added, and then the mixure quenched with a saturated aqueous
solution of NaHCO3. The layers were separated and the organic
layer washed with an EDTA solution (0.1 M, pH=8) until no
green/blue coloration remained. The aqueous layer was extracted
two times with Et2O, and then the combined organic layers dried
A procedure for titration of phenyl bromide Grignard:
A 5 mL flask was flame dried and placed under argon with the use
of a balloon. To this flask was added 14.5 mg of menthol along
with ½ a spatula of 1,10-phenanthroline to be used as an indicator.
Methanol solvent (0.5 mL) was then used to dissolve the solid. To
this mixture was added the Grignard-reagent in a dropwise fashion. over MgSO4, filtered, and concentrated in vacuo. A 1H NMR of the
Upon addition, a milky white solid was formed. After 0.54 mL of
the Grignard-reagent was added, the mixture became a clear, dark
red solution. The titration indicated that the Grignard-reagent had
a concentration of 0.18 M. This concentration varied due to a loss
of solvent during the preparation of the Grignard and activation of
the bromide.
crude reaction product was taken, using 2,6-lutidine as internal
standard. Integration indicated a 60% NMR yield of the desired
enol ether. The crude product was chromatographed on silica gel
(using hexane as eluting solvent) to give 114 mg of product (30%
yield). 1H NMR (600 MHz, Chloroform-d) δ 7.35 (d, J = 1.8 Hz, 1H),
7.31 (d, J = 7.6 Hz, 1H), 7.24 – 7.20 (m, 1H), 7.13 (dd, J = 6.4, 1.6 Hz,
2H), 7.08 (s, 1H), 6.23 (d, J = 1.7 Hz, 1H), 4.65 (q, J = 1.8 Hz, 1H),
4.14 (dd, J = 8.5, 6.1, 2.4 Hz, 1H), 3.88 – 3.78 (m, 2H), 2.42 – 2.37
(m, 1H), 2.32 (ddd, J = 13.0, 8.6, 4.9 Hz, 1H), 1.74 (dq, J = 12.0, 6.8,
5.5 Hz, 2H), 1.23 (q, J = 7.4 Hz, 3H), 0.89 (q, J = 8.5, 7.6 Hz, 18H).
13C NMR (151 MHz, CDCl3) δ 153.87, 143.04, 140.16, 137.00,
134.43, 126.85, 124.25, 124.09, 123.20, 121.88, 108.52, 103.23,
40.50, 31.99, 30.85, 25.79, 19.99, 15.24. Due to acid sensititivity.
The reaction was utilized in the electrolysis without further
purification.
3-((3-(2-(Furan-3-ylmethyl)phenyl)cyclopent-1-en-1-yl)oxy)butan-
2-ol: To a freshly made Grignard solution (0.69 M, 2mL) at 0 oC was
added freshly recrystallized CuI (50 mg). The mixture was stirred at
room temperature for 30 min until a dark red suspension was
o
formed. The mixture was then cooled to -78 C. To this solution
was added the unsaturated ketal (synthesized above) (154 mg, 1.0
mmol, 1 eq) in 1 mL of THF in a dropwise fashion. Following the
addition, BF3-Et2O (0.04 mL, 1 mmol, 1 eq) was added and then
the reaction stirred for 5 h. To the resulting solution was added
2,6-lutidine (0.6 mL). The reaction was then quenched with a
saturated aqueous NaHCO3 solution. The reaction was washed
with EDTA solution (pH=8, 0.1 M) until no blue color remained.
The layers were separated, and the aqueous layer was washed
with ether three times. The combined organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. The crude product
was chromatographed on silica gel (20% EtOAc in hexane, packed
with 1% TEA) to give 148 mg of 43a and 2,6-lutidine (2:1 ratio of
products by proton NMR). The reaction afforded a 28% yield of the
desired product and 28% of the recovered acetal starting material.
Due to acid sensitivity, the product was carried on to the
electrolysis without further purification. 1H NMR (500 MHz,
Chloroform-d) δ 7.47 (t, J = 7.7 Hz, 1.79H), 7.41 – 7.03 (m, 6H),
6.97 (d, J = 7.6 Hz, 2.98H), 6.23 (d, J = 2.3 Hz, 1H), 4.49 (t, J = 1.8
Hz, 1H), 4.26 – 4.11 (m, 1H), 3.98 – 3.69 (m, 4H), 2.50 – 2.24 (m,
4H), 1.35 – 1.14 (m, 6H).
1,3a,7,11b-tetrahydrobenzo[7,8]azuleno[4,5-b]furan-3(2H)-one:
To a three-neck round bottom flask was charged with 36 (0.2
mmol, 1eq), LiClO4 (254 mg, 0.6 M), MeOH/DCM (1:1, 4 mL),
2,6-lutidine (116
8mAL, 5 eq), the r
until 2.5 F/mol current passed. The reaction was then quenched
with water. Aqueous layer was
extracted with DCM for three times. The combined organic layer
was dried over MgSO4, filtered, and concentrated in vacuo. The
residue was chromatographed through silica column using 10%
ethyl acetate in hexane as eluent to give 13.0 mg of product (27%
1
yield). H NMR (500 MHz, CDCl) δ 7.43 – 7.33 (m, 2H), 7.33 – 7.28
(m, 1H), 7.25 – 7.19 (m, 2H), 6.27 (d, J = 1.8 Hz, 1H), 4.14 (dd, J =
16.2, 3.2 Hz, 1H), 3.70 – 3.62 (m, 1H), 3.53 (d, J = 16.2 Hz, 1H),
3.10 (dd, J = 13.6, 2.9 Hz, 1H), 2.77 – 2.68 (m, 1H), 2.52 – 2.40 (m,
3H). 13C NMR (126 MHz, CDCl3) δ 211.78, 144.64, 141.69, 140.15,
139.28, 128.75, 127.37, 127.25, 124.43, 117.94, 112.10, 54.70,
43.12, 37.92, 31.41, 24.44.
((3-(2-(Furan-3-ylmethyl)phenyl)cyclopent-1-en-1-yl)oxy)triisopro
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Robert J. Perkins et al.
Report
6. 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, 12865-12868.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2019xxxxx and includes
spectral data for the new compounds synthesized.
7. (a) For the isolation of Artemisolide see Dim, J. H.; Kim, H. –K.;
Jeon, S. B.; Son, K. –H.; Kim, E. H.; Kang, S. K.; Sung, N. –D.; Kwon,
B. –M. New Sesquiterpene-Monoterpene Lactone Artemisolide,
Isolated from Artemisia Argyi. . Tetrahedron Lett. 2002, 43,
6205-6208. (b) For isolation of the related Arteminolides see
Lee, S. -H.; Kim, H. -K.; Seo, J. -M.; Kang, H. -M.; Kim, J. H.; Son, K.
-H.; Lee, H.; Kwon, B. –M. J. Org. Chem. 2002, 67, 7670-7675.
8. For synthetic studies targeting the related Arteminolides see (a)
Sohn, J. –H. Studies Toward Synthesis of Arteminolides:
Intramolecular [5+2] Oxidopyrylium Ion Cycloaddition Reactions
with Silicon Tether. Bull. Korean Chem. Soc. 2010, 31, 1841-1842.
(b) Sohn, J. –H. [5+2] Oxidopyrylium Ion Cycloaddition Reaction
with Vinylsilane: Construction of Core Structure of Biogenic
Intermediates or Arteminolides. Bull. Korean Chem. Soc. 2009, 30,
2517-2518. (c) Lee, H. –Y.; Sohn, J. –H.; Kim, H. Y. Studies Toward
the Synthesis of Arteminolide: [5+5] Cycloaddition Reaction of
Allenes with Oxidopyrylium Ions. Tetrahedron Lett. 2001, 42,
1695-1698.
Acknowledgement
We thank the National Science Foundation (CHE-1764449)
for their generous support of our work.
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Chin. J. Chem. 2019, 37, XXX－XXX
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Running title
Chin. J. Chem.
12. Miller, A. K.; Hughes, C. C.; Kennedy-Smith, J. J.; Gradl, S. N.;
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(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
Chin. J. Chem. 2019, 37, XXX－XXX
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Entry for the Table of Contents
Page No.
Title
O
O
X
X
OR
n
( )
X
Which intermediate is
the best intermediate?
- e-
vs.
n
( )
OTIPS
+
=
or
R
-CH2CH2OH
Si(iPr)3
n
( )
Anodic cyclization reactions can be channeled down one of two main pathways. This manuscript
describes when to use each.
Robert J. Perkins, Ruozhu Feng, Qingquan Lu,
and Kevin D. Moeller*
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.