Iodonium Cation-Pool Electrolysis for the Three-Component Synthesis of 1,3-Oxazoles

Article abstract of DOI:10.1002/chem.202004140

The synthesis of 1,3-oxazoles from symmetrical and unsymmetrical alkynes was realized by an iodonium cation-pool electrolysis of I₂ in acetonitrile with a well-defined water content. Mechanistic investigations suggest that the alkyne reacts with the acetonitrile-stabilized I⁺ ions, followed by a Ritter-type reaction of the solvent to a nitrilium ion, which is then attacked by water. The ring closure to the 1,3-oxazoles released molecular iodine, which was visible by the naked eye. Also, some unsymmetrical internal alkynes were tested and a regioselective formation of a single isomer was determined by two-dimensional NMR experiments.

Full text of DOI:10.1002/chem.202004140

Communication
doi.org/10.1002/chem.202004140
Chemistry—A European Journal
&
Regioselectivity
Iodonium Cation-Pool Electrolysis for the Three-Component
Synthesis of 1,3-Oxazoles
Lars E. Sattler and Gerhard Hilt*[a]
Abstract: The synthesis of 1,3-oxazoles from symmetrical
and unsymmetrical alkynes was realized by an iodonium
cation-pool electrolysis of I2 in acetonitrile with a well-de-
fined water content. Mechanistic investigations suggest
that the alkyne reacts with the acetonitrile-stabilized I+
ions, followed by a Ritter-type reaction of the solvent to a
nitrilium ion, which is then attacked by water. The ring
closure to the 1,3-oxazoles released molecular iodine,
Figure 1. Selected examples of 1,3-oxazole-containing compounds.
which was visible by the naked eye. Also, some unsym-
metrical internal alkynes were tested and a regioselective
formation of a single isomer was determined by two-di-
substituted 1,3-oxazoles are generated.[6g] Also, catalytic
mensional NMR experiments.
amounts of hypervalent iodine compounds were applied with
mCPBA as oxygen source and iodobenzene as catalyst[6h] or
stoichiometric amounts of PhIO were used to generate the de-
sired 1,3-oxazoles.[6i] A copper-catalyzed process, reported by
1,3-Oxazoles are a well-studies class of heterocyclic com-
pounds and several intra- and intermolecular synthetic ap-
proaches already exist.[1] The structural motif is present in nu-
merous natural products (1),[2] pharmaceuticals (2),[3] chemicals
for crop protection[4] and functional materials (3) so that a con-
stant interest exist for further research in this area (Figure 1).[5]
To the best of our knowledge, an electrochemical synthesis
from alkynes utilizing an iodonium-pool electrolysis has not
been described before. However, an electrochemical approach
for the synthesis of 1,3-oxazoles was reported by Waldvogel,
using ArIF2 as electrochemical generated reagent,[6a] as well as
the electrosynthesis of benzoxazoles were reported by Waldvo-
gel and Huang.[6b,c] Recent chemical methods for the synthesis
of 1,3-oxazoles starting from alkynes and nitriles were de-
scribed utilizing heterogeneous AuI catalyst with N-oxides as a
source of the oxygen,[6d] or via homogeneous AuI catalysts.[6e]
When cyanamides are used instead of nitriles with alkynes and
N-oxides, the 2-amino-substituted 1,3-oxazoles are formed.[6f]
In contrast, when ynamides are transformed with nitriles under
Yb(OTf)3 catalysis using N-iodosuccinimide as oxidizing agent
and water as source of oxygen the corresponding 4-amino-
Jiang utilized under oxygen (1 atm) and water as oxygen
source was able to apply a number of nitriles and alkynes to
generate the 1,3-oxazoles.[6j]
In a recent study for the electrochemical arene TMS-iodine
ipso-substitution,[7] we also performed a compatibility test[8]
with other functional groups and alkynes proved to be not
compatible with such a TMS-iodine exchange reaction. Further
investigations were carried out on the reaction between al-
kynes and iodonium ions and the formation of an 1,3-oxazole
was observed when cation-pool electrolysis in acetonitrile was
performed. Based on the increasing general interest in electro-
organic transformations,[9] we decided to investigate the elec-
trochemical oxazole three-component synthesis from an
alkyne in „wet“ acetonitrile in more detail. We envisaged a
transition-metal free electrochemical process starting from
simple starting materials such as nitriles and alkynes, avoiding
hazardous or sensitive starting materials or catalysts.
Several electrochemical parameters, such as the electro-
chemical cell design (divided/undivided), cation-pool versus
direct electrolysis, supporting electrolyte (type and concentra-
tion), electrode material as well as other chemical parameters,
such as the reaction temperature, the water content of the sol-
vent were investigated.[10] The optimized reaction conditions
are shown in Scheme 1, where the desired oxazole 5a was ob-
tained in quantitative yield.
[a] L. E. Sattler, Prof. Dr. G. Hilt
Institut fꢀr Chemie, Oldenburg University
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 au-
thor(s) of this article can be found under:
https://doi.org/10.1002/chem.202004140.
From many optimization reactions, selected examples are
summarized in Table 1 to exemplify the critical parameters for
the successful oxazole synthesis of product 5a (for more de-
tails, see the Supporting Information, S7–S9).
ꢁ 2020 The Authors. Published by Wiley-VCH GmbH. This is an open access
article under the terms of the Creative Commons Attribution Non-Commer-
cial NoDerivs License, which permits use and distribution in any medium,
provided the original work is properly cited, the use is non-commercial and
no modifications or adaptations are made.
Initially, the content of water was investigated, and the opti-
mal water content was determined to be around 1.0 equiva-
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doi.org/10.1002/chem.202004140
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acetonitrile-stabilized I+ ions (iodonium ion A) which is fol-
lowed by a Ritter-type reaction[13] where acetonitrile attacks
the activated triple bond to generate a nitrilium ion B. Possibly,
even in a concerted addition of the nitrilium ion to B the Z-
isomer C or by a conventional trans-addition intermediate C’ is
formed. Nevertheless, these stabilized intermediates are at-
tacked by water, deprotonated and ready for cyclisation result-
ing in a stepwise overall [2+2+1] cycloaddition process
(Scheme 2).[6h]
Scheme 1. Electroorganic cation-pool synthesis of 1,3-oxazole 5a.
Table 1. Selected reactions performed during the optimization for the
synthesis of 5a.
No.[a]
Changes
Conversion [%] Yield [%]
1
2
3
4
5
6
7
8
H2O (0.5 equiv)
H2O (1.0 equiv)
H2O (1.5 equiv)
H2O (2.0 equiv)
H2O (3.0 equiv)
0.3 m LiClO4
0.3 m Bu4NPF6
0.1 m Bu4NBF4
0.5 m Bu4NBF4
carbon roving
glassy carbon
stainless steel (1.4571)
NaI, 2.0 FmolÀ1
direct vs. cation-pool electrolysis
temperature: 08C
temperature: 508C
current: 5 mA
100
100
100
100
67
100
100
94
72
99
86
73
61
41[b]
61
82
89
70
91
1[c]
34
38
86
57
71
93
31
94
91
–
9
93
10
11
12
13
14
15
16
17
18
19
20
21
22
23
100
100
2
48
99
100
90
86
100
64
100
100
0
Scheme 2. Proposed reaction mechanism of the cation-pool electrolysis and
the stepwise [2+2+1] cycloaddition process.
current: 20 mA
1.0 FmolÀ1
1.8 FmolÀ1
2.3 FmolÀ1
I2 (1.0 equiv), no current
I2 (1.0 equiv), acetamide (2.0 equiv)
The formation of I2 within a few minutes after the addition
of the alkyne to the iodonium-pool indicates that the iodine
atom in intermediate C is not simply liberated as an iodide
anion by a nucleophilic substitution-type reaction but that a
more complex reaction mechanism must be at work. For an
optimal conversion and a high yield of the oxazole 2.0 FmolÀ1
of electricity must be used. This corresponds to a two-electron
process per I2 molecule and the formation of two I+ ions. A ra-
tionale for this observation could be that the second iodonium
ion is needed to interact with the iodine atom in intermediate
D (or the E-configured intermediate D’) and forms a better
leaving group, similar to the super-leaving group I-Ph in aryl-
iodine(III) chemistry to initiate a SN1-type substitution reac-
tion.[6h,14] In rare occasions, intermediates of type D/D’ (without
the coordinated nitrilium reagent) were detected by GCMS in
small amounts. However, isolation and characterization of
these intermediates were not successful, and we were not able
to determine whether the E- or the Z-configured iodoalkenyla-
mides D/D’ were formed. However, for the outcome of the re-
action this seems to be of limited importance.
0
–
[a] Yield determined by GC-FID using n-dodecane as internal standard.
[b] Formation of benzyl as side-product was observed. [c] Only trace
amounts of product could be detected.
lents (entries 1–5). Other supporting electrolytes besides
Bu4NBF4 gave complete conversion as well, but inferior yields
of 5a and the best results were obtained with a 0.3m solution
(entries 6–9). Some other electrode materials, such as glassy
carbon were also applicable and gave satisfactory results (en-
tries 10–12). Also, the use of sodium iodide instead of I2 in a
cation-pool electrolysis gave only moderate results (entry 13)[11]
and a direct electrolysis (in the presence of 4a) resulted in
complete conversion of the starting material. However, only a
moderate yield of 38% of 5a (entry 14) was obtained, most
likely due to further electrochemical transformation of the oxa-
zole product to several unidentified side-products. Further-
more, the reaction temperature, the current density and the
amount of current is of importance to give good results (en-
tries 15–21).[12] As can be seen from the control experiments
(entries 22 and 23), the cycloaddition reaction is not initiated
by I2 alone, but electrochemical current must generate an ace-
tonitrile-stabilized iodonium ion which is the primary initiator
for the reaction. Also, acetamide did not undergo the reaction,
so that an in situ hydrolysis of acetonitrile can be excluded.
Therefore, we conclude that the 1,3-oxazole synthesis is a
stepwise reaction starting with the activation of the alkyne by
Under the optimized reaction conditions various symmetrical
functionalized diaryl alkynes were reacted in acetonitrile under
iodonium cation-pool conditions; the results are summarized
in Scheme 3.
When the optimized reaction conditions for the formation of
product 5a were applied to other diaryl alkynes, good to ex-
cellent results were obtained. Additional methyl groups in
ortho-, meta- and para-position were well tolerated (5b–5d;
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Finally, a selected small number of internal unsymmetrical
alkyl-aryl alkynes and a dialkyl-substituted alkyne (6) were sub-
jected to the electrochemically generated cation-pool to inves-
tigate if also alkyl sidechains are accepted. Furthermore, the
major question was if the [2+2+1] cycloaddition would lead
to a single regioisomer or if a mixture of regioisomeric oxa-
zoles would be formed? The results for the iodonium cation-
pool electrolysis and the reaction with these alkynes are sum-
marized in Scheme 4.
Scheme 4. Results of the cation-pool electrolysis of unsymmetrical alkynes
of 6a and 6b and the dialkyl-substituted alkyne 6c.
Although the overall yields are only moderate for the alkyl-
aryl-substituted alkynes, only single regioisomers (7a and 7b)
could be detected. In addition, the dialkyl-substituted oxazole
7c was synthesized in a rather low yield of 23%. However, it
became a valuable material for the structure determination of
the regioisomers 7a and 7b.
The identity of the formed regioisomers was elucidated by
recording two-dimensional 1H/15N correlation spectra of all
three products (see supporting information, S43–S47). The re-
sults are shown in Figure 2.
Scheme 3. Electroorganic iodonium cation-pool synthesis of oxazoles of
type 5.
82–100%) and electron-withdrawing groups, such as trifluoro-
methyl, ethyl ester and fluoro-substituents in para-position
were also well accepted and gave the desired oxazoles in
>82% yield (5 f–5h). Only the 4-nitro group caused a dimin-
ished yield of only 44% (5e) which might not to be attributed
to the electron-withdrawing effect but also to additional coor-
dination of the iodonium ion to the nitro group. The 4-chloro-
and 4-bromo-substituted derivatives were also applicable as
well as the 4-cyano-substituted substrate (5i–5k) and only the
electron-donating 4-methoxy derivative 5l could be isolated in
moderate 32% yield.
1
Figure 2. Results of the two-dimensional H/15N correlation NMR experi-
ments and structure assignment of the compounds of type 7.
The transformation was not successful for electron-poor di-
ethyl but-2-ynedioate (no conversion) as well as for terminal al-
kynes, such as phenylacetylene and the conjugated 1,3-diyne
(1,4-diphenylbuta-1,3-diyne) led to several unidentified side-
products. The utilization of a trimethylsilyl protected alkyne
would have been another opportunity to apply terminal al-
kynes in this reaction. However, as was anticipated, the appli-
cation of trimethylsilyl-substituted alkynes, such as trimethyl(p-
tolylethynyl)silane, led to the iododesilylation instead of the
formation of an oxazole product. The fact that an iododesilyla-
tion was observed additionally indicates that an iodonium
cation-pool was generated electrochemically.
1
The H/15N correlation spectra of 7a only shows a single cor-
relation signal for the methyl group derived from acetonitrile
(3J coupling) and no correlation signal for the ortho-protons (4J
coupling) of the phenyl ring. When oxazole 7b was investigat-
ed, again only a single signal was detected. For the oxazole 7c
two signals were resolved in the H/15N correlation spectrum;
1
one for the previous observed methyl group and one for the
3
CH2-group of the hexyl sidechain (both J couplings). There-
fore, we assigned the structures of 7a to be the 2-methyl-5-
hexyl-4-phenyloxazole and 7b to be the 2,5-methyl-4-phenyl-
oxazole regioisomer. The rationale for the formation of this re-
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In conclusion, we have realized an iodonium cation-pool
electrolysis, which was applied for the synthesis of various 1,3-
oxazoles from symmetrical alkynes in acetonitrile containing a
well-defined amount of water. Also, a selected number of un-
symmetrical alkynes were applied and a single regioisomer
1
was formed, structure of which was determined by H/15N cor-
relation NMR spectroscopy. The proposed mechanism explain
the fact that two equivalents of the acetonitrile-stabilized iodo-
nium cation are needed and that molecular iodine is visible
within a few minutes after the addition of the alkyne.
Experimental Section
Both compartments of a divided cell were charged with 988 mg
(3.00 mmol) Bu4NBF4 and in each compartment 10 mL of dry
CH3CN was added. Next, 1.0 equiv (0.500 mmol, 127 mg) iodine
was dissolved in the anodic compartment and 15 equiv
(7.52 mmol, 0.43 mL) acetic acid was added to the cathodic com-
partment. Last, 1.0 equiv (0.500 mmol, 9.01 mL) demineralized
water was added to the anodic compartment. The platinum elec-
trodes were submerged into the solution (active surface area:
1 cm2) and a constant current of 10 mA was applied. After con-
sumption of 2.0 FmolÀ1 (2 h 41 min), the electrolysis was stopped
and 89.1 mg (0.500 mmol, 1.0 equiv) diphenylacetylene were
added to the anodic compartment. The color of the solution
turned immediately from bright red to violet within 5 min. The so-
lution was stirred for 1 h and the conversion was determined by
GCMS analysis. The solution of the anodic compartment was dilut-
ed with 15 mL CH2Cl2, 15 mL of aqueous saturated Na2S2O3 and
15 mL of demineralized water were added, and the layers were
separated. The aqueous layer was extracted three times with
15 mL CH2Cl2 each and the combined organic layer was dried over
Na2SO4. After filtration, the solvent was removed under reduced
pressure and the crude product was purified by flash column chro-
matography.
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Open access funding enabled and organized by Projekt DEAL.
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The authors declare no conflict of interest.
Keywords: alkynes
· cation-pool electrolysis · iodonium
cation · oxazoles · regioselectivity
Manuscript received: September 11, 2020
Revised manuscript received: October 7, 2020
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Accepted manuscript online: && &&, 0000
Version of record online: && &&, 0000
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COMMUNICATION
Cation-pool electrolysis: The iodonium
cation-pool electrolysis is the key-step
in the three-component synthesis of
1,3-oxazoles by a stepwise [2+2+1] cy-
cloaddition of internal alkynes in water-
containing acetonitrile (see scheme).
&
Regioselectivity
L. E. Sattler, G. Hilt*
&& – &&
Iodonium Cation-Pool Electrolysis for
the Three-Component Synthesis of
1,3-Oxazoles
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