Synthesis of Highly Functionalized N,N-Diarylamides by an Anodic C,N-Coupling Reaction

Article abstract of DOI:10.1002/chem.201901442

We report an innovative, sustainable and straightforward protocol for the synthesis of N,N-diarylamides equipped with nonprotected hydroxyl groups by using electrosynthesis. The concept allows the application of various substrates furnishing diarylamides with yields up to 57 % within a single and direct electrolytic protocol. The method is thereby easy to conduct in an undivided cell with constant current conditions offering a versatile and short-cut alternative to conventional pathways.

Full text of DOI:10.1002/chem.201901442

A Journal of
Accepted Article
Title: Metal- and Reagent-free Synthesis of highly functionalized N,N-
Diarylamides by Anodic C,N-Coupling Reaction
Authors: Siegfried R Waldvogel, Maurice Dörr, Sebastian Lips, Carlos
Martínez-Huitle, Dieter Schollmeyer, and Robert Francke
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To be cited as: Chem. Eur. J. 10.1002/chem.201901442
Link to VoR: http://dx.doi.org/10.1002/chem.201901442
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Synthesis of highly functionalized N,N-Diarylamides by Anodic
C,N-Coupling Reaction
Maurice Dörr,[a] Sebastian Lips,[a] Carlos Alberto Martínez-Huitle,[a,b] Dieter Schollmeyer,[a] Robert
Franke,[c,d] and Siegfried R. Waldvogel*[a]
Abstract: We report an innovative, sustainable and straightforward
protocol for the synthesis of N,N-diarylamides being equipped with
non-protected hydroxyl groups by using electrosynthesis. The
concept allows application of various substrates furnishing the
diarylamides with yields up to 57% within a single and direct
electrolytic protocol. The method is thereby easy to conduct in an
undivided cell with constant current conditions offering a versatile and
short-cut alternative to conventional pathways.
Most recently, electrochemical synthesis of various bi-[11–13] and
terarylic[14] compounds were reported. Topically, in particular
electrochemical coupling reactions of phenols with heterocycles
offer an invaluable access to hetero biaryls with sometimes
unforeseen convenient reaction pathways.[15]
N,N-Bis(2-hydroxyphenyl)amides represent important structural
features for the synthesis of crown ether architectures,[1,2] and as
intermediates of active pharmaceutical ingredients (see scheme
1).[3] Current syntheses for these building blocks require so far
multi-step protocols involving copper-catalyzed reactions.[1,4] In
addition, leaving- and protecting groups at the phenol-hydroxyl
moiety are necessary to ensure a selective C,N-coupling process.
Thus, these elaborate multi-step protocols are time-consuming
and generate significant amounts of reagent waste. Due to
necessity of inert conditions, usually sophisticated reaction
conditions are required. A simple protocol that shortens the actual
multi-step-sequences would therefore be highly advantageous to
generate the desired compounds in a significantly shorter and
greener way.[5]
Organic electrochemistry has proven its great value for C,H bond
activation and even the formation of C,N bonds.[6, 7] Although it
should be mentioned that photochemistry offers an alternative to
that.[7, 8] While anodically conducted dehydrogenative coupling
reactions have emerged as a powerful tool for the formation of
new C,C bonds between aromatic systems.[9] Other electrode
materials such as graphite, glassy carbon, or platinum can also
be employed in such coupling reactions. However, boron-doped
diamond (BDD) is superior because of clean electron transfer.[10]
Scheme 1. Examples for relevant molecular architectures accessible from
N,N-diarylamides.[1-3]
By using these electrochemical conversions, only electric current
serves as an inexpensive and renewable reactant avoiding
occurring reactant waste and leading to an improved atom
economy. In addition, these conversions can be easily controlled
by switching on or off electric current, making them inherently safe
and scalable.[16] Lei and co-workers thereby reported a simple and
sustainable electrochemical protocol allowing the synthesis of N-
aryl phenothiazines from unprotected phenols and phenothiazine
derivatives.[17] Besides high yields for the second step of the ring-
opening reaction a reduction system of NiCl2·6 H2O and NaBH4 is
required leading to only low-functionalized triarylamines and a
limited substrate diversity.
[a]
[b]
M. Dörr, S. Lips, Carlos Alberto Martínez-Huitle, Dr. D.
Schollmeyer, Prof. Dr. S. R. Waldvogel
Institut für Organische Chemie
Johannes Gutenberg-Universität Mainz
Duesbergweg 10–14, 55128 Mainz (Germany)
E-mail: waldvogel@uni-mainz.de
Homepage: http//www.chemie.uni-mainz.de/OC/AK-Waldvogel/
Prof. Dr. Carlos Alberto Martínez-Huitle
Universidade Federal do Rio Grande do Norte,
Instituto de Química, Avenida Senador Salgado Filho, 3000
Campus Universitario, Lagoa Nova, Natal, 5907800, RN (Brazil)
Prof. Dr. R. Franke
In this case, we present the first example of an electrochemical
access to highly functionalized N,N-diarylamides.
[c]
[d]
Evonik Performance Materials GmbH
Paul-Baumann-Straße 1, 45772 Marl (Germany)
Prof. Dr. R. Franke
Lehrstuhl für Theoretische Chemie, Ruhr-Universität Bochum
44780 Bochum (Germany)
Supporting Information for this article is given via a link at the end
of the document.
Scheme 2. General schematic overview of reported electrochemical conversion.
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10.1002/chem.201901442
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available or were easily synthesized according to standard
procedures,[25] allowing a fast conduction of this transformation
(see Supporting Information).
The protocol avoids the use of metals, exclusion of moisture and
anaerobic reaction conditions, thus opening up a cost-efficient
and environmentally friendly alternative to existing multi-step
synthetic routes. By using readily accessible benzoxazoles and
phenols the reaction can be conducted by a simple and direct
electrolysis.
The electrolysis can be performed in an undivided cell equipped
with a simple two-electrode arrangement using galvanostatic
conditions. Evaluation of electrochemical parameters was
conducted within several initial screening experiments in small
Teflon cells.[18] Thereby, 5-methylbenzoxazole and 2-(1,1-
dimethylethyl)-4-methoxyphenol served as test substrates for
elaboration of electrolytic conditions, such as current density,
amount of charge, equivalents as well as supporting electrolytes
at different concentrations.
As a key for success of our coupling reaction we use 1,1,1,3,3,3-
hexafluoroisopropanol as solvent, whose stabilizing effect on
generated reactive intermediates, such as radicals or radical
cations, is known since the 1990s.[19] It was found by our group
that this is due to HFIPs capability to build up strong hydrogen
bonding networks.[10] In addition, it is outstandingly stable under
electrolytic conditions.[20] Furthermore, due to the solvent-
modulated nucleophilicity of the individual substrates, HFIP is
also the source of the striking selectivity of anodic coupling
reactions.[21] Current studies reveal an even more complex picture
of HFIP as a solvent. Thereby, the fluorous alcohol is capable in
forming nano-domains leading to a separation of hydroxyl groups,
protic additives and fluorinated alkyl moieties.[22] This unusual
microheterogeneous feature can also be transferred to the
outstanding source of selectivity for anodic coupling reactions.
Full recovery and recycling HFIP by simple distillation and the
above mentioned advantages of missing reagent waste,
designate this transformation also as an attractive method in
ecological and economical terms.[23]
Applying the optimized electrolysis parameters, the following
scope of bis(N,N-hydroxyphenyl)carboxamides was isolated.
As indicated in Scheme 3 various substrates for the developed
conversion were applied. With regard to the benzoxazoles as
starting materials, a broad variety of the substitution pattern lead
to a successful conversion. In particular, the high variability of R3
of the initial benzoxazole allowing access to different lengths of
alkyl chains for the corresponding amides is remarkable.
Scheme 3. Scope of synthesized bis(N,N-hydroxyphenyl)carboxamides.
Electrolytic conditions: constant current (j = 7.2 mA/cm2), BDD electrodes,
undivided beaker-type cell, ratio A/B = 1:3.
For the conducted electrolyses, no formation of homo-coupling
products, were observed by gas chromatography from the crude
mixture. However, uncontrolled formation of non-defined high-
molecular products cannot be fully excluded. Never the less, non-
converted substrates can be recovered entirely as part of the final
column chromatography.
The reported conversion is based on an oxidative interceded C,N
coupling reaction between position 2 of the phenol and the
nitrogen in position 3 of the benzoxazole probably leading to a
cyclisation reaction furnishing
a
hydrobenzoxazolo[2,3-
b]benzoxazole intermediate by an intramolecular attack. The final
product is generated by simple hydrolytic workup. We anticipate
that this step is already occurring, when the crude product is in
first contact with silica containing absorbed water. Mass
spectrometry studies conducted directly after electrolysis indicate
the formation of this hydrobenzoxazolo[2,3-b]benzoxazole
intermediate. Further investigations by NMR spectroscopy
additionally demonstrate formation of the H NMR signal for the
formamide, which is absent directly after performed electrolysis.
For further details please see Supporting Information.
Figure 1. Scope of different amides.
In addition, for R2 even the use of halo substituents at the initial
benzoxazole leading to products 6 and 8 are compatible enabling
potential subsequent reactions using conventional cross-
coupling reactions.[24]
1
The tolerance of tert-butyl moieties, that play a decisive role for a
later catalytic application, seem to be suitable as well since they
are usually not compatible with strong electrophilic conditions.
The corresponding benzoxazoles were either commercially
For the C,N-coupling reaction, we propose an initial oxidation of
the phenol component leading to a phenoxyl radical. This radical
is attacked by the nitrogen atom of the benzoxazole leading to the
formation of an inner salt. By an intramolecular attack of the
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nucleophilic phenolic oxygen, formation of the proposed
intermediate can be rationalized. Conducted CV measurements
underline by the fact that applied phenols exhibit a lower oxidation
S.R.W. thanks the DFG (Wa1276/14-1) for financial support. S.L.
and S.R.W. acknowledge the Carl-Zeiss Foundation for granting
a fellowship and the research network ELYSION, respectively.
potential than the corresponding benzoxazoles.
A similar
mechanistic rationale has already been reported for several
published anodic C,C cross-coupling reactions.[11-14] Thus, an
extraordinary reaction pathway, which would not be easy to
realize by conventional methods, enables access to highly
functionalized mixed N,N-diarylamides by simply choosing a
Keywords: C,N-coupling • electrochemistry • C-H activation •
oxidation • sustainable chemistry
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Figure 2. Scaling-up of electrochemical coupling reaction. 25 mL beaker-type
cell (left), 200 mL beaker-type cell (right).
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Easy scalability of this protocol was proven by a scale-up
experiment from a 25 mL beaker-type electrolysis cell (using
5.00 mmol A and 15.0 mmol B) to a 200 mL beaker-type cell (40.0
mmol A and 120 mmol B) was performed. Application of the same
electrolytic protocol provides 4 in an even higher yield of 51%
(6.77 g) confirming clear evidence of an easy scalability of this
protocol. General set-up is shown in Figure 2. More detailed
information can be found within the Supporting Information.
We herein present the first direct approach to bis(N,N-
hydroxyphenyl)amides by an anodic dehydrogenative coupling
reaction. Compared to other protocols, in this case no metal- and
multi-step-sequences or protecting groups are required leading to
a short-cut in synthesis. Due to the simple set-up using an
undivided cell with a two-electrode arrangement, the protocol is
even attractive with moderate yields up to 57%.
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Experimental Section
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M. Dörr, S. Lips, C. A. Martínez-Huitle,
D. Schollmeyer, R. Franke, and S. R.
Waldvogel*
Page No. – Page No.
Metal- and Reagent-free Synthesis of
highly functionalized N,N-
Diarylamides by Anodic C,N-Coupling
Reaction
Electrochemical, dehydrogenative C,N coupling can be conducted in a simple
undivided cell, is scalable and inherently safe providing highly substituted
diarylamides.
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