Electrochemical Iodine-Mediated Oxidation of Enamino-Esters to 2H-Azirine-2-Carboxylates Supported by Design of Experiments

Article abstract of DOI:10.1002/chem.202001465

An electrochemical iodine-mediated transformation of enamino-esters for the synthesis of 2H-azirine-2-carboxylates is presented. In addition, a thermic conversion of azirines to 4-carboxy-oxazoles in quantitative yield without purification was described.

Full text of DOI:10.1002/chem.202001465

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Accepted Article
Title: Electrochemical Iodine-Mediated Oxidation of Enamino-Esters to
2H-Azirine-2-Carboxylates supported by Design of Experiments
Authors: Gerhard Hilt and Emre Babaoglu
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To be cited as: Chem. Eur. J. 10.1002/chem.202001465
Link to VoR: http://dx.doi.org/10.1002/chem.202001465
Supported by

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Electrochemical Iodine-Mediated Oxidation of Enamino-Esters to
2H-Azirine-2-Carboxylates supported by Design of Experiments
Emre Babaoglu[a,b] and Gerhard Hilt*[a]
Dedicated to the late Prof. Dr. Kilian Muniz in remembrance of our time in the Noyori laboratory.
[a]
[b]
Institut für Chemie, Carl von Ossietzky Universität Oldenburg
Carl-von-Ossietzky Straße 9-11, 26129 Oldenburg, Germany
E-mail: Gerhard.Hilt@uni-oldenburg.de
Fachbereich Chemie
Philipps-Universität Marburg
Hans-Meerwein-Straße 4, 35043 Marburg, Germany
Supporting information for this article is given via a link at the end of the document.
Abstract: An electrochemical iodine-mediated transformation of
enamino-esters for the synthesis of 2H-azirine-2-carboxylates is
presented. In addition, a thermic conversion of azirines to 4-carboxy-
oxazoles in quantitative yield without purification was described. Both
classes 2H-azirines-2-carboxylates and the 4-carboxy-oxazoles are
substructures in natural products and therefore are of considerable
interest for synthetic and pharmaceutical chemists. The optimization
was not performed in a conventional manner with a one-factor-at-a-
time process but with a Design of Experiments (DoE) approach.
Beside a broad substrate scope the reaction was also employed to a
robustness screen, a sensitivity assessment, and complemented with
mechanistic considerations from cyclic voltammetry experiments.
these reactions; therefore, a simple conversion with a mild oxidant in
catalytic amounts under mild conditions would overcome most of the
drawbacks of the described synthetic methods (Scheme 1). In initial
experiments based on previous work, we discovered that under
electrochemical conditions an enamino ester, such as 1a, was
converted into the azirine 2a in moderate yield (19%) when iodine was
present in the anodic cell compartment of a divided electrolysis under
galvanostatic conditions. Intrigued by this finding, we decided to
investigate this electrochemical cyclization reaction towards such a
strained unsaturated heterocycle in more detail.
Azirines are rather unusual strained unsaturated three-membered
rings with a nitrogen atom where two types of isomers are possible:
1H-azirines, containing a carbon-carbon double bond that are not
stable and isomerize to 2H-azirines containing an imine subunit. One
special class of azirines are the 2H-azirine-2-carboxylates (marked in
blue, Figure 1), which occur in natural products such as dysidazirine,
and antazirine from the dysidea fragilis sponge,[1] as well as
azirinomycin from streptomyces aureus.[2]
Scheme 1. Electrochemical cyclization of enamino ester 1 to the azirine 2.
Nowadays, electrochemical processes are favourable compared to
chemical oxidants and reductants, because less waste is
accumulated beside the usage of supporting electrolyte and
hazardous reagents can be avoided; in addition to economic
reasons.[14] The main challenge of electrochemical methods are the
additional parameters (e.g. electrode material, cell design, supporting
electrolyte),[15] which need to be optimized on top of the reaction
conditions of an ordinary organic reaction (e.g. temperature,
concentration, reaction time). The additional parameters aggravate
the optimization, that is why we decided to utilize the design of
Figure 1. Natural products with 2H-azirine-2-carboxylate moieties.
The common synthesis of azirines can be achieved in several ways
like the usage of azides to form nitrenes under thermal conditions,[3]
addition of nitrenes to alkynes or addition of carbenes on nitriles,[4] ring
contraction of isoxazoles,[5] elimination reactions from oxime
derivatives,[6] or by strong oxidants like PIDA or PIFA from
enamines.[7–10] Unfortunately, the use of mild oxidants, such as
iodine[11-13] for the oxidation of enamines is rare and in all cases over
stoichiometric amounts of oxidants are needed. Hazardous reagents
like azides, strong bases, strong oxidants, or high temperatures as
well as a disadvantageous atom economy are great drawbacks of
experiments (DoE) approach[16,17] where
a large number of
parameters can be optimized at once very effectively and with higher
statistical significance by running a small set of experiments. The aim
of this optimization procedure is to perform a small set of experiments,
1
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where all parameters are changed at the same time in a systematic
order. The interaction of each parameter among themselves and the
influence on the yield are described mathematically by using DoE.
The outcome of this analysis is statistically proven and the influence
of each parameter can be quantified (Figure 2). Cross interactions,
outliers due to experimental errors, and the optimal reaction
conditions can easily be found. In earlier work we already
demonstrated that DoE in combination with electrochemical
transformations can be a valuable tool to improve the reaction
performance significantly.[18,19] For the screening process, we choose
1b (ethyl (E)-2-(amino(4-fluorophenyl)methylene)-3-oxobutanoate;
compare Scheme 2) as the test substrate in order to determine yields
by 19F NMR directly from the electrolyte because the product 2b
decomposes under the thermal conditions of gas chromatographic
analysis. Initially in the DoE optimization, we started to investigate
categorical parameters in a rough extensive screening. It seems that
the optimization of categorical parameters very often relied on
accidental discoveries of trial and error experiments because they
With these best categorical parameters, we started with a D-optimal
optimization design which has been extended for the coverage of
cross interactions. We needed 25 experiments for the numerical
parameters containing mediator loading (0.20 - 0.30 eq., optimal: 0.30
eq.), 2,6-lutidine equivalents (1.00 - 3.00, optimal: 2.40), electrolyte
concentration (0.08 - 0.24 mol·L-1, optimal: 0.24 mol·L-1), temperature
(25 – 55 °C, optimal: 25 °C), applied charge (1.8 - 2.4 F·mol-1, optimal:
2.4 F·mol-1) and charge density (6 - 10 mA, optimal: 10 mA). The
predicted yield by using DoE is correlated with the actual yield
(Figure 2) showing a very good representation of the influence
between the numerical parameters and the yield. Some of the
numerical parameters are at the limits of the prior defined range. We
didn’t want to extend the range to keep the reaction conditions mild,
the experimental set up easy, and avoid large excess of additives.
The resulting model identified 10 relevant interactions (see SI) where
a quadratic term of the base equivalents had the greatest significance
besides the electrolyte concentration and a cross interaction between
temperature and electric current was also relevant (all p-values <
0.01); thus, resulting in a high R2 value of 0.98. After the initial
optimization by the DoE approach, the assessment of systematic
and/or random errors[20] was investigated to increase the
reproducibility of the electrochemical methodology, which has hitherto
only been performed in photochemical reactions.[21,22] Therefore, the
reaction was tested with the sensitivity assessment and examined
beside typical parameters like concentration or moisture content, also
parameters unique for electrochemical conversions, such as the
distance between the electrodes and the surface area of the
electrodes (Figure 3). Fortunately, the electrochemical reaction
proved to be very insensitive to systematic or random errors so that
the reaction should be reproducible also for other researchers even if
small deviations of the reaction conditions are applied.
have
a non-linear correlation. For systematic optimization of
categorical parameters in an one-factor-at-a-time process, it is
necessary to cover the whole reaction space by testing all possible
combinations, which would lead to extensive experimental efforts. The
selection of the categorical parameters and the limits of the numerical
parameters were made especially with respect to mild and less
hazardous reaction conditions avoiding large excesses of additives or
electric current to be applied. The following categorical parameters
were investigated and for the solvents (MeOH, DMF, MeCN), the
iodide source (KI, Bu4NI, NaI, KI, PhI), the base (pyridine, DBU, KOPiv,
2,6-lutidine), the supporting electrolyte (NBu4BF4, LiClO4, NEt4OTs),
the anode material (graphite, platinum, glassy carbon), and the
cathode material (graphite, platinum, glassy carbon) the bold
formatted parameters were identified to be optimal in terms of the
yield. The screening of the categorical parameters required 65
experiments by using DoE instead of 1620 experiments (5 ∙ 4 ∙ 34) for
coverage of the complete reaction space (see SI).
Figure 3. Sensitivity assessment. See supporting information for more details.
After completion of the optimization and sensitivity assessment, we
examined the scope and limitations of the electrochemical cyclization
reaction towards azirines (Scheme 2). Unfortunately, the isolated
yields differed from those determined by 19F NMR (67% compared to
87%). Therefore, we performed an intensive analysis of all individual
work-up steps and evaluated how much product was lost in every
work-up step (see SI). Since the azirine moiety is very labile the
highest isolated yield was obtained when extraction with aqueous
saturated NH4Cl solution as well as flash chromatography on neutral
silica gel was performed. However, independent from the work-up
procedure, loss of a fraction of the product could not be avoided.
Figure 2. Reaction optimization using Design of Experiments. Predicted yields
are plotted versus measured yields (in total 25 experiments: 21 for the
optimization, 4 for replication of different experiments). All reactions were
carried out on a 0.5 mmol scale using substrate 2b. Yields were determined by
19F NMR spectroscopy using 2-nitro-fluorobenzene as the internal standard.
2
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Scheme 2. Substrate scope of the electrochemical iodine-mediated oxidation of enamines to azirines. 19F NMR yields (2-nitro-fluorobenzene as internal standard)
and the applied currents are given in parenthesis. Some yields are given additionally as borsm (based on recovered starting material) yields.
The isolated yields of the azirines of type 2, obtained from the
electrochemical reaction, are quite acceptable and range for a
considerable large number of products between 40-67%. The scope
of the reaction with respect to the substituent R2 ranges from electron-
deficient to electron-rich arene moieties which are both tolerated with
similar results. The reaction is limited to aromatic substituents as R2
which is in line with the previously reported chemical reaction
conditions, where a new hypervalent iodine (III/V) oxidant was used
to prepare azirines from enaminoesters.[23] The position of the
substituent on the arene ring in R2; either in meta or para position
(substrates 2f/2g and 2k/2l) seems to have a negligible effect upon
the yield of the reaction. However, a substrate of type 1 with a
substituent in ortho position was not accessible. The scope of the
substituent R1 ranged from simple methyl -keto esters (2a-2m) over
cyclopropyl (2n) and phenyl (2o) substituted carbonyl compounds and
malonates (2q-2s). As expected, electron-poor substrates gave better
yields: accordingly, the nitrile 2i, products 2f/2g with nitro substituents
and ester 2e could be isolated in good yields. We expected that the
yield of product 2d and 2h would be lower, since electrochemical
direct iodination could occur,[24] but in both cases such side products
were not observed. Further functional groups like halides were
investigated (fluoride, bromide, CF3) and the corresponding products
were isolated in moderate to good yields. Interestingly, the substrate
1p (4-amino-4-phenylbut-3-en-2-one) led to a different product and
the analytical data revealed that the dimer (2p) was formed in 28%
yield. The reaction was not successful when an additional double
bond in conjugation to the enamine was present (2t). Likewise, the
reaction was not applicable when a trisubstituted enamine was utilized
(compounds 2u and 2w, R1 = H). Unfortunately, compound 2v does
not react under electrochemical conditions, while a conventional
method with iodine was successful.[11] We reasoned that the oxidation
potential of the enamine or the corresponding azirine must be lower
than iodine, therefore we tried an ex-cell approach where we
electrolyzed 1.20 equiv. of sodium iodide under equal conditions
without enamine for 2.4 F∙mol-1 and then added the enamine to the
solution without applying further charge; surprisingly, still no formation
of the azirine was observed.
Since many substrates of type 1 are difficult to synthesize[25,26] and to
screen a large amount of functional groups very effectively we applied
a robustness screen[27,28] upon the electrochemical transformation of
enamino esters to azirines (Table 1, see SI for more examples). The
reaction proceeds in good yields in the most cases even though
additives are present. Some additives are stable under the conditions
(entries 1, 6 and 13), while primary amines (entry 7), sulfolane (entry
8), or amides (entry 12) were not tolerated. N-Methyl indole (entry 11)
inhibit the reaction, because iodination of the indole occurs as shown
3
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via GC-MS analysis (similar outcome for N-benzyl pyrrole, see SI for
complete table). Surprisingly alkenes and alkynes (entries 4 and 9)
were tolerated in moderate yields, although iodination of the
unsaturated units could occur but was not observed. However, the
presence of an additional conjugated double bond as in substrate 2t
was not tolerated under the electrochemical reaction conditions. A
reason for the relatively high functional group tolerance could be that
the reactive iodine species is generated continuously in low
concentration in situ, which could be the decisive advantage of
electrochemical methods over conventional synthesis in this case.
NEt4OTs + NaI
NEt4OTs + enamine 1a
NEt4OTs + lutidine
NEt4OTs + azirine 2a
NEt4OTs
1.2
0.8
0.4
0.0
scan rate: 100 mV/s
Table 1. Functional group tolerance test utilizing screening substrate 1b.[a]
Yield
Additive
Yield 1b[b]
Yield 2b[b]
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
additive[c]
Potential (V) vs. Ag/AgCl
no additive
2-chlorochinoline
benzaldehyde
phenole
0%
3%
87%
69%
73%
1%
–
Figure 4. Cyclic voltammogramms of NaI, enamine 1a, 2,6-lutidine,
azirine 2a and supporting electrolyte (NEt4OTs).
1
>95%
49%
39%
56%
32%
>95%
3%
2
2%
3
78%
10%
0%
To verify the formation of I+ we replaced the enamine carboxylate with
4-tolyl trimethylsilane under equal conditions.[19] The appearance of 4-
iodotoluene in GC-MS analysis indicates the formation of I+ ions in the
electrochemical reaction which underwent an ipso-substitution
reaction by iododesilylation. We assumed that under electrochemical
conditions another oxidation of I2 to I+ or presumably a lutidine
stabilized adduct (A) takes place. In the absence of 2,6-lutidine the
reaction of starting material 1a to 2a does not take place which could
indicate that a complex of an iodine species and lutidine (or a lutidine-
acetonitrile complex) is involved to stabilize I+ in the reaction mixture
(intermediate A, Scheme 3) or is necessary to deprotonate the
intermediates B and D. In the absence of iodide, direct oxidation of
enamine 1a does not lead to the desired product 2a despite full
consumption of the enamine is observed. Oxidation of enamine 1a
takes place at higher potentials (Figure 4, red curve) but under
galvanostatic conditions NaI will be oxidized first. The cyclic
voltammetry also showed that neither 2,6-lutidine nor the azirine 2a
or the supporting electrolyte were oxidized.
4
1-dodecyne
acetanilide
70%
53%
69%
72%
70%
57%
67%
1%
5
6
1-chlorooctane
dodecylamine
sulfolane
2%
7
15%
3%
8
0%
9
1-octene
17%
0%
55%
58%
0%
10
11
12
13
14
benzothiazole
N-methyl indole
Boc-piperidone
benzonitrile
89%
2%
72%
73%
76%
0%
2%
67%
61%
1,2-epoxyoctane
10%
[a] All reactions were carried out on a 0.5 mmol scale. [b] Yields were determined
by 19F NMR spectroscopy using 2-nitro-fluorobenzene as the internal standard.
[c] Yields were determined by GC-FID analysis using n-dodecane as the internal
standard. More examples are given in the supporting information.
For mechanistic considerations cyclic voltammetry experiments were
performed. Yu and Chang[11] postulated a nucleophilic attack from the
enamine on iodine (I2) to transfer I+ onto the substrate and liberation
of iodide anions (I-). Our initial hypothesis was that iodide was oxidized
electrochemically to molecular iodine and then undergoes the desired
reaction. However, direct oxidation of iodide occurs only in aqueous
media and it is described that oxidation of iodide in organic solvents
can be more complex.[29] To verify that I2 was generated
electrochemically under these reaction conditions, we performed the
reaction in a flask under the same reaction conditions except
replacing NaI by 1.2 equivalents of I2 and without applying electrical
current to the reaction; the product was formed only in trace amounts.
Even if the amount of I2 was increased up to 3.6 equivalents, only 25%
of product 2a was formed and 60% of the starting material remaining
unchanged. This result and the absence of any reaction with enamine
nitrile 1v lead to the hypothesis that another oxidized iodine species
might be involved. It is likely that iodide anions were oxidized
-
electrochemically to form triiodide (I3 ) in the first step (Ep = 0.75 V vs.
Ag/AgCl) and another oxidation to molecular iodine occurred in a
second step (Ep = 1.05 V vs. Ag/AgCl; Scheme 3).[30–32]
Scheme 3. Postulated reaction mechanism.
4
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Analog complexes of pyridine ligands with I+ have been described and
characterized by 13C NMR.[33] The enamine carboxylate 1 then reacts
with the formal I+-reagent A to form intermediate B which is stabilized
the electrochemical synthesis of the above-mentioned natural
products are under current investigation.
by
a hydrogen bond with the adjacent carbonyl group. The
Keywords: azirine • design of experiments • electrochemical
oxidation • iodine • oxazole
stabilization of the intermediates B and C could rationalize why
enamino keto esters react more readily than enamino diesters and
enamino nitriles, while substrates such as 2u and 2w do not react.
After deprotonation by 2,6-lutidine towards C, the ring closure occurs
to form intermediate D under liberation of iodide anions and another
deprotonation generates the desired product 2 with a total number of
2 electrons consumed in this oxidation.
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isomer. Therefore, thermal treatment of the azirines of type 2 in a
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same time increase statistical significance of the optimization, we
performed the reaction optimization with the Design of Experiments
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broad substrate scope and a wide robustness screen; above all, we
performed a sensitivity assessment in an electrochemical reaction.
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5
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6
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Entry for the Table of Contents
United we stand – divided we electrolyze! The electrochemical oxidation of iodide anions to lutidine-stabilized iodonium ions
(lutidine∙I+) in organic solvents allowed the mediated cyclisation of enamino carboxylates in moderate to good yields. The reaction
conditions were optimized utilizing the Design of Experiment approach. The electrochemical reaction conditions were tested in a
sensitivity assessment and a robustness screen was performed. Finally, the thermal treatment of the azirine products led to several
oxazoles in quantitative yields.
7
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