Alternating Current Electrolysis as Efficient Tool for the Direct Electrochemical Oxidation of Hydroxamic Acids for Acyl Nitroso Diels–Alder Reactions

Article abstract of DOI:10.1002/anie.202107148

The acyl nitroso Diels–Alder reaction of 1,3-dienes with electrochemically oxidised hydroxamic acids is described. By using alternating current electrolysis, their typical electro-induced decomposition could be suppressed in favour of the 1,2-oxazine cycloaddition products. The reaction was optimised using Design of Experiments (DoE) and a sensitivity test was conducted. A mixture of triethylamine/hexafluoroisopropanol served as supporting electrolyte in dichloromethane, thus giving products of high purity after evaporation of the volatiles without further purification. The optimised reaction conditions were applied to various 1,3-dienes and hydroxamic acids, giving up to 96 % isolated yield.

Full text of DOI:10.1002/anie.202107148

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How to cite:
International Edition: doi.org/10.1002/anie.202107148
German Edition: doi.org/10.1002/ange.202107148
Electrosynthesis
Alternating Current Electrolysis as Efficient Tool for the Direct
Electrochemical Oxidation of Hydroxamic Acids for Acyl Nitroso
Diels–Alder Reactions
Jan Fꢀhrmann and Gerhard Hilt*
Abstract: The acyl nitroso Diels–Alder reaction of 1,3-dienes
with electrochemically oxidised hydroxamic acids is described.
By using alternating current electrolysis, their typical electro-
induced decomposition could be suppressed in favour of the
1,2-oxazine cycloaddition products. The reaction was opti-
mised using Design of Experiments (DoE) and a sensitivity test
was conducted. A mixture of triethylamine/hexafluoroisopro-
panol served as supporting electrolyte in dichloromethane, thus
giving products of high purity after evaporation of the volatiles
without further purification. The optimised reaction conditions
were applied to various 1,3-dienes and hydroxamic acids,
giving up to 96% isolated yield.
T
he Diels–Alder reaction is one of the most important
cycloaddition reactions in organic chemistry and was hon-
oured with the Nobel Prize in chemistry in 1950. Since then,
many new discoveries in its research field were reported,[1] for
instance the hetero Diels–Alder reaction as a direct variation
of its original but with hetero-atoms like N, O and/or S in the
diene or dienophile functionality.[2] Especially nitroso com-
pounds are interesting substrates for this reaction since the
obtained 1,2-oxazine unit is represented in biological active
molecules[3] or can be used as strategic intermediate in their
total synthesis, for example, in dihydronarciclasine.[4] Even
hydroxamic acids are suitable substrates for the nitroso Diels–
Alder reaction (NDA). Various oxidants can be used to
generate a short-lived acyl nitroso compound which can be
trapped by 1,3-dienes (Scheme 1).[5] By electrochemical
oxidation hydroxamic acids tend to decomposition under
anodic conditions, thus forming acylium cation intermediates
which react with various nucleophiles.[6] Recently, Han
published a method for the electrochemical cycloaddition of
N-phenylhydroxamic acids with alkenes for the synthesis of
benzo-1,2-oxazines (Scheme 1).[7] By N-arylation, the anodic
decomposition of the hydroxamic acid was suppressed and the
cycloaddition products could be isolated in high yields.
Scheme 1. Previous work in the oxidation of hydroxamic acids.
In this article, we present the direct electrochemical
oxidation of hydroxamic acids and the subsequent cyclo-
addition with 1,3-dienes. The rarely used alternating current
(AC) electrolysis[8] enabled the classic acyl NDA by electro-
oxidation for the first time (Scheme 1). Firstly, the readily
available benzohydroxamic acid (1a) and 3.0 equiv of 1,3-
diene 2a were electrolysed in a 0.1m solution of nBu4NBF4 as
supporting electrolyte in CH2Cl2.
The electrolysis was performed in an undivided cell with
platinum electrodes at 10 mA direct current (DC, Table 1,
entry 1). After 4.0 F, the conversion of the starting material
was complete, but only benzoic acid was formed by anodic
decomposition of the hydroxamic acid (Scheme 1). However,
when the same reaction mixture was electrolysed under
alternating current conditions (AC, 1.0 Hz) the cycloadduct
3a was obtained in 25% yield. By addition of hexafluoroi-
sopropanol (HFIP, 10%vol.)[9] the yield increased to 34%
(entry 2) and was further improved to 54% by the addition of
2.4 equiv of pyridine as base (entry 3). Lowering the current
of this reaction setup to 1.7 mA gave the maximum yield in
the preliminary tests of 79% (entry 4). Further optimisation
including variation of the solvent, the supporting electrolyte
and the electrode materials were performed (see Supporting
Information). When these pre-optimised reaction parameters
were used in a DC electrolysis, the oxazine 3a was formed in
[*] J. Fꢀhrmann, Prof. Dr. G. Hilt
Institut fꢁr Chemie, Universitꢀt Oldenburg
Carl-von-Ossietzky-Straße 9–11, 26111 Oldenburg (Germany)
E-mail: gerhard.hilt@uni-oldenburg.de
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202107148.
ꢂ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
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Table 1: Summarised optimisation experiments.
one for using AC and the other using DC to identify which
type of current (AC/DC) is more suitable for this reaction.
The DC experimental design was performed with a total of 21
experiments, whereas the AC design needed 31 experiments
to be fully resolved due to two additional parameters
(frequency and quiet time). Both designs were realised with
high precision (R2 = 0.97 AC and R2 = 0.95 DC) and have low
p-values (both < 0.01, Figure 1).
The optimum amount of HFIP is consistent for both
models and should ideally be about 20%vol. in CH2Cl2
(Figure 1). For the DC reaction, high electrolyte and base
concentrations gave the best results, indicating that a high
conductivity was necessary to obtain a high yield of the
oxazine. However, when AC was applied, the lowest possible
electrolyte concentration was best for a high generation of the
desired product with an ideal base concentration of 2.4 equiv-
alents. Both reactions run preferably at a low current,
however the AC electrolysis setup proved to be less sensitive
to a high current (compare entries 5–8, Table 1). When AC
was applied, a frequency of 20 Hz with no quiet time is
recommended.
Both reactions were performed at each optimised reaction
conditions to yield 95% at the optimised AC setup and 77%
at the DC reaction setup (entry 11). Both yields matched their
model predictions of 93% for AC and 75% for DC and thus
confirm the correctness of the models. Unfortunately, the
current of 1.0 mA at the optimised reaction conditions is
accompanied by long reaction times (107 h per mmol).
Therefore, it was necessary to increase the applied current
as far as reasonable with respect to the accompanying loss of
oxazine yield. Doubling the current to 2.0 mA in the DC
Entry
Yield[a] AC
Changes from initial conditions
Yield[a] DC
1
2
3
4
25%
34%
54%
79%
none
0%
0%
0%
10%vol. HFIP in CH2Cl2
entry 2 + 2.4 equiv pyridine
entry 3, but 1.7 mA
50%
Entry
Yield[a] AC
Changes from optimal conditions[b] Yield[a] DC
5
6
7
8
95%
95%
92%
79%
none
77%
59%
0%
n.d.
n.d.
n.d.
n.d.
2.0 mA current
5.0 mA current
10 mA current
9
low conductivity entry 7, no supporting electrolyte
10
11
91%
66%
entry 9, NEt3 instead of pyridine
entry 10, 1.5 equiv 1,3-diene 2a
The electrolysis was performed with 0.25 mmol hydroxamic acid 1a in
a total volume of 10 mL. Active surface of the Pt electrodes was 150 mm2
each. See Supporting Information for the complete list of optimisation
experiments. [a] Determined by GC-FID analysis of the crude reaction
mixture with n-dodecane as internal standard. [b] Optimal reaction
conditions were carried out by DoE (Figure 1 and Supporting Informa-
tion).
50% yield (entry 4). It seemed that AC is not indispensable
but has a positive impact on this reaction. For the optimisa-
tion of the numerical reaction parameters we applied the DoE
approach.[10] Here, we established two experimental designs,
Figure 1. Results of the reaction optimisation by DoE. See Supporting Information for the full evaluation of the DoE results.
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electrolysis already led to a relevantly reduced yield (59%,
entry 6), while 2.0 mA AC electrolysis did not reduce the
yield. When the current was further increased to 5.0 mA, the
yield at DC electrolysis dropped to 0%, whereas it remained
high at the AC reaction setup (92%, entry 7). Even 10 mA
AC could be applied and still 79% of oxazine 3a were
received. Overall, the AC electrolysis proved to be more
suitable for this reaction due to a higher oxazine yield, higher
economy in terms of electrolyte concentration and the higher
applicable current, leading to drastically reduced reaction
times. For the further investigations, 5.0 mA alternating
current were used as the best compromise between reaction
time and the product yield.
The results of the DoE proved, that the AC electrolysis is
best performed at a low concentration of the supporting
electrolyte, whereas omitting the electrolyte caused a too low
conductivity for a successful electrolysis (entry 9). A stronger
nitrogen-base than pyridine is able to partially deprotonate
HFIP, thus generating an electrolyte in situ and making the
addition of an external electrolyte dispensable.[9] Triethyl-
amine proved to be a suitable base for this reaction (see
Supporting Information), achieving a high conductivity with-
out a supporting electrolyte (91% yield, entry 10). Conse-
quently, the separation from the product is omitted as well,
because the solvent mixture can be removed under reduced
pressure. As shown in the crude NMR spectrum (Figure S38
and S39), oxazines of high purity can be received without any
purification steps if the 1,3-diene is volatile too. When the
excess of 1,3-diene was reduced to 1.5 equiv, a lower yield was
observed (66%, entry 11) and therefore 3.0 equiv of the 1,3-
diene was kept as standard.
The optimised reaction conditions were used to inves-
tigate the substrate scope utilizing 1a and various 1,3-dienes
(Scheme 2). The oxazine 3a was isolated in 85% yield on
a larger scale of 0.50 mmol. Subsequently, when isoprene (2b)
was added, the unsymmetrical 1,3-diene led to two regioisom-
ers of the oxazines 3b which were isolated in 66% as a 77:23
mixture of the distal and the proximal product. A possible
reason for the lowered yield with respect to 2a might be the
lower boiling point of isoprene and associated partial
evaporation of the 1,3-diene during the electrolysis. When
the less volatile 1,4-dimethyl substituted diene 2c was used,
the product yield of 3c remained high at 79%. Since penta-
1,3-diene also tends to evaporation, 1-cyclohexylbuta-1,3-
diene (2d) was used as model for a 1-monosubstituted 1,3-
diene. The branched product 3d was isolated in a good yield
of 86% with a distal to proximal ratio of 35:65. However, the
1,1-disubstituted diene 2e gave a moderate yield of 36% as
a single regioisomer (distal).[11] The oxazine 3 f was synthes-
ised from cycloocta-1,3-diene (2 f) and isolated in 82% yield,
confirming that cyclic 1,3-dienes can also be used for the
electrochemical acyl NDA. On the other hand, electron-rich
1,3-dienes (2g, 2i and 2j) with a phenyl- or oxygen-
substituent attached to the 1,3-diene could not be used for
this reaction, probably due to their low redox potential.[12]
However, aryl substituents are tolerated if the aromatic
substituent is not directly bound to the 1,3-diene functionality.
Thus, the 1,3-diene 2h afforded the oxaxine 3h in 67% yield
in a 50:50 distal to proximal ratio and even sorbic alcohol (2k)
Scheme 2. Substrate scope with varied 1,3-dienes. The electrolysis was
performed with 0.50 mmol hydroxamic acid 1a in a total volume of
10 mL. The active surfaces of the Pt electrodes were 150 mm2 each.
[a] Determined by integration of separated 1H NMR signals of the
crude reaction mixture. Bz=benzoyl, Cy=cyclohexyl.
could be used successfully to yield the distal-configured
oxazine 3k in 68% as a single regioisomer.
For the variation of the hydroxamic acids 1a–1k, diene 2a
was chosen as reactant due to its commercial availability and
the avoidance of distal-proximal product mixtures
(Scheme 3). In the first step, the electronic influence on
aromatic hydroxamic acids was investigated. When an
electron-withdrawing nitro-substituent was included in the
aromatic moiety, only traces of the oxazine 4a were observed
by GC-MS analysis. Since the oxazine 5a with an electron-
À
withdrawing CF3 group was isolated in a high yield of 89%,
the electrochemical reduction of the nitro group is a plausible
explanation for the low yield of 4a. Electron-rich arenes 1d
and 1e afforded similar yields compared to the unsubstituted
benzohydroxamic acid 1a (81% for 6a and 77% for 7a). In
contrast, the aliphatic hydroxamic acids gave the desired
products 8a–11a in moderate yields ranging from 41% to
64%. In these cases, steric hindrance seems not to be relevant
because the tert-butyl substituted product 10a was formed in
54%. The reason might be associated with less effective
deprotonation of the hydroxamic acids prior to oxidation (see
below). The hydroxyl carbamates 1j and 1k represent the
hydroxamic acid of the common protection groups Boc (1j)
and Cbz (or Z, 1k). These substrates are of special interest
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Scheme 4. Proposed reaction mechanism.
the electrochemical oxidation also reveals that a fast follow-
up deprotonation and a second oxidation towards the acyl
nitroso compound C are likely to happen.[16] Upon addition of
the 1,3-diene to this solution, only relatively small changes
were observed in CV. However, a drastic reduction of the
peak current and a shift of the peak potential was observed
when additional CVs were measured shortly thereafter. Thus,
electrode fouling is likely to occur under the increasing
oxidation potential of the CV, which might be similar to the
DC electrolysis over a short period of time. Accordingly, only
small current densities are acceptable when preparative DC
electrolysis were used for the NDA reaction to keep the
working electrode passivation on a low level. In contrast, AC
electrolysis has been applied in the past successfully to
remove passivating films from working electrodes[17] to set
higher current densities and minimise electrode fouling. From
our perspective, this seems to be a key point why AC gave
considerably better results over DC electrolysis in this case.
The need of 2.4 equivalents base can be rationalised by the
double deprotonation of the hydroxamic acid towards the acyl
nitroso intermediate and the formation of a HFIP-base
electrolyte. Also, HFIP as co-solvent might stabilise the
radical intermediate B, in analogy to the suggestions made by
Waldvogel.[18]
Scheme 3. Substrate scope with varied hydroxamic acids. The reaction
conditions are consistent to Scheme 2.
since cleavage of the amide bond in the product can be
realised easily to give the free oxazine for further manipu-
lations.[13] These hydroxamic acids were used to generate the
highly interesting oxazines 12a and 13a in good to excellent
yields (75% and 96%, respectively).
To identify the most influential parameters of the reaction
conditions and thus support the reproducibility of this
reaction, we performed a sensitivity test.[14] The results of
these manipulations are summarised in Figure 2. A large
In conclusion, we optimised the electrochemical acyl
NDA of benzohydroxamic acid (1a) with 2,3-dimethylbuta-
diene (2a) using DoE to obtain the desired 1,2-oxazine 3a in
95% yield. By using two different experimental designs we
compared the product formation using AC and DC, in which
alternating current electrolysis gave the best results and prove
to be much more robust at high current than the DC
electrolysis. The supporting electrolyte consisted of a volatile
solvent-base mixture so that the reaction products can be
isolated in high purity without purification after evaporation
of the solvent. Various hydroxamic acids and 1,3-dienes were
applied successfully whereas the application of electron-rich
1,3-dienes is limited by their lower oxidation potential.[12]
Figure 2. Sensitivity test of the electrochemical NDA reaction.
electrode surface led to a significant loss in productivity. Also,
the yield was lowered noticeably when the amount of base
varied from 2.4 equivalents. In particular, a low concentration
of base resulted in a greater loss of the product than a high
concentration. Little fluctuations in room temperature did
not have a significant impact on the product yield. The
reaction seemed to be not sensitive in terms of inert
conditions and applied current. The NDA reaction could be
performed under air without dried solvents since water and
oxygen and applied current had little impact (Æ 3–5% yield)
when differed by Æ 1.0 F.
Conflict of Interest
In a brief survey of electroanalytical control experiments
by cyclic voltammetry (CV, see Supporting Information) the
onset potential for the oxidation of 1a shifted from + 1.2 V to
+ 0.6 V (Pt electrodes vs. Ag/AgCl) by addition of NEt3.[15]
The deprotonation of 1a seems to lower the oxidation
potential considerably for the transformation from A to
a short-lived intermediate B (Scheme 4). The irreversibility of
The authors declare no conflict of interest.
Keywords: alternating current · cycloaddition · Diels–Alder ·
electrochemistry · nitroso compounds
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Manuscript received: May 28, 2021
Accepted manuscript online: July 7, 2021
Version of record online: && &&, &&&&
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Communications
Electrosynthesis
J. Fꢀhrmann, G. Hilt*
&&&& — &&&&
Alternating Current Electrolysis as
Efficient Tool for the Direct
Electrochemical Oxidation of Hydroxamic
Acids for Acyl Nitroso Diels–Alder
Reactions
Hydroxamic acids were electrochemically
oxidised to initiate acyl nitroso Diels–
Alder reactions with 1,3-dienes. By using
alternating current, their often encoun-
tered electrochemical induced decom-
position could be suppressed to generate
the desired cycloaddition products in up
to 96% yield. The optimisation of this
reaction was performed using the Design
of Experiments approach.
6
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