Electrochemical synthesis of benzoxazoles from anilides-a new approach to employ amidyl radical intermediates

Article abstract of DOI:10.1039/c7cc00927e

A novel electrochemical method for the synthesis of benzoxazoles from readily available anilides is reported. Various functionalities are tolerated and good yields can be achieved. By employing common electrode materials and a simple constant current protocol, this method is an attractive new alternative to conventional pathways.

Full text of DOI:10.1039/c7cc00927e

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Kehl, D. Schollmeyer, K. D. Moeller and S. R. Waldvogel, Chem. Commun., 2017, DOI:
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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
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DOI: 10.1039/C7CC00927E
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Electrochemical Synthesis of Benzoxazoles from Anilides – A New
Approach to Employ Amidyl Radical Intermediates
Tile Gieshoff,a,b,c Anton Kehl,a Dieter Schollmeyer,a Kevin D. Moellerc and Siegfried R.
Received 00th January 20xx,
Accepted 00th January 20xx
Waldvogel*a,b
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel electrochemical method for the synthesis of benzoxazoles reaction pathways.5,6 This combination of sustainability and
from readily available anilides is reported. Various functionalities mechanistic opportunity has led to the recent development of
are tolerated and good yields can be achieved. By employing a variety of valuable electrolysis protocols.5,7,8–10
common electrode materials and a simple constant current
Here, we report the first direct, reagent-free electroorganic
protocol, this method is an attractive new alternative to synthesis of benzoxazoles based on alkyl and aryl anilides in a
conventional pathways.
simple electrochemical set-up cell (Scheme 1). The reaction
employs easily accessible starting materials, inexpensive
electrode materials, and a low concentration of supporting
electrolyte. The result is a synthetically attractive alternative to
conventional methods for synthesizing the target structure. We
anticipate that amidyl radicals act as intermediates, which are
directly generated at the anode.5,10 The efficient formation of
amidyl radicals has been of great interest for the chemical
community.11 Their structure and reactivity has been mostly
explored in the context of rearrangements and hydroamination
reactions.8,12
Benzoxazoles represent an important structure in
heterocyclic chemistry and are key motifs of several natural
products, pharmaceuticals, and biologically active compounds.1
Thus, they are a significant topic of contemporary research, and
efficient synthetic strategies starting from simple starting
materials are highly desired. Traditionally, benzoxazoles have
been synthesized by treating 2-aminophenols with activated
acids or aldehydes under oxidative conditions.2 In recent years,
this approach has been complemented by methods capitalizing
on anilide or benzoxazole core scaffolds that can be employed
as substrates in a variety of coupling reactions. Coupling
strategies using substrates prefunctionalized with a leaving
group and capitalizing on CH-activation have been reported.3
The use of electrochemistry can offer a mechanistically
distinct and significantly sustainable approach to
benzoxazoles.4 In addition, this method can be considered as
inherently safe. In an electrochemical reaction, electric current
serves as an inexpensive and potentially renewable reagent that
avoids the need to a stoichiometric redox reagent. This both
minimizes the waste produced in the reaction and removes the
limitations on redox potential associated with every chemical
reagent. This later point is important because it enables
electrochemical reactions to readily access extraordinary
Scheme 1 Electrochemical synthesis of benzoxazoles.
The transformation illustrated in Scheme 1 was discovered in
the course of our studies concerning the electrochemical
formation of N,N bonds.5 The addition of an amidyl radical to a
neighbouring aryl ring was observed in cases wherein the
desired N,N bond formation was slow. In these cases, a mixture
of N,N bond coupling and the formation of benzoxazoles was
obtained. The mixture issue was quickly resolved by using
monoanilides in order to exclude the intramolecular N,N bond
formation.
a.Institute of Organic Chemistry, Johannes Gutenberg University Mainz,
Duesbergweg 10-14, D-55128 Mainz, Germany. E-mail: waldvogel@uni-mainz.de
b.Graduate School Materials Science in Mainz, Staudingerweg 9, D-55128 Mainz,
Germany.
c. Department of Chemistry, Washington University in St. Louis, St. Louis, Missouri
63130, United States.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
N-(4-Chlorophenyl)benzamide (1a) was then chosen as a test
substrate for optimization studies. The aromatic substitution
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pattern was known to afford high yields for reactions leading to With the optimized electrolysis conditions in hand, the scope of
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N,N bond formation,5 a scenario that suggested the systems this electrosynthetic method was elucidaDteOdI:.10.1039/C7CC00927E
compatibility with the formation of a reactive amidyl radical.
When the reaction was screened for its compatibility with
different electrolyte systems,13 only the use of
hexafluoroisopropyl alcohol (HFIP) as a solvent enabled the
desired formation of the benzoxazole. Methanol and other
solvents commonly applied in electrochemical transformations
lead to degradation of the anilides, even though conventional
and electrochemical reactions of amidyl radicals in methanol
are described in literature.8–10,14 This result suggested that the
cyclization was slow and thus required sufficient stabilization by
the solvent. HFIP is able to effectively stabilize radical
intermediates.15 The almost quantitative recovery of this
particular solvent (b.p. 56 °C) allows minimization of the
fluorine footprint.5,16 By employing a low concentration of
tetrabutylammonium hexafluorophosphate (0.01 M) as
supporting electrolyte, the atom economy and work-up are
significantly improved.
Electrochemical reactions are usually sensitive to the current
density applied and the electrode geometry.10 Hence, we
optimized the applied current for the two most commonly used
laboratory scale electrochemical set-ups. Set-up A relies on a
25 mL three-necked flask, wherein a reticulated vitreous carbon
(RVC) anode and a platinum wire cathode are placed angular to
each other. Set-up B is a beaker-type cell with a flat isostatic
graphite anode and a platinum plate cathode, which are
orientated parallel to each other.5 The latter provides a more
defined and homogenous electric field. More detailed
information about both reaction setups can be found within the
supporting information.
Table 1 Optimization of electrolysis parameters
Scheme 2 Scope. A: Set-up A, B: Set-up B.
Several valuable functionalities are tolerated by the method
leading to the synthesis of a variety of benzoxazoles in good to
very good yield. Electron donating substituents on either the
amide or the anilide part of the substrate have a beneficial
Entry
Set-upa
j [mA/cm2]
I [mA]
1.1
4.1
8.4
Isolated yield [%]
1
2
3
4
5
6
7
8
A
A
A
A
B
B
B
B
-
-
-
31
54
56
49
50
53
66
57
effect onto the yield (2b, 2g and 2h). In addition, typical leaving
group functionalities are also tolerated. In particular, chloro and
triflate moieties are compatible with the reactions opening up
the opportunity to further functionalize and diversify the
scaffolds make using an assortment of subsequent
transformations, i.e. cross-coupling reactions. On the amide
part of the substrate, aromatic systems and quaternary alkyls
-
12.4
1.3
1.9
2.5
5.0
-
-
-
-
a Set-up A: 25 mL three-necked flask, RVC (100 PPI) anode, platinum wire cathode,
0.4 mmol substrate, 0.01 M TBAPF6 in 10 mL HFIP, amount of charge = 2 F; Set-up
B: beaker-type cell, isostatic graphite anode, platinum cathode, 8 cm2 electrode
surface, 1.0 mmol substrate, 0.01 M TBAPF6 in 25 mL HFIP, 2 F amount of charge.
are tolerated, while
degradation processes. The different anilides were converted
with both electrolysis set-ups and . The respective yields for
these set-ups were compared using substrates 1a and 1b. The
formation of 2a afforded a higher yield using set-up , while the
α hydrogens lead to unselective
A
B
B
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formation of 2b proceeded better with set-up
about this finding deserve comment. First, note that both substantial radical nature. This observation is supported by
setups generated product and could be used to determine the experimental data. An aryl radical would be expected to
synthetic potential of the reaction. So, for exploratory purposes undergo significant coupling chemistry at the position para to
the nature of the reaction setup is not important. However, the amidyl group. In practice, this occurs, and a substituent is
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A
. Two points The proposed mechanism suggests that the aromatic ring has
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DOI: 10.1039/C7CC00927E
when optimizing the reactions the observations underscore the required at the para-position of the N-substituted aryl-ring in
5
need to pay attention to electrochemical conditions. order to prevent side reactions at this position.
The
Electrochemical reactions depend not only on how the reactive mechanism also explains why electron-releasing substituents
intermediates are generated, but also on how those on the ring favor the observed reaction since they both aid in
intermediates interact with the chemical environment the oxidation steps and stabilize the intermediate radical.
immediately surrounding the electrode, diffuse away from the Interestingly, if an ortho position is blocked by a substituent in
electrode involved in their generation, and the gradient of the substrate, no product is formed. Evidently, a substituent in
chemical environments encountered during that diffusion this position prevents rotation along the carbon nitrogen bond
process. All of these things depend on the nature of the to generate the planar orientation required for resonance of the
electrochemical field in the cell, a field that relies on electrode N-based radical into the aromatic ring.19
configuration, spacing, etc. The point is simple. If the yield of a
In conclusion, we have developed a straightforward and
desired electrochemical reaction is lower than one might sustainable electrochemical synthesis for the direct
prefer, then one should look at alterations of the electrolysis construction of benzoxazoles from easy accessible anilides. A
set-up and the electrode geometry as one means of influencing variety of functional groups are tolerated by the reaction, and
that yield.
these groups a well-positioned to enable further synthetic
Regarding the mechanism of the transformations observed, manipulation of the products. The comparison of the two most
we propose that oxidation of the substrate leads to an amidyl commonly used electrolysis set-ups in synthetic labs
radical that is stabilized by the neighboring aromatic ring by demonstrate that the method can be readily adopted by others.
resonance.17 This first oxidation step might be facilitated by
deprotonation of the amide via in-situ generated alcoholate T.G. is a recipient of a DFG fellowship by the Excellence Initiative
anions derived from HFIP at the cathode. Bond formation by the Graduate School Materials Science in Mainz (GSC 266).
between the amidic oxygen and the ortho carbon of the The work done in the labs of KDM was supported by the US
aromatic ring leads to the formation of a heterocyclic radical. A National Science Foundation (CHE-1463913).
second oxidation followed by the loss of a proton then
completes product formation. It is also possible that the
reaction proceeds through a second oxidation that occurs prior
Notes and references
to the cyclization followed by an electrocyclic oxa-Nazarov-type
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