Insights into the Mechanism of Anodic N-N Bond Formation by Dehydrogenative Coupling

Article abstract of DOI:10.1021/jacs.7b07488

The electrochemical synthesis of pyrazolidine-3,5-diones and benzoxazoles by N-N bond formation and C,O linkage, respectively, represents an easy access to medicinally relevant structures. Electrochemistry as a key technology ensures a safe and sustainabl

Full text of DOI:10.1021/jacs.7b07488

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Article
Insights into the Mechanism of the Anodic N-
N Bond Formation by Dehydrogenative Coupling
Tile Gieshoff, Anton Kehl, Dieter Schollmeyer, Kevin D. Moeller, and Siegfried R. R Waldvogel
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b07488 • Publication Date (Web): 09 Aug 2017
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Insights into the Mechanism of the Anodic N-N Bond Formation by
Dehydrogenative Coupling
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†
†
Tile Gieshoff,†,‡, Anton Kehl, Dieter Schollmeyer, Kevin D. Moeller, Siegfried R. Waldvo-
⊥
⊥
gel*,†,‡
†Institute of Organic Chemistry, Johannes Gutenberg University Mainz, 55128 Mainz, Germany
‡Graduate School Materials Science in Mainz, 55128 Mainz, Germany
⊥
Department of Chemistry, Washington University in St. Louis, St. Louis, Missouri 63130, United States
ABSTRACT: The electrochemical synthesis of pyrazolidine-3,5-diones and benzoxazoles by N-N bond formation and C,O
linkage respectively represents an easy access to medicinally relevant structures. Electrochemistry as key technology en-
sures a safe and sustainable approach. We gained insights in the mechanism of these reactions by combining cyclovoltam-
metric and synthetic studies. The electron transfer behavior of anilides and dianilides was studied and led to the following
conclusion: The N-N bond formation involves a diradical as intermediate, whereas the benzoxazole formation is based on
a cationic mechanism. Besides these studies, we developed a synthetic route to mixed dianilides as starting materials for
the N-N coupling. The compatibility with valuable functionalities like triflates and mesylates for follow-up reactions as well
as the comparison of different electrochemical set-ups also enhanced the applicability of this method.
Introduction
slower N-N bond formation led to competitive formation
of a benzoxazole ring by the generation of a C,O linkage.11
While the yield of the reaction was low, the finding sug-
gested that it might be possible to convert easy accessible
anilides into either a pyrazolidin-3,5-dione or benzoxa-
zoles by the control of reactions conditions and selection
of substrates. However, developing such a strategy requires
an understanding of the reaction mechanisms that govern
product formation in two competing pathways. We report
here those mechanistic details along with a general strat-
egy for elucidating the pathways that originate from the
generation of an amidyl radical intermediate under oxida-
tive conditions.
Pyrazolidin-3,5-diones and benzoxazoles are important
heterocyclic motifs appearing in natural products and
drugs.1 Phenylbutazon,2 pseudopteroxazole,3 UK-1,4 and
ERB-0415 represent just a few examples of the medicinally
relevant compounds that possess these key ring skeletons.
Because of this relevance, several methods to access such
heterocyclic motifs have been reported.6 Nevertheless, lim-
itations regarding the sustainability and generality of these
reactions are consistent with the need for the development
of alternative methods. For example, the conventional syn-
thesis of pyrazolidine-3,5-diones requires the use of highly
carcinogenic N,N’-diarylhydrazines. This leads to the need
for additional safety precautions and challenges in connec-
tion with reaction scale-up.7 Moreover, complex substitu-
tions patterns require additional synthetic steps following
construction of the central ring skeleton.8 For the synthesis
of benzoxazoles, the principle synthetic strategies are
based on condensation reactions involving 2-aminophe-
nols or coupling reactions of anilide substrates. These ap-
proaches usually require elevated temperatures, catalysts,
and result in significant reagent waste.9
Scheme 1. Competing formation of the N-N bond and
C-O bond.
As an alternative, we recently reported a simple route to
pyrazolidin-3,5-diones via the electrochemical formation
of a N-N bond. The reactions can be conducted in a simple
undivided cell at constant current conditions.10 This ap-
proach dispenses with the need of toxic N,N’-diarylhydra-
zines and gives a straightforward access to more complex
substitution patterns. When the approach was applied to
the formation of six-membered rings, we learned that a the
Scheme 2. Electrochemical formation of pyrazolidin-
3,5-diones and benzoxazoles.
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fast and, in this case, can be supported by cathodically gen-
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erated alcoholate anions derived from HFIP. After genera-
tion of the amidyl radical, there are two possible mecha-
nistic pathways that can be followed. One possibility is that
the amidyl radical will be oxidized again at the anode to
form a cation (II). This cation is then trapped by the sec-
ond anilide to form the N-N bond. The second involves an
oxidation not of the amidyl radical but of the second ani-
lide present in the substrate. In this case, the N-N bond
would be formed by an intramolecular recombination of
diradical I.
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Scheme 3. General Steps of the Anilide Oxidation and
Possible Mechanisms of the N-N Bond Formation to
Pyrazolidine-3,5-diones.
As suggested in the preceding statement, the key reac-
tive species central to both reaction pathways is an amidyl
radical. The structure, generation, and reactivity of such
amidyl radicals is an important topic in contemporary re-
search because the intermediates play a role in rearrange-
ment reactions, cyclizations, and hydroamination reac-
tions. The generation of amidyl radicals typically rely on
the cleavage of halogenated amides.12 In contrast, the elec-
trochemical approach used here allows for the direct for-
mation of the intermediates from an amide, and hence the
generation of amidyl radicals from non-activated starting
materials. The use of electrochemistry for the oxidation re-
actions was selected because of the opportunities it pro-
vides for sustainability and extraordinary reaction path-
ways.13 In the current reactions, only a minimal amount of
waste is generated and electric current serves as inexpen-
sive and renewable redox reagent. The use of a low sup-
porting electrolyte concentration (0.01 M) and 1,1,1,3,3,3-
hexafluoroisopropanol (HFIP) as a recyclable solvent min-
imized both reagent use and the fluorine footprint of the
reaction. HFIP has a key role in these transformations,
since it exclusively enables efficient conversions due to its
radical stabilizing properties.14
In order to differentiate these possibilities, it is im-
portant to understand the oxidation potentials involved. If
the oxidation potential (Eox) of the amidyl radical (Scheme
2) is lower than the oxidation potential of the other anilide
site, the formation of cation II would be favored. If the ox-
idation potential of the second anilide is lower than the
amidyl radical, then the formation of diradical I would be
promoted. To gain insight into these relative oxidation po-
tentials, we undertook an electroanalytical study to com-
plement the synthetic investigations. It was our hope that
a combination of oxidation potential measurements and
synthetic verification of the insights provided would allow
us to distinguish between the two possible mechanistic
pathways.
Work to understand the mechanism of the current reac-
tions initially focused on the formation of N-N bonds. This
effort was motivated by the synthetic potential of the reac-
tions, and the opportunity to further enhance that poten-
tial by expanding the scope of the reactions to include sub-
stituents (like triflates15 or mesylates16) that are compatible
with further elaboration of the products. The key, of
course, is understanding how such substituents alter the
reactivity of the intermediates involved, an understanding
that not only impacts the current reactions but potentially
a wide variety of oxidative processes.
Cyclovoltammetric Measurements of Test Sub-
strates. Since it is not possible to measure the oxidation
potential of an isolated anilide moiety in a dianilide, the
oxidation potentials were measured for a monoanilide test
substrate. Pivaloyl anilides with different substitution pat-
terns were used to test the electronic parameters required
for a successful reaction. The substrates were easily acces-
sible by treatment of the corresponding anilines with
pivaloyl chloride. Each substrate was then investigated by
cyclic voltammetry in order to determine the oxidation po-
tential for both the initial anilide (Eox,1) and the resulting
amidyl radical (Eox,2) (Scheme 4).
Results and Discussion
Elucidation of Mechanistic Assumptions. The elec-
trochemical N-N bond formation reaction is initiated by
the direct oxidation of the anilide at the anode. After a sin-
gle electron transfer (SET), the radical cation formed is
more acidic than the corresponding anilide by several or-
ders of magnitude.17 Deprotonation of the radical cation is
Scheme 4. Oxidation steps of anilides.
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Figure 1. Cyclic voltammogramms of pivaloyl anilides as test compounds (Conditions: 1 mM substrate in 0.1 M NBu4PF6 (5 mL),
WE: glassy carbon, CE: glassy carbon, RE: Ag/AgCl in sat. LiCl in EtOH, scan rate: 200 mV/s), final reference vs. FcH/FcH+.
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Figure 1 displays the cyclic voltammogramms of the
pivaloyl derivatized anilines. The blank measurement re-
veals a potential limit of the electrolyte around 1.8 V and -
0.5 V vs. Fc/Fc+. In the voltammogramms of compounds 8a
and 8c-8g, two distinct oxidation peaks are visible. De-
pending on the substitution pattern, the Eox,1 peak can
overlap with the current at the potential limit, leading to
“shoulder-shaped” peaks. This becomes most visible at
substrate 8f. Since it demands a higher voltage to oxidize
the corresponding amidyl radical, the peak for the Eox,2 step
frequently shows this behavior. In the case of the triflate
substituted derivative (8f), Eox,2 is completely buried under
the potential limit wave. The results of the cyclovoltam-
metric measurements are in accordance with the electron
density of the aromatic ring. The voltage difference of Eox,1
and Eox,2 dependents on the substituents on the rings and
their ability to stabilize cation formation. For example,
para-methyl groups lead to a smaller voltage difference (8a
240 mV and 8d 230 mV, respectively) than other substrates
(8c 380 mV and 8e 410 mV, respectively). For substrate 8b
with the even more electron-releasing para-methoxy
group, no difference between the two oxidation potentials
was observed. The second oxidation step is favored, since
the cation formed is stabilized by resonance by the meth-
oxy group as a quinone imine-like structure. Substrate 8g
results in a differently shaped voltammogramm with a low
peak current of the Eox,2 step. The small current seen for the
amidyl oxidation is consistent with decomposition of the
amidyl radical, a suggestion that manifests at the low yield
of product obtained from reactions with this substrate (see
below). A rationale might be the interplay of the electron-
withdrawing chloro substituent and the strong electron-
releasing methoxy-group, potentially leading to polymeri-
zation and decomposition. Table 1 displays the data for
both oxidation steps.
Table 1. Oxidation potentials Eox,1 and Eox,2 of test sub-
strates vs Fc/Fc+.
Entry
Substrate
Eox,1 / V
1.28
1.10
Eox,2 / V
1.52
1.10
1
8a
8b
8c
8d
8e
8f
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3
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5
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7
1.31
1.69
1.57
1.76
-
1.34
1.35
1.69
1.31
8g
1.49
This study was conducted to achieve an insight into the
electron transfer steps of the electrochemical oxidation of
anilides.
In general, the measurement of two distinct peaks for ox-
idations steps immediately suggested a diyl mechanism,
since symmetric dianilides always lead to N-N bond for-
mation.10 With the success of these studies, attention was
turned toward understanding the more complex dianilide
systems.
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of the electron transfer behavior, mixed dianilides 4a, 4b,
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and 4c are expected to form a cationic intermediate, and
substrates 4d, 4e, 4f, and 4g a diradical intermediate. For
example, consider the data shown for substrate 4a. In this
case, both the oxidation potentials for anilide site B (1.10 V)
are below the initial potential for site A (1.35 V). Hence, the
second oxidation at site B should occur prior to the initial
oxidation at site A; the conditions required for cation for-
mation. Compare that data with that for substrate 4d.
Here, the second oxidation at site B occurs at a higher po-
tential than the initial oxidation at site A; the conditions
required for diradical behavior.
Synthesis and Electrolysis of Mixed Dianilides.
Based on oxidation potentials of the individual anilide moi-
eties, we synthesized several mixed dianilides. We focused
on the combination of anilides with Eox values, which based
on the data presented would lead either to the formation
of a diradical or to the formation of a cation. The goal was
to probe what products would form from each of the pro-
posed mechanistic pathways. In addition, the selective ac-
cess to mixed dianilides enables both the synthesis of a va-
riety of products and the ability to design a product that is
ideally functionalized for further development in subse-
quent synthetic transformations. In order to gain access to
a variety of dianilides, the synthetic route shown in Scheme
5 was developed. In this chemistry, a coupling reaction was
performed using substrate 9 and a variety of anilines, the
alcohol converted to an acid, and then a second coupling
performed. The oxidation step in the sequence could be
conducted with a catalytic amount of the chromate reagent
in a number of cases.18
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Table 2. Overview of the electrolysis of mixed diani-
lides.
Scheme 5. Synthetic route to mixed dianilides.
En-
try
Sub-
strate
Anilide
site
Eox,1
V*
/
Eox,2
V*
/
Product
A
B
A
B
A
B
A
B
A
B
A
B
A
B
1.35
1.10
1.76
1.10
1.52
1.10
1.52
-
10a
(56%)
1
4a
4b
4c
4d
4e
4f
1.28
1.10
1.28
1.69
1.35
1.31
10b
(60%)
2
3
4
5
6
7
10c
(37%)
1.76
1.49
1.76
-
11 (10%)
5a (11%)
1.35
1.69
1.35
1.31
5b (34%)
5c (49%)
5d (55%)
1.76
1.69
1.76
1.57
1.35
1.34
4g
*Red color indicates that these are the first two proceeding
oxidation steps.
The detailed syntheses of the substrates can be found in
the supporting information. One variation of note here is
that the synthesis of the triflate derivatives 4c and 4e could
not be obtained directly from the chemistry shown. In
these cases, the phenol derivative was initially synthesized
and the triflate group added with triflic anhydride in a sub-
sequent step.19
Chart 1. Electrolysis products derived from the con-
version of mixed dianilides.
An overview about the oxidation potentials of the com-
bined anilide sites and the corresponding products are dis-
played in Table 2. The electrolysis products of the conver-
sion are shown in Chart 1. If we take the determined Eox
data of the test substrates into account for the prediction
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N bond, dianilides 4a, 4b, and 4c formed HFIP incorpo-
1
rated products 10a, 10b, and 10c and only small traces of
N-N bond formed products were detectable. When para-
methoxy substituted anilides were used, the addition of
HFIP occurred at the aromatic ortho-position. In case of a
para-methyl substitution, addition occurred at the ben-
zylic position. This substitution is most consistent with the
loss of a proton from the cationic intermediate (IV) to form
an azoquinone methide derivative. This result would ap-
pear to confirm the accuracy of the prediction made based
on the oxidation potentials shown in Table 2. Compounds
4e, 4f, and 4g formed pyrazolidine-3,5-diones 5b, 5c, and
5d as products by an N-N bond formation. The Eox values
for these compounds were all consistent with the for-
mation of a diradical intermediate. Substrate 4d formed a
product (10d) consistent with alcoholysis of the amidyl
group along with the desired pyrazolidine-3,5-dione prod-
uct (5a). This decomposition product is consistent with the
different CV behavior for the group noted above in connec-
tion with Figure 1. Based solely on the oxidation potentials,
N-N bond formation is more likely than cation formation,
so at this time the mechanistic origin of the decomposition
pathway remains unsolved. Competing diradical and cati-
onic pathways are possible.
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Cyclovoltammetric Measurements of Mixed Diani-
lides. Beside the cyclovoltammetric study of the test sub-
strates and the synthetic study, we were also interested in
the electron transfer behavior of the dianilides within a cy-
clic voltammetric study.
aYields for substrate 5c and 5d were already reported in a
former publication.
The electrolysis of the mixed dianilides revealed the for-
mation of interesting products. Instead of forming the N-
Figure 2. Cyclic voltammogramm of mixed dianilides (Conditions: 1 mM substrate in 0.1 M NBu4PF6 (5 mL), WE: glassy carbon,
CE: glassy carbon, RE: Ag/AgCl in sat. LiCl in EtOH, scan rate: 200 mV/s), final reference vs. FcH/FcH+.
As expected, the voltammogramms of the mixed diani-
lides demonstrate a different electron transfer behavior for
cation forming and diradical forming dianilides. The volt-
ammogramms substrates 4a, 4b, and 4c show a significant
difference between the oxidation potentials of the two
groups, whereas compounds 4e and 4g reveal two oxida-
tion peaks very close to each other. This data once again
suggests cation formation in 4a-c and diradical formation
for substrates 4e and 4g. In this way, the data is again fully
consistent with the observations made above. It appears
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that N-N bond formation is the result of a diradical inter-
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2
mediate (Scheme 3, intermediate I).
Theoretical considerations also support this argument.
The unpaired electron can populate both, σ- and π-orbit-
als, while the exact structure depends on many factors, e.g.
substitution pattern.20 Moreover, there is an attractive in-
teraction among σ–radical and σ*–orbital. The correspond-
ing cation is located in the π-orbital and stabilized by the
aromatic ring. It is likely that a σ-radical facilitates the sub-
sequent recombination, whereas a π-cation would exacer-
bates a selective cyclization reaction and rather leads to
side reactions.
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Adaption to the Benzoxazole Mechanism. As men-
tioned in the introduction, much of this work was moti-
vated by the opportunity to generate both the N-N bond
forming products and benzoxazole products from closely
related substrates. The benzoxazole was initially a unex-
pected side product found in a reaction planned for N-N
bond formation. With an understanding of how the N-N
bond forming reactions can be designed, we were in posi-
tion to tackle the challenge of selectively generating the
benzoxazole ring system. One observation made during
the synthesis of benzoxazoles11 provided significant guid-
ance for this endeavor. That observation is that a para-me-
thyl substitution on the anilide significantly inhibits ben-
zoxazole formation. Instead, the reactions tend to lead to
HFIP ether derivatives (6a) in a fashion directly analogous
to the earlier formation of product 10c. This finding was
initially unexpected, since para-methyl groups are benefi-
cial for the generation of N-N bonds. This suggested that
benzoxazole formation might be derived from the genera-
tion of a cationic intermediates. In such a case, the for-
mation of amidyl cation (III) can lead to deprotonation at
the benzylic carbon, the formation of an azoquinone
methide (IV), and solvent trapping. The combination of
this finding with the mechanistic study above led us to
conclude that the mechanism for the benzoxazole for-
mation most likely proceeds through a cationic intermedi-
ate (III), which can undergo an oxa-Nazarov-type cycliza-
tion.21
With this knowledge, the design of new substrates for
benzoxazole products becomes viable. In this context, it is
interesting to note that in the benzoxazole syntheses, the
solvent trapping products that appear to interfere with the
N-N bond forming reactions above are not a problem, even
when para-methoxy groups are present (Chart 1). This di-
vergent behavior originates from a competition between
carbonyl oxygen addition to the aryl ring (benzoxazole for-
mation) and solvent (HFIP) trapping of the ring. This com-
petition is shifted toward solvent trapping when a dianilide
is used as the substrate. It appears that hydrogen bonding
between the carbonyl and the second anilide in the mole-
cule lowers the nucleophilicity of the carbonyl oxygen and
favors HFIP addition. The hydrogen bonding is detectable
in crystallographic studies of substrate 10c (see supporting
information).
Optimization of scope and reaction set-up. With the
mechanism for the reaction determined, we turned our at-
tention toward evaluating the synthetic scope and utility
of the reactions. In our previous work, para-chloro and
meta-bromo substitutions were most valuable from a syn-
thetic point of view. However, the latter only afforded the
desired N-N product in a 33% yield. Moreover, the reac-
tions were restricted to products that contained a para-
substituent.10 With the selective synthesis for mixed diani-
lides and the mechanistic insights in hand, these limita-
tions could be addressed. To this end, the chemistry was
explored for its compatibility with synthetically versatile
triflate and mesylate groups. In addition, we investigated
the influence of bulky meta-substitutions in order to deter-
mine if they would prevent side reactions at substituent-
free para-positions. As shown in Chart 2, the conversion of
symmetric triflates and mesylates substrates into the de-
sired products showed that the groups were tolerated by
the reactions, and the use of a bulky meta-substituent did
have a positive effect on the reactions.
Scheme 6. Solvent trapping product and the cationic
intermediate in the benzoxazole formation.
Chart 2. Extension of the scope to triflates, mesylates,
and para-unblocked derivatives.a
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Figure 3. Set-ups A (left) and B (right).
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Conclusion
The formation of 5b was particularly interesting because
it involved the generation of an unsymmetrical product
wherein the two aromatic rings were synthetically differ-
entiated, but the initial yield for this reaction was low
(34%). When we worked on the benzoxazoles formation,
we demonstrated the utility of varying the reaction setup
as a means of optimizing the yield for a particular product.11
With several substrates, we tested the two main electro-
chemical setups used for constant current electrolysis with
regards to their influence on the N-N bond formation. Set-
up A includes a beaker-type cell with a flat isostatic graph-
ite anode and a platinum plate cathode in a parallel orien-
tation to each other.22 Set-up B is based on a 25 mL three-
necked flask with a reticulated vitreous carbon (RVC) an-
ode and a platinum wire cathode placed angularly to each
other. Chart 3 demonstrates that the performance of the
cells was dependent on the the substrate used. On one
hand, compound 5b was isolated in 84%, when set-up B
was used. On the other hand, set-up A worked better with
compound 5j. Compound 5i gives similar yields in both set-
ups, but RVC as anode material enables higher currents
and therefore a more time-efficient conversion. It is im-
portant to note that for an initial pass, either setup can be
used to test the viability of a reaction. One can then adjust
the nature of the reaction setup after it is clear that the
electrolysis works.
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The advancement of electroorganic synthesis is depend-
ent on both, the development of new reactions of synthetic
value and the development of the mechanistic insights
necessary to make conclusions about and extend the scope
of those reactions. In the example presented here, we out-
lined both, the synthetic potential of anodic oxidations
leading to amidyl radicals and subsequent N-N bond for-
mation reaction and benzoxazole synthesis and data sup-
porting the mechanistic parameters that govern product
formation. In addition, we highlighted how a combination
of cyclovoltammetric and synthetic studies can be used to
gain those insights. N-N bond formation in the systems
studied is the result of a diradical coupling mechansim,
whereas benzoxazole formation is the result of a cationic
oxa-Nazarov-type cyclization. These insights led to the for-
mation of products from mixed dianilide substrates, the
use of synthetically valuable triflate and mesylate sub-
strates in the reactions, and an important illustration of
how different reaction set-ups can be used to optimize an
electro-organic conversion.
Experimental Section
Electrolysis Protocol, Set-up A. A solution of 0.2 mmol
electrolysis substrate and 19 mg tetrabutylammonium hex-
afluorophosphate (0.01 M) in 5 mL hexafluoroisopropanol
(HFIP) is placed in a 5 mL Teflon cell.22 The solution is elec-
trolyzed with a current of 0.5 mA/cm2 (active electrode
area 1.6 cm2) using an isostatic graphite plate anode and a
platinum plate cathode, until 2-3 F are applied. The con-
version is controlled via GC. After electrolysis, the solvent
is recovered by distillation and the product is isolated via
column chromatography on silica with mixtures of cyclo-
hexane and ethyl acetate.
Chart 3. Comparison of electrolysis set-up.a
Electrolysis Protocol, Set-up B.
A solution of
0.4 mmol anilide derivative and 38 mg tetrabutylammo-
nium hexafluorophosphate (0.01 M) in 10 mL hexafluoroi-
sopropanol (HFIP) is placed in a 25 mL three-necked
round-bottom flask. A reticulated vitreous carbon (100
PPI) anode and a platinum wire cathode is placed in the
solution and sonicated for 30 s. The solution is electrolyzed
with a constant current of 8.4 mA until 2-2.2 F are applied.
Full conversion is checked by TLC. After electrolysis, the
solvent is removed via distillation and product is isolated
aYield for substrate 11e and 11f using set-up A were already
reported in a previous publication, isolated from a 25 mL cell.10
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Journal of the American Chemical Society
via column chromatography on silica with mixtures of hex-
Page 8 of 11
Hz), 50.84, 23.30; 19F NMR (377 MHz, CDCl3) δ = -74.32;
HRMS for C14H1235ClF6NO3 (ESI+) [M+H]+: calc.: 392.0483,
found: 392.0484.
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anes and ethyl acetate.
Cyclic Voltammetry Protocol. A 1 mM solution of sub-
strate in 5 mL HFIP (0.1 M TABPF6) was placed in a 10 mL
cell. Cyclic voltammetry was performed with a 200 mV/s
scan rate using a glassy carbon working electrode, glassy
carbon counter electrode, and Ag/AgCl reference electrode
in saturated LiCl in EtOH. The peak potentials were refer-
enced versus Fc/Fc+ and in case of an overlap, the exact
value was determined by calculating the minimum of the
slope.
1-(4-chlorophenyl)-2-(3-methoxy-4-chlorophenyl)-4,4-
dimethylpyrazolidin-3,5-dione (5a). Electrolysis in set-up
A yielded 8 mg colorless oil (0.021 mmol, 11%): H NMR
(400 MHz, CDCl3) δ = 7.37 – 7.32 (m, 2H), 7.32 – 7.27 (m,
3H), 7.00 (d, J = 2.4 Hz, 1H), 6.79 (dd, J = 8.5, 2.4 Hz, 1H),
3.86 (s, 3H), 1.53 (s, 6H); 13C NMR (101 MHz, CDCl3) δ =
174.12,174.09, 155.31, 135.29, 134.54, 132.49, 130.28, 129.35,
123.20, 120.71, 114.18, 106.63, 56.27, 44.39, 21.81; HRMS for
C18H1635Cl2N2O3 (ESI+) [M+H]+: calc.: 379.0611, found:
379.0612.
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Synthesis and Characterization of Electrolysis Prod-
ucts. N-(4-chlorophenyl)-N’-(2-(1,1,1,3,3,3-hexafluoropro-
pan-2-yloxy)-4-methoxy)-2,2-dimethylmalondiamide
(10a). Electrolysis in set-up A yielded 57 mg colorless oil
1-(4-chlorophenyl)-2-(4-trifluoromethylsulfonyloxy-
phenyl)-4,4-dimethylpyrazolidin-3,5-dione (5b). Electroly-
sis in set-up B yielded 146 mg colorless solid (0.34 mmol,
84%): mp 89.0-89.5 °C (EtOAc); 1H NMR (400 MHz,
CDCl3) δ = 7.47 – 7.41 (m, 2H), 7.38 – 7.32 (m, 2H), 7.31 –
1
(0.11 mmol, 56%): H NMR (400 MHz, CDCl3) δ = 9.20 (s,
1H), 8.36 (s, 1H), 8.21 (d, J = 9.0 Hz, 1H), 7.63 – 7.48 (m, 2H),
7.38 – 7.24 (m, 2H), 6.72 (dd, J = 9.0, 2.6 Hz, 1H), 6.61 (d, J
= 2.6 Hz, 1H), 4.91 (hept, J = 5.6 Hz, 1H), 3.83 (s, 3H), 1.68
(s, 6H); 13C NMR (101 MHz, CDCl3) δ = 172.58, 170.26, 157.26,
147.89, 136.43, 129.22, 128.91, 123.30, 121.35, 121.16, 120.78 (q, J
= 280.9 Hz), 108.57, 101.97, 76.53 (hept, J = 33.7 Hz), 55.75,
50.89, 24.03; 19F NMR (377 MHz, CDCl3) δ = -74.64; HRMS
for C21H1935ClF6N2O4 (ESI+) [M+Na]+: calc.: 535.0835, found:
535.0845.
13
7.25 (m, 4H), 1.52 (s, 6H); C NMR (101 MHz, CDCl3) δ =
174.24,174.04, 147.05, 135.68, 134.46, 132.65, 129.47, 123.12,
123.07, 122.19, 44.30, 21.82; 19F NMR (377 MHz, CDCl3) δ = -
73.95; HRMS for C18H1435ClF3N2O5S (ESI+) [M+Na]+: calc.:
485.0162, found: 485.0158.
1,2-bis-(4-trifluoromethylsulfonyloxyphenyl)-4,4-dime-
thylpyrazolidin-3,5-dione (5e). Electrolysis in set-up B
yielded 137 mg colorless solid (0.24 mmol, 60%): mp 90.4-
91.4 °C (EtOAc); 1H NMR (400 MHz, CDCl3) δ = 7.48 – 7.41
(m, 4H), 7.33 – 7.27 (m, 4H),), 1.54 (s, 6H); 13C NMR (101
MHz, CDCl3) δ = 174.11, 147.18, 135.74, 122.99, 122.36, 118.63
(q, J = 320.8 Hz), 44.30, 21.85; 19F NMR (377 MHz, CDCl3) δ
= -73.94; Anal. Calcd for C19H14F6N2O8: C, 39.59; H, 2.45; N,
4.86; S, 11.12. Found: C, 39.74; H, 2.69; N, 4.83; S, 11.14.
N-(2-(1,1,1,3,3,3-hexafluoropropan-2-yloxy)-4-methoxy)-
N’-(4-methylphenyl)-2,2-dimethylmalondiamide
(10b).
Electrolysis in set-up A yielded 58 mg colorless oil
1
(0.12 mmol, 58%): H NMR (400 MHz, CDCl3) δ = 8.88 (s,
1H), 8.22 (s, 1H), 8.22 (d, J = 9.0 Hz, 1H), 7.54 – 7.39 (m, 2H),
7.21 – 7.08 (m, 2H), 6.71 (dd, J = 9.0, 2.5 Hz, 1H), 6.61 (d, J =
2.3 Hz, 1H), 4.94 (hept, J = 5.5 Hz, 1H), 3.81 (s, 3H), 2.32 (s,
3H), 1.68 (s, 6H); 13C NMR (101 MHz, CDCl3) δ = 172.45,
170.29, 157.10, 147.90, 135.21, 133.99, 129.39, 123.29, 121.65 (q,
J = 280.9 Hz), 121.56, 120.01, 108.49, 101.96, 76.22 (hept, J =
33.8 Hz), 55.70, 50.87, 23.99, 20.83; 19F NMR (377 MHz,
CDCl3) δ = -74.63; HRMS for C22H22F6N2O4 (ESI+) [M+Na]+:
calc.: 515.1381, found: 515.1390.
1,2-bis-(4-mesylphenyl)-4,4-dimethylpyrazolidin-3,5-di-
one (5f). Electrolysis in set-up B with 0.31 mmol dianilide
in 8 mL HFIP (30 mg NBu4PF6) yielded 99 mg colorless
1
solid (0.21 mmol, 68%): mp 140.0-141.0 °C (EtOAc); H
NMR (400 MHz, CDCl3) δ = 7.44 – 7.38 (m, 4H), 7.33 – 7.27
(m, 4H), 1.52 (s, 6H); 13C NMR (101 MHz, CDCl3) δ = 174.28,
147.08, 134.92, 123.26, 122.91, 44.27, 37.57, 21.82; HRMS for
C19H20N2O5S2 (ESI+) [M+Na]+: calc.: 491.0559, found:
491.0566.
N-(4-(1-(1,1,1,3,3,3-hexafluoropropan-2-yloxy)-me-
thyl)phenyl)-N’-(4-trifluoromethylsulfonyloxyphenyl)-2,2-
dimethylmalondiamide (10c). Electrolysis in set-up A
yielded 45 mg colorless solid (0.07 mmol, 37%): mp 102.0-
103.0 °C (cyclohexane); 1H NMR (400 MHz, CDCl3) δ = 8.90
(s, 1H), 8.33 (s, 1H), 7.67 – 7.61 (m, 2H), 7.59 – 7.52 (m, 2H),
7.36 – 7.30 (m, 2H), 7.25 – 7.19 (m, 2H), 4.82 (s, 2H), 4.10
(hept, J = 5.9 Hz, 1H), 1.68 (s, 6H 13C NMR (101 MHz, CDCl3)
δ = 171.90, 171.29, 145.57, 137.69, 137.53, 131.35, 129.60, 121.97,
121.54, 121.51 (q, J = 284.5 Hz), 120.65, 118.71 (q, J = 320.5),
75.37, 74.26 (hept, J = 33.3 Hz), 50.91, 24.12; 19F NMR (377
MHz, CDCl3) δ = -73.95, -74.74; HRMS for C22H19F9N2O6
(ESI+) [M+H]+: calc.: 611.0898, found: 611.0916.
1,2-bis-(3-(1,1-dimethylethyl)phenyl)-4,4-dimethylpyra-
zolidin-3,5-dione (5g). Electrolysis in set-up A yielded 34
mg colorless oil (0.087 mmol, 43%): H NMR (400 MHz,
CDCl3) δ = 7.30 – 7.24 (m, 2H), 7.23 – 7.17 (m, 6H), 1.56 (s,
6H), 1.19 (s, 18H); 13C NMR (101 MHz, CDCl3) δ = 173.12,
152.09, 135.25, 128.57, 123.56, 120.06, 44.54, 34.70, 31.06, 21.81;
HRMS for C25H32N2O2 (ESI+) [M+Na]+: calc.: 415.2361,
found: 415.2366.
1
1,2-bis-(3,5-di(1,1-dimethylethyl)phenyl)-4,4-dime-
thylpyrazolidin-3,5-dione (5h). Electrolysis in set-up A
N-(4-chlorophenyl)-O-(1,1,1,3,3,3-hexafluoropropan-2-
yl)-2,2-dimethylmalonmonoamide (11). Electrolysis in set-
up A yielded 8 mg colorless oil (0.020 mmol, 10%): 1H NMR
(400 MHz, CDCl3) δ = 7.86 (s, 1H), 7.49 – 7.42 (m, 2H), 7.38
– 7.31 (m, 2H), 5.83 (hept, J = 6.0 Hz, 1H), 1.68 (s, 6H 13C
NMR (101 MHz, CDCl3) δ = 171.75, 167.77, 135.62, 130.12,
129.13, 121.60, 120.16 (q, J = 282.6 Hz), 67.25 (hept, J = 35.2
1
yielded 44 mg colorless oil (0.088 mmol, 44%): H NMR
(400 MHz, CDCl3) δ = 7.15 (t, J = 1.7 Hz, 2H), 7.03 (d, J = 1.7
Hz, 4H), 1.55 (s, 6H), 1.16 (s, 36H); 13C NMR (101 MHz,
CDCl3) δ = 173.00, 151.47, 134.30, 120.23, 117.69, 44.72, 34.84,
31.18, 21.79; HRMS for C33H48N2O2 (ESI+) [M+H]+: calc.:
505.3794, found: 505.3787.
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Journal of the American Chemical Society
All authors have given approval to the final version of the
manuscript.
1,2-bis-(4-chlorophenyl)-4,4-dimethyl-
tetrahydropyridazine-3,6-dione (2). Electrolysis in set-up A
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5
6
7
8
using 1 mmol dianilide in a 25 mL cell (25 mL HFIP, 100 mg
NBu4PF6) yielded 63 mg yellow solid (0.17 mmol, 17%): mp
211.0-211.8 °C; 1H NMR (400 MHz, DMSO-d6) δ = 7.52 – 7.46
(m, 2H), 7.44 – 7.40 (m, 2H), 7.39 – 7.34 (m, 4H) 2.93 (s,
2H), 1.24 (s, 6H); 13C NMR (101 MHz, CDCl3) δ = 173.22,
167.58, 136.33, 135.79, 132.49, 132.41, 129.10, 128.98, 125.58,
125.07, 43.38, 38.12, 23.49; HRMS for C18H1635Cl2N2O2 (ESI+)
[M+H]+: calc.: 363.0667, found: 363.0666.6-Chloro-2-(N-
(4-chlorophenyl)-1,1-dimethyl)propanamide-1,3-
ACKNOWLEDGMENT
T. G. is a recipient of a DFG fellowship by the Excellence
Initiative by the Graduate School Materials Science in Mainz
(GSC 266). The work done in the labs of KDM was supported
by the US National Science Foundation (CHE-1463913). The
support by The Advanced Lab for Electrochemistry and Elec-
trosynthesis – ELYSION (Carl Zeiss Stiftung) and the DFG
(WA 1276/17-1) is highly appreciated.
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benzoxazole (3a) and 6-Chloro-2-(N-(4-chlorophenyl)-2,2-
dimethyl)propanamide-1,3-benzoxazole (3b). Electrolysis
in set-up A using 1 mmol dianilide in a 25 mL cell (25 mL
HFIP, 100 mg NBu4PF6) yielded 55 mg red solid as a 3:1 mix-
ture of both isomers, whereby 3a is the main compound
ABBREVIATIONS
WE working electrode; RE reference electrode; CE counter
electrode; FcH Ferrocene.
REFERENCES
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(0.15 mmol, 15%): H NMR (400 MHz, CDCl3) δ = 9.14 (s,
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1H), 8.81 (s, 0.2H), 7.80 (s, 0.2H), 7.65 – 7.63 (m, 1H), 7.54
(d, J = 1.9 Hz, 0.7H), 7.40 – 7.37 (m, 2H), 7.35 (dd, J = 8.5,
1.9 Hz, 0.8H), 7.23 – 7.19 (m, 2H), 2.94 (s, 1.5H), 2.93 (s,
0.5H), 1.57 (s, 6H); 13C NMR (101 MHz, CDCl3) δ = 174.10,
172.91, 168.38, 168.15, 150.89, 149.31, 139.98, 138.90, 136.56,
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yielded 10 mg white solid (0.026 mmol, 13%): mp 150.0-
150.3 °C 1H NMR (400 MHz, CDCl3) δ = 7.90 (s, 1H), 7.89 –
7.85 (m, 2H), 7.72 – 7.67 (m, 2H), 7.60 – 7.54 (m, 1H), 7.52 –
7.47 (m, 2H), 7.40 – 7.35 (m, 2H) 4.85 (s, 2H), 4.12 (hept, J
= 6.0 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ = 165.75, 138.63,
134.70, 132.04, 130.55, 129.76, 128.85, 127.00, 121.57 (q, J =
284.5 Hz), 120.22, 75.43, 74.05 (hept, J = 32.7 Hz); HRMS for
C17H13F6NO2 (ESI+) [M+H]+: calc.: 378.0923, found:
378.0914.
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ASSOCIATED CONTENT
General information
Experimental and analytical details for the synthesis of test
substrates, symmetric dianilides, and mixed dianilides, NMR
spectra and crystallographic details (PDF)
Crystallographic data for 2 (CIF)
Crystallographic data for 3a (CIF)
Crystallographic data for 10c (CIF)
This material is available free of charge via the Internet at
http://pubs.acs.org.”
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AUTHOR INFORMATION
Corresponding Author
*waldvogel@uni-mainz.de
Author Contributions
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