Intramolecular Electrochemical Oxybromination of Olefins for the Synthesis of Isoxazolines in Batch and Continuous Flow

Article abstract of DOI:10.1002/ejoc.202100640

A highly regioselective protocol for the synthesis of isoxazolines through cascade C?O and C?Br bond formation has been developed. The electrochemical approach uses traceless electrons as a sole source of oxidant, thus avoiding the use of stoichiometric o

Full text of DOI:10.1002/ejoc.202100640

Communications
doi.org/10.1002/ejoc.202100640
Intramolecular Electrochemical Oxybromination of Olefins
for the Synthesis of Isoxazolines in Batch and Continuous
Flow
Ajit Prabhakar Kale+,[a] Pavlo Nikolaienko+,[a] Kristina Smirnova,[a] and Magnus Rueping*[a]
A highly regioselective protocol for the synthesis of isoxazolines
through cascade CÀ O and CÀ Br bond formation has been
developed. The electrochemical approach uses traceless elec-
trons as a sole source of oxidant, thus avoiding the use of
stoichiometric organic or inorganic oxidants and provides a
mild and environmentally benign alternative pathway for the
synthesis of a wide range of valuable substituted isoxazolines
from alkenyl oximes in good yields.
Synthetic organic chemistry is considered a fast-developing
field in science as it continuously provides new routes towards
the synthesis of novel materials via green, sustainable, and
economical techniques.[1,2] Electrochemical synthetic methods
have gained increasing attention since they provide mild
conditions, good functional group tolerance, high regioselectiv-
ity and chemoselectivity, and reduced waste by avoiding costly
oxidants or reductants in favor of electricity.[3]
Figure 1. Examples of 2-isoxazoline containing biologically-active molecules.
Nitrogen-containing heterocycles are important building
blocks and part of many commercial products. Among them,
isoxazolines are an important class of heterocyclic compounds
and their derivatives are frequently found in a wide range of
natural products, biologically active compounds, agrochemicals,
and pharmaceuticals.[4,5] (Figure 1) Moreover, isoxazolines can
serve as versatile synthetic intermediates in organic
chemistry.[6–11] Therefore, the development of sustainable
methods providing isoxazolines and their derivatives remains
an important target for synthetic organic chemists. Approaches
for their synthesis range from the use of the 1,3-dipolar
cycloaddition reactions of nitrile oxides with allyl halide[12,13] to
oxyhalogenation of allylic oximes.[14,15]
In many instances, these methods not only require the use
of transition metal catalysts, high temperature or toxic, costly,
organic or inorganic oxidizing agents but also suffer from low
to moderate yields. However, progress in the oxyhalogenation
reaction has been made recently and examples include Pd,[15a]
Fe[15b] Cu,[15c] or Al[15d] or TBHP[15e] mediated protocols. Further-
more, molecular bromine was applied in the cyclization, albeit
with varying yields and the observation of side reactions.[15f]
Hence, the development of a simple, economically viable, and
complementary environmentally friendly way to access isoxazo-
lines is desirable. Based on our interest in synthetic
electrochemistry,[16] we decided to explore the electrochemical
oxyhalogenation for the synthesis of bromomethyl substituted
isoxazolines starting from allylic oximes, although being aware
that the base mediated electrochemical oxime cyclization via
the formation of oxime radicals[17] leads to the unwanted
isoxazoles.[18] However, by choice of an electrolyte that also acts
as the halogen source, the desired bromomethyl substituted
isoxazolines could be accessible.
Readily available β,γ-unsaturated ketoxime 1a was therefore
chosen as our model substrate and potassium bromide as both
electrolyte and source of bromine to reduce waste production.
We decided to use an undivided cell with a graphite anode and
a stainless-steel cathode. Initially, different reaction parameters
were evaluated (Table 1). The use of solvents such as MeOH,
gave a trace amount of product (Table 1, entry 1), and THF, or
dioxane yielded no detectable product (Table 1, entry 2). A
mixture of MeCN:H2O (3:1) provided two cyclization products
2a and 3a in a 3:2 ratio (Table 1, entry 3).
Changing the solvent to DMSO:H2O increased the yield to
85% (Table 1, entry 4). Furthermore, increased current density
resulted in better yield (Table 1, entry 5, 6). The best conditions
proved to be 70 mA/cm2 for 20 min and provided the product
in 95% GC yield and 74% isolated yield. Further increasing
current density to 100 mA/cm2 did not give a better yield
(Table 1, entry 7). Using neat DMSO or DMF resulted in lower
[a] Dr. A. Prabhakar Kale,+ Dr. P. Nikolaienko,+ K. Smirnova,
Prof. Dr. M. Rueping
KAUST Catalysis Center (KCC)
I King Abdullah University of Science and Technology (KAUST)
Thuwal 23955-6900, Saudi Arabia
E-mail: magnus.rueping@kaust.edu.sa
[+] These authors contributed equally to this work.
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Table 1. Optimization of Reaction Conditions.[a]
Entry
J
Base
Solvent
Time
GC Yield
[%]
[mA/cm2]
1
2
3
10
10
10
–
–
MeOH
THF:Dioxane
MeCN:H2O
4 h
4 h
4 h
trace
nr
51
NaOAc·3H2O
2a:3a
85
86
95
92
52
44
40
4
5
6
7
8
9
10
11
12[b]
13[c]
10
30
70
100
10
10
10
–
NaOAc·3H2O
NaOAc·3H2O
NaOAc·3H2O
NaOAc·3H2O
NaOAc·3H2O
NaOAc·3H2O
–
NaOAc·3H2O
NaOAc·3H2O
NaOAc·3H2O
DMSO:H2O
DMSO:H2O
DMSO:H2O
DMSO:H2O
DMSO
5 h
1 h
20 min
20 min
4 h
4 h
4 h
4 h
20 min
DMF
DMSO:H2O
DMSO:H2O
DMSO:H2O
DMSO:H2O
nr
86
89
70
70
20 min
[a] Reaction conditions: graphite anode, stainless steel cathode, 1a
(1.0 equiv., 0.2 mmol, 0.05 M), KBr (5 equiv., 1.0 mmol), NaOAc·3H2O
(0.5 equiv., 0.1 mmol), DMSO:H2O (7:1) 4 mL, rt=room temperature,
CCE=Constant Current Electricity J (mA/cm2), Yields were determined by
CC using benzoxazole as an internal standard. All reactions are performed
under air. [b] Graphite is used as cathode instead of Stainless Steel. [c]
Reaction is performed under argon. nr=no reaction.
yields of the desired product (Table 1, entry 8,9). Addition of
base NaOAc·3H2O remained crucial, and without base, the
reaction yield decreased to 40% (Table 1, entry 10). Electric
current was also essential for the reaction to take place (Table 1,
entry 11). Reaction worked fine under Argon atmosphere giving
product in 86% yield. Other electrode materials such as silver,
copper, glassy carbon, and RVC resulted in diminishing yields.
During the reaction, we did not observe a significant increase in
solution temperature. No noticeable degradation or fouling of
electrodes was witnessed and the same electrodes were used
after a simple cleaning procedure (See supporting information).
We further explored the effect of concentration on the reaction
mixture. To our delight, we achieved a good yield of desired
product 2a with a 5-fold increase of substrate concentration to
0.25 M. Similar yields were obtained when other electrolytes
and bromine sources such as tetrabutylammonium bromide
were used.
Given the good shelf life of potassium bromide, we decided
to use it in all further experiments. However, other halide
sources such as potassium iodide and tetrabutylammonium
chloride can also be used and provide the iodo- and chloro-
substituted 2-isoxazolines as products. With the optimized
reaction conditions in hand, we started to explore the substrate
scope by using a variety of substituted allylic oximes. The
substrate scope was found to be rather general (Scheme 1).
Different allylic ketoximes can be applied and provide the
corresponding isoxazolines in good yields (2a-d). Substrates
with more sensitive functional groups, such as allyloxy ether or
methylenedioxy substitution were readily converted into the
desired products (2k) and (2l), respectively. Halogen substitu-
Scheme 1. Substrate Scope of 2-Isoxazolines.- Reaction conditions: graphite
anode, stainless steel cathode, 1a (1.0 equiv., 0.2 mmol, 0.05 M), KBr (5 equiv.,
1.0 mmol), NaOAc·3H2O (0.5 equiv., 0.1 mmol), DMSO:H2O (7:1) 4 mL,
current density=70 mA/cm2 (4.3 F/mol), rt=room temperature, time
t=20 min. All reactions are performed under air.
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ents such as iodo (2e), bromo (2f), chloro (2g) and fluoro (2h)
To further gain information about reaction mechanism, we
treated the allylic oxime 1a, under the standard reaction
conditions in the presence of radical scavenger 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO). However, no product
was detected, implying that a radical process is involved in the
catalytic cycle. We also performed another experiment with 1,1-
diphenylethylene under standard reaction conditions and we
successfully detected 5 in GCMS which supports the participa-
tion of bromine radical in the reaction mechanism (Scheme 2).
Based on our observations a plausible mechanism is
proposed in Scheme 3. In the bromide-mediated electrochem-
ical reaction, electro-oxidation of bromide (BrÀ ) at the anode
leads to the formation of bromine, which is immediately
captured by excess bromide (Br ) to generate tribromide (Br3 )
anion. The latter reacts with DMSO to form intermediate A (See
supporting information Figure S6A and Figure S6B for more
information).[19] Subsequently, A reacts with C=C double bonds
to form B which further undergoes an intramolecular cyclization
via nucleophilic attack of À OH of allyl ketoxime to form 2a.
Alternatively, A could react with 1a to form a bromonium
intermediate C which can react to 2a via 5-exo-trig cyclization
(path a). There is also the possibility of a 6-endo-trig cyclization
which leads to by-product 3a (path b). The evolution of
molecular hydrogen (H2) gas was observed at the cathode due
to electrochemical water reduction. This reaction also generates
an in-situ base needed for the oxime deprotonation.
remained untouched, and desired products were isolated in
good yields. Reactants with electron-donating groups such as
methoxy (2i, 2j, 2n) and amines (2m) also reacted smoothly.
Trifluoromethyl groups are of great interest in medicinal and
agrochemical sciences. We are delighted to see that the CF3
group was also tolerated during the reaction to produce 72%
product (2p) yield. The reaction conditions were also suitable
for substrates bearing heterocyclic aromatics such as furan (2s),
and thiophene (2r, 2t). The 2-bromo-substituted 2-isoxazolines
are also useful precursors for nucleophilic substitution reactions
to synthesize valuable products as previously demonstrated.[14]
The commercially available IKA electrosynthesizer ES-2.0 was
used to assess the reproducibility of the reaction. We are
pleased to see that it gives similar yields.
À
À
Given the fast reaction time, we assumed that the oxy-
bromination would be ideal for a continuous flow regime
(Table 2). Reaction optimization was conducted in an Asia Syrris
flow reactor (Scheme 4).
Scheme 2. Radical-trapping experiments.
Scheme 3. Plausible Reaction Mechanism for Oxybromination of Allylic Oximes.
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Conflict of Interest
Table 2. Optimization of the Reaction Conditions using a Continuous Flow
Reactor.[a]
Entry
The authors declare no conflict of interest.
J
Flow rate
[μl/min]
T
GC Yield
[%]
[mA/cm2]
[ C]
°
1
2
3
4
5
6
7
8
100
100
100
100
100
100
100
100
100
100
100
100
300
400
500
600
700
800
900
200
300
200
rt
16
70
70
71
67
68
56
69
56
55
86
Keywords: Electrosynthesis
Isoxazolines · Oxybromination
·
Flow electrosynthesis
·
2-
rt
rt
rt
rt
rt
rt
rt
40
40
20
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Although the initial trials provided only little product, we
were able to fine-tune the reaction parameters including flow
rate and temperature to obtain the desired product in 86%
yield (Table 2, entry 11). Thus, the newly developed reaction
can be used both in batch and continuous flow processes
which is crucial for further scale-up.
In summary, we have developed a new electrochemical
method for the synthesis of 2-isoxazolines. The reaction
operates under atmospheric conditions and tolerates air and
moisture. Besides, the use of potassium bromide as both
electrolyte and bromine source precludes the need for toxic,
air-sensitive inorganic oxidants or transition metal catalysts.
This method is, therefore, an attractive alternative for the
synthesis of functionalized 2-isoxazolines.
Acknowledgements
This work was financially supported by the King Abdullah
University of Science and Technology (KAUST), Saudi Arabia.
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Manuscript received: May 27, 2021
Revised manuscript received: May 29, 2021
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