Access to Pyrazolidin-3,5-diones through Anodic N–N Bond Formation

Article abstract of DOI:10.1002/anie.201603899

Pyrazolidin-3,5-diones are important motifs in heterocyclic chemistry and are of high interest for pharmaceutical applications. In classic organic synthesis, the hydrazinic moiety is installed through condensation using the corresponding hydrazine building blocks. However, most N,N′-diaryl hydrazines are toxic and require upstream preparation owing to their low commercial availability. We present an alternative and sustainable synthetic approach to pyrazolidin-3,5-diones that employs readily accessible dianilides as precursors, which are anodically converted to furnish the N?N bond. The electroconversion is conducted in a simple undivided cell under constant-current conditions.

Full text of DOI:10.1002/anie.201603899

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201603899
German Edition: DOI: 10.1002/ange.201603899
Pyrazolidin-3,5-diones
Access to Pyrazolidin-3,5-diones through Anodic N–N Bond Formation
Tile Gieshoff, Dieter Schollmeyer, and Siegfried R. Waldvogel*
Abstract: Pyrazolidin-3,5-diones are important motifs in
heterocyclic chemistry and are of high interest for pharma-
ceutical applications. In classic organic synthesis, the hydra-
zinic moiety is installed through condensation using the
corresponding hydrazine building blocks. However, most
N,N’-diaryl hydrazines are toxic and require upstream prep-
aration owing to their low commercial availability. We present
an alternative and sustainable synthetic approach to pyrazo-
lidin-3,5-diones that employs readily accessible dianilides as
patterns can require upstream steps with negative effects on
yield and efficiency.[7]
Recently, electroorganic chemistry has experienced a ren-
aissance in the field of preparative organic methodology.[8]
Conventional chemical oxidizers or reducing agents are
replaced by electric current as an inexpensive and sustainable
reagent. The generation of reagent waste can be avoided,
leading to improved atom economy. By combining these
advantages with long-lasting electrode materials, this method
can generally be considered as “green chemistry”.[9] More-
over, electrochemistry enables extraordinary reaction path-
ways that are not easily realized by conventional methods.[10]
Electroorganic conversions have also been established for the
generation of heterocyclic compounds.[11]
We present a preparative electroorganic route to 1,2-
diarylpyrazolidin-3,5-diones using an undivided cell equipped
with a very simple two-electrode arrangement. The reaction is
based on an oxidative cyclization reaction between the two
aryl-substituted nitrogen atoms of malonic dianilide deriva-
tives (Scheme 1). Therefore, an amidyl radical (3) as an
intermediate can be anticipated. The structure and reactivity
of amidyl radicals have been broadly investigated in the past
decades. They have mainly been explored in relation to
rearrangements and intramolecular hydroamination reactions
of alkenes.[12] As a challenge for the chemical community, the
efficient formation of these reactive intermediates has always
been of great interest. Especially in the past 15 years, much
work has focused on the conversion of non-activated amides
or relatives thereof.[13] Recently, the first electrochemical
approaches to amidyl radicals have been reported, either as
À
precursors, which are anodically converted to furnish the N N
bond. The electroconversion is conducted in a simple undi-
vided cell under constant-current conditions.
T
he discovery of pyrazolidin-3,5-diones dates back to Emil
Fischer, who identified them as condensation products of
malonic acid and phenylhydrazine in the late 19th century.[1]
After a more detailed study on synthetic routes and expansion
of the scope in the first decade of the 20th century, their
physiological effects were described in 1940 by Hans Ruh-
kopf, a pharmaceutical chemist.[2] He pointed out the
similarity of their biological profile to that of pyrazolones,
which were already known as analgesic, anti-inflammatory,
and antipyretic substances.[3] This research lead to the broad
application of N,N’-diarylpyrazolidin-3,5-dione derivatives as
analgesic drugs, with phenylbutazon as the most prominent
drug for rheumatism. Even though the market for these
compounds has decreased in the last decades owing to
undesired side effects, they still play a major role in veterinary
medicine. Moreover, possible applications for derivatives of
pyrazolidin-3,5-diones are still a hot topic in contemporary
research.[4] Consequently, novel methods for a modular access
to such heterocyclic systems are highly desired.
The retrosynthetic approach to pyrazolidin-3,5-diones is
based on an activated malonic acid derivative and an N,N’-
diarylhydrazine.[5] Although this can be an effective approach
for the synthesis of simple substrates, this approach exhibits
two major drawbacks. First, most hydrazine building blocks
are highly carcinogenic.[6] Therefore, extra safety arrange-
ments are required and up-scaling is problematic. Second,
only simple hydrazine derivatives are commercially available
and the use of derivatives with more-complex substitution
[*] T. Gieshoff, Dr. D. Schollmeyer, Prof. Dr. S. R. Waldvogel
Institute of Organic Chemistry
Duesbergweg 10-14, 55128 Mainz (Germany)
E-mail: waldvogel@uni-mainz.de
Homepage: http://www.chemie.uni-mainz.de/OC/AK-Waldvogel/
T. Gieshoff, Prof. Dr. S. R. Waldvogel
Graduate School Materials Science in Mainz
Staudingerweg 9, 55128 Mainz (Germany)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201603899.
Scheme 1. The conventional approach to pyrazolidin-3,5-diones and
our novel approach.
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direct oxidation or as a ferrocene-mediated process.[14] We
were able to use these electrogenerated intermediates for an
innovative and effective synthesis of pyrazolidin-3,5-diones.
Only few comparable coupling reactions of nitrogen moieties
are known for the electrochemical formation of alkyl
hydrazines, tetrazenes, and thiaziridine-1,1-dioxides, and the
anodic dimerization of carbazole derivatives.[10c,15] The start-
ing materials can be easily prepared in high yields starting
from malonyl chloride and the corresponding aniline deriv-
atives.[16] In contrast to N,N’-diarylhydrazines, a broad variety
of anilines is commercially available. To facilitate successful
conversion, 2,2-dimethylmalonyl dianilides (2a–m) were
used. The Thorpe–Ingold effect means that the smaller
angle between the coupling moieties facilitates the cyclization
tendency of these groups.[17]
0.5 mAcmÀ2 provided the best yields, and even slightly
elevated current density had a tremendous effect onto the
yield (Table 1). Interestingly, a low concentration of 0.01m of
the supporting electrolyte was beneficial and led to a slight
increase in yield (Table 2). These low concentrations of
Table 1: Influence of the current density on the yield of derivative 1a.[a]
Entry
Current density [mAcmÀ2
]
Yield[b] [%]
1
2
3
0.5
1
2
70
57
30
[a] 0.01m TBAPF6, anode: graphite, cathode: platinum. [b] 1H NMR yield,
standard: 2,4,6-triiodophenol.
The electrochemical oxidation of amides and related
substances is primarily known in the context of a Shono-type
oxidation. This reaction is well explored and is mainly used
for amidoalkylation reactions.[18] For N-aryl amides with no
abstractable hydrogen, several degradation reactions, which
are strongly dependent on the substitution pattern on the
aromatic ring, have been observed.[19]
Table 2: Influence of the supporting electrolyte concentration on the
yield of derivative 1a.[a]
Entry
Supporting electrolyte
concentration [molLÀ1
Yield[b] [%]
]
1
2
0.1
0.01
69
70
[a] TBAPF6, anode: graphite, cathode: platinum, current density:
0.5 mAcmÀ2. [b] 1H NMR yield, standard: 2,4,6-triiodophenol.
In initial screening experiments, several dianilides, sol-
vents, and electrode materials were evaluated. For a time-
efficient screening process, small undivided screening cells
made of Teflon were employed.[20] 2,2-Dimethyl-N,N’-di-(4-
methylphenyl)malonic diamide (2a) served as test substrate
for elaboration of the electrolysis conditions. Important
electrolysis parameters are current density, anode material
(graphite, boron-doped diamond, glassy carbon, or platinum),
cathode material (platinum, leaded bronze, graphite, or
nickel), and solvents, as well as supporting electrolytes at
different concentrations (TBABF4, TBAPF6, TBAClO4, trie-
thylmethylammonium methyl sulfate, and LiClO4; TBA =
tetrabutylammonium). First optimization studies were per-
formed in methanol, since it showed a favorable side-product
profile. However, high amounts of charge were necessary and
only low yields of under 10% were realizable in this system.
Moreover, most dianilides are poorly soluble in methanol.
After exploring various combinations of different dianilides,
solvents, and electrode materials, the use of 1,1,1,3,3,3-
hexafluoroisopropanol (HFIP) delivered promising yields
and a good solubility. In electroorganic studies, this particular
fluorinated solvent turned out to be outstandingly stable.[21]
The optimized electrolysis conditions are displayed in
Scheme 2.
supporting electrolyte facilitate the workup and lead to
a more sustainable atom economy. The solvent is quantita-
tively recycled by distillation to minimize the fluorine foot-
print. The cathode material exhibits significant influence onto
the anodic process. In comparison to graphite, platinum as
a cathode required a much lower applied charge for full
conversion to be reached. Additionally, only undivided cells
enabled this conversion, thus supporting the crucial role of
the cathode within the system. This beneficial effect is found
when the counter reaction or species generated facilitate the
overall transformation.[10d] Here, the specific nature of both
the solvent and the cathode material play a role: HFIP
provided the best results in combination with platinum
cathodes. The acidic character of HFIP (pKa = 9.3)[21d] in
combination with the low overpotential for hydrogen evolu-
tion at platinum cathodes leads to the generation of alcohol-
ate anions. This basic milieu facilitates the anodic oxidation of
amide nitrogen through prior deprotonation.
The elaborated electrolysis conditions were adapted to
a variety of substituted 2,2-dimethylmalonic dianilides, lead-
ing to a wide substrate scope for this novel electroorganic
transformation. (Scheme 3). The results indicate the general
nature of the method regarding the substitution pattern on
the aromatic ring. Most substrates could be converted in good
to excellent yields, and several heterofunctionalized substitu-
tions were tolerated, for example, fluoro (1g, 1j), chloro (1h,
1l), bromo (1k) and methoxy (1i) substituents. Moreover, the
reaction also tolerates the introduction of an additional
aromatic system to give a biphenyl substitution pattern (1 f).
Another interesting result is the successful conversion of two
non-symmetric substrates (1l and 1m) as a further argument
for the diversity of the method (Scheme 4). In particular, the
introduction of the bromo substitution (1m) broadens the
The optimization process revealed some interesting
features of the conversion. Low current densities of
Scheme 2. Anodic cyclization to 2,2-dimethyl-N,N’-(4-methylphenyl)-
pyrazolidin-3,5-dione.
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correlate with a more effective conversion. Specific stabiliza-
tion of the para position and the influence of oxidizable
benzylic positions seems to be more important. Substrates
with an unsubstituted benzylic position showed lower yields
in comparison to those with heteroatom-functionalized or
quaternary carbon atoms. The negative effect of additional or
more-stabilized benzylic positions is apparent from molecules
1a, 1c, 1e, and 1k. For derivative 1k, the bromo substitution
seems to have a further negative effect. Interestingly, ethyl
substitution (1b) increased the yield to 81% in comparison to
methyl substitution (1a, 52% yield) and 2-methylethyl
substitution (1c, 30% yield). A possible rationale in this
particular case is competition between steric effects and
stabilized benzylic positions.
Regarding the mechanism, two potential routes can be
postulated (see the Supporting Information). In accordance
with previous postulations for anodic oxidations, subsequent
oxidation and deprotonation of the amidic nitrogen atom is
conceivable.[14] In basic media, the presence of deprotonated
amide functionalities can be assumed at equilibrium. In
addition to oxidation at the anode, intramolecular nucleo-
philic attack of the other amide function is thereby facilitated.
A second option is the formation of a diamidyl radical species,
which forms the pyrazolidin-3,5-dione through recombina-
tion. The thermal homolytic cleavage of N,N’-diarylhydra-
zines is an equilibrium process.[22] This indicates an analogous
backward reaction between two amidyl radicals.
Dianilides with an unsubstituted para position or an ortho
methyl group failed under a broad spectrum of different
conditions owing to unselective degradation or oligomeriza-
tion. The fact that a change in the conditions had no effect on
the negative outcome of these reactions suggests a substrate-
induced obstacle. In most other solvents, only traces of
product were detectable and the dianilides were badly
soluble.
À
Scheme 3. Substrate scope of the electrochemical N N coupling to
give symmetrical pyrazolidin-3,5-diones.
In conclusion, we established a novel access to 1,2-
diarylpyrazolidin-3,5-diones without the need for toxic hy-
drazine building blocks. Combining the sustainability of
electrochemical conversions with easily accessible and inex-
pensive starting materials, this approach is a favorable alter-
native to the conventional methods. A broad substitution
pattern is tolerated and non-symmetric substrates can also be
converted. Naturally, further work needs to be done to
elucidate the mechanism.
Scheme 4. Successfully synthesized non-symmetric pyrazolidin-3,5-
diones. Center: molecular structure of derivative 1l by X-ray analysis.
Acknowledgements
scope for regioselective follow-up reactions. The exact
molecular structures of the derivatives were determined by
the substituents on the aromatic ring. While the planarity of
the heterocycle in substrates 1e, 1i, and 1l is distorted, the
pyrazolidin-3,5-dione system of derivative 1 f is planar.
Interestingly, one of the two biphenyl motifs of molecule 1 f
is propeller twisted, while the other one is not, thus leading to
an interesting packing pattern (the detailed structure is shown
in the Supporting Information).
T.G. is a recipient of a DFG fellowship by the Excellence
Initiative by the Graduate School Materials Science in Mainz
(GSC 266).
Keywords: electrochemistry · green chemistry · heterocycles ·
À
N N coupling · pyrazolidin-3,5-diones
Nevertheless, a tremendous effect of the substitution
pattern of the aromatic ring on the yield was observed.
Unexpectedly, activation of the aromatic ring does not
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Published online: && &&, &&&&
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Communications
Pyrazolidin-3,5-diones
T. Gieshoff, D. Schollmeyer,
S. R. Waldvogel*
&&&& — &&&&
Access to Pyrazolidin-3,5-diones through
Anodic N–N Bond Formation
Tying up loose Ns: A novel synthetic
easy and efficient access to N,N’-diary-
approach to pharmacologically relevant
lpyrazolidin-3,5-diones without the need
for N,N’-diarylhydrazines as building
blocks.
À
heterocycles through anodic N N bond
generation was established. Readily
accessible malonic dianilides provide an
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