Electrochemically Induced Synthesis of Sulfonylated N-Unsubstituted Enamines from Vinyl Azides and Sulfonyl Hydrazides

Article abstract of DOI:10.1021/acs.orglett.0c00139

Sulfonylated N-unsubstituted enamines were synthesized through a chain of chemical and electrochemical transformations via sulfonylation of vinyl azides. The disclosing of the N-unsubstituted enamines synthesis was based on a unique property of the azido group, which is its ability to eliminate the N₂ molecule. Furthermore, a formal paradox is observed: A double bond reacts and a double bond is retained. Electrosynthesis proceeded in an undivided cell equipped with a graphite anode and a stainless steel cathode; NH₄I was used as a supporting electrolyte.

Full text of DOI:10.1021/acs.orglett.0c00139

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Letter
Electrochemically Induced Synthesis of Sulfonylated
N‑Unsubstituted Enamines from Vinyl Azides and Sulfonyl
Hydrazides
Olga M. Mulina, Nataliya V. Zhironkina, Stanislav A. Paveliev, Dmitry V. Demchuk,
and Alexander O. Terent’ev*
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ABSTRACT: Sulfonylated N-unsubstituted enamines were synthesized through a chain of chemical and electrochemical
transformations via sulfonylation of vinyl azides. The disclosing of the N-unsubstituted enamines synthesis was based on a unique
property of the azido group, which is its ability to eliminate the N2 molecule. Furthermore, a formal paradox is observed: a double
bond reacts and a double bond is retained. Electrosynthesis proceeded in an undivided cell equipped with a graphite anode and a
stainless steel cathode; NH4I was used as a supporting electrolyte.
Scheme 1. Transformations of Vinyl Azides
xidative coupling is becoming an increasingly attractive
method for the formation of carbon−carbon and
O
carbon−heteroatom bonds.1,2 In general, such an approach
does not require prefunctionalization of the starting materials
with heavy leaving groups and provides compounds, which are
often inaccessible through other synthetic pathways without
elimination of a significant amount of waste. Among all
oxidants used in oxidative coupling, electric current is one of
the cheapest and the most environment-friendly.3−8 A number
of processes for C−C,9−11 C−N,12−15 C−O,16−19 C−S,20−22
C−P,23 and S−N24,25 bond formation were conducted
electrochemically. Electrosynthesis in an undivided cell is the
most promising instrumentally, as well as the most challenging
from the chemical point of view, because all starting
compounds and products are subject to both cathodic and
anodic processes, which can cause some side reactions and
result in low efficiency of electrosynthesis.
α-Substituted vinyl azides possess versatile reactivity: they
can serve as nucleophiles, electrophiles, 1,3-dipoles, and radical
acceptors (Scheme 1).26 The possibility of N2 elimination from
vinyl azides during their transformations makes them
convenient precursors of many classes of organic compounds.
As a result of radical transformations of vinyl azides, various
products can be synthesized: ketones,27 imines,28 and
Received: January 10, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00139
Org. Lett. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

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Letter
unsubstituted enamines.29,30 Among all possible products,
selective synthesis of functionalized N-unsubstituted enamines
is a quite challenging task31,32 due to a limited substrate scope
or need for tedious and hydrolysis-sensitive operations.33
Development of an efficient method for N-unsubstituted
enamines synthesis will allow them to become accessible as
synthetic intermediates on the way to various nitrogen-
containing heterocycles34−39 and chiral amines.40,41
a
Table 1. Optimization of Enamine 3a Electrosynthesis
molar ratio
1a:2a
electrolyte
(mol/mol 1a)
anode−
yield 3a
(%)
b
c
no.
solvent
cathode
d
1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1.5
1:2
KI (1)
H2O−
C−Pt
28
THF
The sulfonyl group is present in many agrochemical42,43 and
medicinal44−46 agents. SO2-containing molecules are often
applied for the construction of double bonds47−50 and
heterocycles,51−55 as well as in arylation reactions.56−58 Thus,
the structures which have both N-unsubstituted enamine and
sulfonyl fragments are quite useful in organic and medicinal
chemistry.
2
KI (1)
H2O−
C−Pt
C−Pt
C−Pt
C−Pt
C−Fe
C−Ni
Pt−Pt
C−Fe
C−Fe
C−Fe
C−Fe
C−Fe
C−Fe
C−Fe
C−Fe
43
THF
e
3
KI (1)
H2O−
38
THF
f
4
KI (1)
H2O−
11
THF
g
5
KI (1)
H2O−
26
THF
In continuation of our studies in the formation of carbon−
sulfur and sulfur−heteroatom bonds based on electrogenera-
tion of sulfonyl radicals,59−62 we wondered if we could carry
out electrochemical reactions of vinyl azides with sulfonyl
hydrazides as precursors of sulfonyl radicals. Surprisingly,
selective formation of sulfonyl derivatives of N-unsubstituted
enamines was observed.
6
KI (1)
H2O−
45
THF
7
KI (1)
H2O−
14
THF
8
KI (1)
H2O−
13
THF
9
NH4I (1)
TBAI (1)
NH4Br (1)
LiClO4(1)
NH4I (0.5)
NH4I (2)
NH4I (1)
NH4I (1)
H2O−
47
THF
We began our investigations of the electrochemically
induced reaction of vinyl azides and sulfonyl hydrazides by
optimizing of the electrosynthesis conditions with the reaction
between (1-azidovinyl)benzene 1a and p-toluenesulfonyl
hydrazide 2a, resulting in 1-phenyl-2-tosylethenamine 3a.
The data concerning the influence of the amount of passed
electricity, current density, nature and amount of supporting
electrolyte, molar ratio of starting compounds, solvent nature,
and electrode materials are summarized in Table 1. Initial
electrolysis conditions (Table 1, entry 1), namely electrode
materials and solvent, were chosen for their inertness under
electrochemical conditions and easy handling. Iodides are
often utilized in organic electrosynthesis, because they can
10
11
12
13
14
15
16
H2O−
25
THF
H2O−
trace
trace
40
THF
H2O−
THF
H2O−
THF
H2O−
30
THF
H2O−
65
THF
H2O−
40
THF
17
18
1:1.5
1:1.5
NH4I (1)
NH4I (1)
DMSO
C−Fe
C−Fe
38
81(74)
serve both as supporting electrolytes and as redox catalysts.63
A
DMSO−
current density of 20 mA/cm2 was chosen for two reasons: full
conversion of starting compounds was achieved within only a
few hours, while minimal side reactions occurred.
THF
a
General procedure: a solution of vinyl azide 1a (145 mg, 1 mmol, 1
equiv), p-toluenesulfonyl hydrazide 2a (186−372 mg, 1−2 mmol, 1−
2 equiv), and supporting electrolyte (0.5−2 mmol, 0.5−2 equiv) in 20
mL of H2O−THF (1:1), DMSO or DMSO−THF (1:1) was
electrolyzed under constant current conditions (3.5 F/mol 1a, I =
Entries 1−3 showed that 3.5 F/mol 1a was an optimal
electricity amount (1.5 h of electrolysis). Both a decrease
(entry 4) and an increase (entry 5) of the current density led
to a fall in target product 3a yield. A screening of applicable
electrode materials (entries 6−8) demonstrated that the best
result was achieved with the use of a graphite anode and
stainless steel cathode (entry 6): enamine 3a was obtained
with a 45% yield. Obviously, the presence of the iodide anion is
required for this reaction: application of NH4I and TBAI as
supporting electrolytes resulted in the formation of 3a with
47% and 25% yields respectively, but when NH4Br and LiClO4
were applied, the target product was observed only in trace
amounts (entries 11 and 12). Thus, NH4I was chosen as an
optimal supporting electrolyte, and then the influence of its
amount on 3a yield was studied. Usage of 50 mol % NH4I
caused a slight drop in the yield of enamine (entry 13), while
application of 2 equiv of NH4I resulted in 3a only in 30% yield
(entry 14). The molar ratio of starting compounds turned out
to be one of the key factors influencing the reaction efficiency
(entries 15−16). Employment of a 1.5 excess of sulfonyl
hydrazide 2a resulted in a significant rise of target enamine 3a
yield up to 65% (entry 15). It should be noted that in all
previous entries corresponding ketosulfone A (1-phenyl-2-
tosylethanone) was formed as a side product with a 5−20%
b
60 mA, j = 20 mA/cm2) for 90 min under magnetic stirring. C,
c
graphite; Pt, platinum; Fe, stainless steel; Ni, nickel. The yield was
determined by 1H NMR using 1,4-dinitrobenzene as an internal
d
standard; the isolated yield is reported in parentheses. The reaction
mixture was electrolyzed for 2 h (4.5 F/mol 1a). The reaction
mixture was electrolyzed for 1 h (2.5 F/mol 1a). The reaction
e
f
mixture was electrolyzed for 4.5 h (3.5 F/mol 1a, I = 20 mA, j = 7
g
mA/cm2). The reaction mixture was electrolyzed for 45 min (3.5 F/
mol 1a, I = 120 mA, j = 40 mA/cm2).
yield, which also complicated the isolation of 3a. Its formation
is apparently caused by enamine 3a hydrolysis during the
reaction. That is why we decided to replace solvent that we
used. Application of DMSO led to 3a only in 38% yield (entry
17), but in this case the formation of the ketone was not
observed at all. When electrolysis was conducted in the
DMSO−THF (1:1) mixture, target enamine 3a was obtained
with an 81% yield (entry 18). Hence, according to the
obtained experimental data, the reaction proceeded optimally
in DMSO−THF with a 1.5 excess of sulfonyl hydrazide 2a, 1
equiv of NH4I as a supporting electrolyte, graphite anode and
B
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Letter
stainless steel cathode at 20 mA/cm2 for 90 min (Table 1,
entry 18).
Scheme 3. Synthesis of Various Enamines 3j−3w from Vinyl
a b
,
Azide 1a and Sulfonyl Hydrazides 2
With the optimized conditions in hand, we tested the
substrate scope on a variety of vinyl azides 1 (Scheme 2) and
sulfonyl hydrazides 2 (Scheme 3).
Scheme 2. Synthesis of Various Enamines 3a−3i from Vinyl
a b
,
Azides 1 and p-Toluenesulfonyl Hydrazide 2a
a
General procedure: a solution of vinyl azide 1 (1 mmol, 1 equiv), p-
toluenesulfonyl hydrazide 2a (279 mg, 1.5 mmol, 1.5 equiv), and
NH4I (145 mg, 1 mmol, 1 equiv) in 20 mL of DMSO−THF (1:1)
was electrolyzed under constant current conditions (3.5 F/mol 1, I =
a
General procedure: a solution of vinyl azide 1a (145 mg, 1 mmol, 1
equiv), sulfonyl hydrazide 2 (1.5 mmol, 1.5 equiv), and NH4I (145
mg, 1 mmol, 1 equiv) in 20 mL of DMSO−THF (1:1) was
electrolyzed under constant current conditions (3.5 F/mol 1a, I = 60
b
60 mA, j = 20 mA/cm2) for 90 min under magnetic stirring. Isolated
b
mA, j = 20 mA/cm2) for 90 min under magnetic stirring. Isolated
yields.
yields.
Various aryl-substituted vinyl azides 1a−1i, possessing both
electron-donating and electron-withdrawing groups, success-
fully entered the developed process resulting in the formation
of target enamines 3a−3i with yields from moderate to high
(Scheme 2). Even sterically hindered enamine 3i was formed
with a 69% yield. The scope of sulfonyl hydrazides 2j−2w was
shown to be quite wide (Scheme 3). Application of various
aryl-substituted sulfonyl hydrazides 2j−2t gave coupling
products 3j−3t in good yields almost in all cases. Methyl 2u
and heteroaryl-substituted 2v−2w sulfonyl hydrazides also
gave target enamines 3u−3w but in lower yield.
In order to demonstrate the scalability of our procedure, the
reaction with 5 mmol of vinyl azide 1a and 7.5 mmol of
hydrazide 2a was conducted. As a result, target enamine 3a was
obtained with a 63% yield (Scheme 4).
In order to propose the reaction mechanism, cyclic
voltammetry (CV) studies and some control experiments
were conducted. CV curves were recorded (Figure 1) on a
working glassy-carbon electrode in a DMSO−THF solution.
Tetrabutylammonium tetrafluoroborate, which cannot be
oxidized under such experimental conditions, was chosen as
a supporting electrolyte.
Scheme 4. Scaling up of Enamine 3a Electrosynthesis
was responsible for the oxidation of I3 into I2.64 Addition of
−
hydrazide 2a to NH4I led to the shift of the I− oxidation peak
to +0.39 V, probably due to association of hydrazide 2a and I−,
and the appearance of a new peak at +1.07 V, which was
presumably responsible for the oxidation of the product of the
reaction between hydrazide 2a and iodine or its derivatives.
Hence we can conclude that under experimental conditions
sulfonyl hydrazide 2a was oxidized by I2 or its derivatives.
Addition of vinyl azide 1a to hydrazide 2a and the NH4I
mixture did not significantly change the curve, which
confirmed that vinyl azide 1a did not affect the iodine-
mediated oxidation of sulfonyl hydrazide 2a. Reaction between
1a and 2a under the action of I2 without electricity resulted in
coupling product 3a only in trace amounts (Scheme 5, eq a).
This fact provided evidence that I2 was not the key reagent in
sulfonyl hydrazide oxidation. Usage of the divided electro-
chemicall cell for the electrosynthesis of 3a in the anodic
chamber led to the target product in 73% yield (Scheme 5, eq
First, the investigation of redox properties of NH4I and
starting vinyl azide 1a and p-toluenesulfonyl hydrazide 2a was
carried out. As we can see from voltammograms, vinyl azide 1a
and sulfonyl hydrazide 2a did not undergo oxidation up to
+1.60 V. The iodide anion was oxidized in the earliest
potentials (+0.26 V); the second peak on this curve (+0.74 V)
C
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Letter
Scheme 6. Proposed Mechanism for Enamine 3a
Electrosynthesis
Figure 1. CV curves for 5.0 mmol/L solutions of vinyl azide 1a
(yellow), p-toluenesulfonyl hydrazide 2a (green), NH4I (brown),
mixture of 2a with NH4I (blue), and mixture of 1a, 2a, and NH4I
(violet) in 0.1 M Bu4NBF4 solution in DMSO−THF (1:1) on a
working glassy-carbon electrode (d = 3 mm) under a scan rate of 0.1
V/s.
Scheme 5. Control Experiments on the Confirmation of
Enamines Electrosynthesis Mechanism
stainless steel cathode. Ammonium iodide served as both a
supporting electrolyte and a redox catalyst. With the use of
cyclic voltammetry and control experiments the possible
reaction pathway was proposed. Presumably, during the
reaction, sulfonyl radical generation, followed by its trapping
with vinyl azide, N2 elimination, and hydrogen atom
abstraction, takes place. Thus, the transformation of sulfonyl
hydrazides into S-centered radicals and their addition to vinyl
azides with the formation of C-centered radicals, followed by
elimination of the N2 molecule, represents a versatile and
nontrivial radical chain approach to the generation of N-
centered radicals.
b). That is why we can conclude that cathodic processes did
not significantly affect the formation of 3a.
On the basis of CV studies, control experiments, and
literature data,30,65−77 we propose the following pathway of
enamine 3a electrosynthesis (Scheme 6). The reaction begins
from the anodic oxidation of the iodide anion to form
molecular iodine,65−70 which can further react with the iodide
anion to result in I3− formation or with traces of water from the
solvent, as well as hydroxide anions generated on the cathode
to give electrophilic iodine species.71 In the next step, p-
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00139.
−
toluenesulfonyl hydrazide 2a is oxidized with I2 or I3 or
Experimental details, characterization data (PDF)
electrophilic iodine-containing species [I]+ forming S-centered
sulfonyl radical B directly or through the formation of p-
toluenesulfonyl iodide A.72−75 Generated from A, via
homolytic cleavage or probably, anodic oxidation, radical B
is trapped with vinyl azide 1a resulting in a benzylic C-centered
radical, which eliminates N2 to form N-centered radical
C.30,76,77 Finally, abstraction of a hydrogen atom from 2a or
THF by radical C leads to the formation of target product 3a
via the imine D.
AUTHOR INFORMATION
Corresponding Author
■
Alexander O. Terent’ev − N. D. Zelinsky Institute of Organic
Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation; D. I. Mendeleev University of Chemical
Technology of Russia, 125047 Moscow, Russian Federation;
orcid.org/0000-0001-8018-031X; Email: terentev@
ioc.ac.ru
In summary, we have disclosed the electrochemical synthesis
of sulfonyl derivatives of N-unsubstituted enamines from vinyl
azides and sulfonyl hydrazides in moderate to high yields.
Elimination of the N2 molecule from vinyl azides allows
energetically favorable formation of enamines derivatives from
them. Application of an electric current makes it possible to
conduct the reaction without application of unrecoverable
chemical oxidants. The process was carried out under constant
current conditions in an experimentally simple undivided
electrochemical cell equipped with a graphite anode and
Authors
Olga M. Mulina − N. D. Zelinsky Institute of Organic
Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation
Nataliya V. Zhironkina − N. D. Zelinsky Institute of Organic
Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation; D. I. Mendeleev University of Chemical
Technology of Russia, 125047 Moscow, Russian Federation
D
https://dx.doi.org/10.1021/acs.orglett.0c00139
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Stanislav A. Paveliev − N. D. Zelinsky Institute of Organic
Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation
Dmitry V. Demchuk − N. D. Zelinsky Institute of Organic
Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00139
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Russian Foundation for Basic
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