Electrochemical synthesis of sulfonamides in a graphite powder macroelectrode

Article abstract of DOI:10.1039/d0gc01360a

The electrochemical generation of sulfinyl radicals from commercially available and non-expensive sodium salts of sulfinic acids is described. Electrooxidation reactions were carried out in a graphite powder macroelectrode using an aqueous electrolyte and cavity cell. Further reaction with primary or secondary amines gave the corresponding sulfonamides, a unit present in several biologically active compounds and pharmaceuticals, in good yields.

Full text of DOI:10.1039/d0gc01360a

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Received 00th January
20xx,
Electrochemical Synthesis of Sulfonamides in Graphite Powder
Macro Electrode
Dmistocles A. Vicente, Danilo Galdino, Marcelo Navarro* and Paulo H. Menezes*†
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The electrochemical generation of sulfinyl radicals from Despite the wide variety of methods described for the
commercially available and non-expensive sodium salts of sulfinic preparation of sulfonamides, the need to use transition metals,
acids is described. Electrooxidation reactions were carried out in toxic solvents and excess oxidants make them difficult to apply
graphite powder macroelectrode using aqueous electrolyte and in the manufacture of pharmaceutical products, since its
cavity cell. Further reaction with primary or secondary amines gave preparation suffers a limitation of residual tolerance level limit
the corresponding sulfonamides,
a
unit present in several on active pharmaceutical ingredients (API).17
biologically active compounds and pharmaceuticals, in good yields. The use of electrochemical techniques is no longer just a
curiosity from research laboratories Electrolysis is a centuries-
old synthesis methodology18 that can be applied to the
preparation of both organic19,20 and inorganic21 compounds.
More specifically, it also has been increasingly used in the
synthesis of pharmaceutical compounds.22
The synthesis of sulfonamides is a subject of great interest, not
only due to their application in pharmaceuticals,1-4 but also as
protecting group.5 These class of compounds have a wide range
of applications as chemotherapeutical agents against several
diseases and, due to date several drugs containing the
sulfonamide functionality, they are available for clinical use.
Perhaps, the most famous example of commercial drug
containing the sulfonamide function is the sildenafil, better
known under its commercial name, Viagra.6
The classical method for the synthesis of sulfonamides is based
on the reactions of sulfonyl chlorides7 or thiols8 with amines. In
both cases, there is a need for manipulate thiols (known for
their unpleasant odor) or sulfonyl halides (sensitive to moisture
and difficult to store or handle).
Salts of sulfinic acids appeared as an alternative to the use of
sulfonyl chlorides and thiols. These chemicals are stable,
inexpensive and a wide range of them is now commercially
available.9 These characteristics made these reagents attractive
for the synthesis of sulfonamides. To date methodologies based
on the use of copper (II) bromide,10-11 iodine,12-15 and TBAI16
were already described.
Within this context, electrochemistry provides a green23 and
efficient method of synthesis, particularly due to the high yield
of the products, current efficiency and control of the process.24
There are some reports for the electrochemical synthesis of
sulfonamides based on the use of the I-/I2 redox pair as
catalyst.25,26
In an attempt to improve electrosynthesis processes, keeping in
mind the environmental requirements,23 our research group
has developed a new way of performing electrochemical
reactions in a cavity cell (Fig. 1) and absence of solvent.27,28 The
procedure involves an easy to handle cell where redox reactions
are performed inside a graphite powder macroelectrode.
Essentially, the graphite powder (a renewable material)29 works
as reaction medium and the reagents are directly
reduced/oxidized, avoiding redox mediators or catalysts. After
electrolysis, the aqueous supporting electrolyte can be
recycled, and the products are extracted from graphite powder
with small amounts of solvent, avoiding waste production.27
In this work, an alternative strategy for the synthesis of
sulfonamides based on the electrochemical oxidation of sodium
aryl sulfinates, using the newly developed electrochemical
cavity cell (Fig. 1).27-29 Electrolyses were carried out with
different amines, without the need of any catalyst. The
macroelectrode (anode) is prepared by mixing reagents and
Universidade Federal de Pernambuco, CCEN, Departamento de Química
Fundamental, Recife–PE, Brazil (paulo.menezes@pq.cnpq.br)
Electronic Supplementary Information (ESI) available: [Experimental details and
characterization of the obtained compounds]. See DOI:
This journal is © The Royal Society of Chemistry 20xx
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graphite powder (particle size < 20m), and added into the did not fully adsorb the reagent used. In additionV,ietwheArtsictleaOrtnilninge
cavity of the cell. Experimental details are described in material 1a was not fully consumed duriDnOgIt:h10e.1r0e3a9c/Dti0oGnC. 0W13h6e0nA
Supporting Information (Figs. S1 to S5).
the amount of graphite powder was increased to 200 mg, 3a
was obtained in 57% yield together with a similar amount of 4a
(Table 1, entry 2). Better results were observed when 300 mg of
graphite powder was used in the reaction, where 3a was
obtained in 95% yield together with a small amount of by-
product 4a (Table 1, entry 3).
Graphite Rod
Cathode (-)
The increase in current from 20 mA to 30 mA or 40 mA led to
mixtures of 3a, 4a and 5a (Table 2, entries 4 and 5). The current
is proportional to the potential applied in the cell, elevated
potentials led to an increase in concentration of radical species
involved in the reaction medium, decreasing the selectivity.
The time required for electrolysis has also been evaluated. It
was observed that the increase in reaction time led to a
decrease in the yield and in the selectivity of the reaction (Table
1, entries 6-8). Finally, a study of the best supporting electrolyte
to promote the reaction was carried out. The preference was
given to water-soluble electrolytes, and also to verify if the use
of LiClO4, would indeed be the best choice. When a solution of
KNO3 was used, lower yields and selectivities were observed
(Table 1, entry 9). The use of NaI as electrolyte was chosen in an
attempt to improve the selectivity of the reaction based on a
literature procedure.25 However, no improvement in yield or
selectivity of the reaction was observed (Table 1, entry 10).
When the reaction was carried out at constant potential, 3a was
obtained in 77% yield (Table 1, entry 11).
Electrolytic
Solution
Filter
Paper
Graphite Powder
Macroeletrode
Anode (+)
Graphite
Rod
Figure 1. Representative illustration of electrochemical cavity cell.
In the course of developing the best reaction conditions, 1a (0.5
mmol) and 2a (1.0 mmol) were used as model-substrates and
different reaction parameters were evaluated. The results are
depicted on Table 1. When the reaction was carried out by using
100 mg of graphite powder, the heterocoupling product 3a was
not obtained, being traces of 5a observed as a by-product (Table
1, entry 1). This result can be explained by the low
homogenization of 2a in the graphite powder, which probably
Table 1. Optimization of reaction conditions for the synthesis of sulfonamide 3a.a
i
p-TolSSO p-Tol
+
Ph
p-TolSO2Na
Ph
NHSO p-Tol Ph
3a
N
4a
+
NH2
+
2
Ph
2
[conditions]
1a
2a
5a
(%)b
Graphite powder (mg)
Supporting electrolyte
(0.1 mol.L-1)
LiClO4
Entry
i (mA)
Time (h)
(anode)
100
200
300
300
300
300
300
300
300
300
300
3a
-
4a
-
40
5
30
25
5
10
25
34
15
8
1
2
20
20
20
30
40
20
20
20
20
20
1.0
1.0
1.0
1.0
1.0
2.0
3.0
4.0
1.0
1.0
2.5d
LiClO4
LiClO4
LiClO4
LiClO4
LiClO4
LiClO4
LiClO4
KNO3
NaIc
LiClO4
57
95
65
57
81
75
65
32
71
77
3
4
5
6
7
8
9
10
d
11
-
a Reaction conditions: 2a (1.0 mmol) and the appropriate amount of graphite powder were mixed and then transferred to the macroelectrode cavity (anode). 1a (0.5 mmol)
was added to the macroelectrode cavity containing the graphite powder and 2a, and submitted to electrolysis using the indicated parameters. A graphite rod was used as
cathode. 0.1 mol.L-1 salt solution was used as supporting electrolyte (Fig.1). b Determined by GC with respect to 1a. c Adapted from Ref. 25. d Electrolysis was carried out at
constant potential E = 0.8 V vs. Ag/AgCl, KCl (sat.), passing Q = 53 C (1F.mol-1 + 10%).
An additional study was performed in order to determine the electrolyte, and the macroelectrode (anode) was composed of
best ratio between starting materials 1a and 2a. The previously 300 mg of graphite powder. Table 2 shows that the use of an
established parameters were fixed and the model-substrates excess 2a gave better results, while 3a was obtained as the
were submitted to a constant current (i) electrolysis at 20 mA major product in all cases (Table 2, entries 1-3), being the best
for 1 h. 0.1 mol.L-1 LiClO4 solution was used as supporting result observed when 0.5 mmol of 1a and 1.0 mmol of 2a were
4 | J. Name., 2012, 00, 1-3
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used (Table 2, entry 3). Equimolar amounts of 1a and 2a led to From Scheme 1 it can be seen that the method proved to be
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to the desired product 3a in a good yield together with a small versatile since different amines canDObI:e10.u10s3e9d/,D0aGnCd0136th0Ae
amount of 4a (Table 2, entry 4). When an excess of 1a was used, corresponding sulfonamides were obtained in good yields, in
lower yields of the desired product were observed along with most cases. In addition, the reaction did not appear to be
an increase in the formation of 4a (Table 2, entries 5-7).
sensitive to electronic or steric effects. Since primary or
secondary amines, as well as benzylamines containing electron-
donating or electron-withdrawing groups in the aromatic ring,
gave the corresponding products in high yield. For example,
benzylamines containing electron-donating groups in the
aromatic ring gave the corresponding products 3b and 3c in
good yield. Likewise, the presence of the fluorine, a strong
electron-withdrawing group, in the aromatic ring gave the
corresponding product 3d in excellent yield. When an aliphatic
primary amine was used, the corresponding product 3e was
also obtained in good yield after 1h. When pyrrolidine was used,
3f was obtained in 90% yield indicating that the reaction was
not sensitive to sterics. The electrochemical reaction was also
efficient for heteroaromatic compounds where 3g was obtained
in good yield.
The chemoselectivity of the method was evaluated using an
amino alcohol. The corresponding sulfonamide 3h was obtained
exclusively, however, in low yield. When an amine containing
an unsaturated chain was used, the corresponding product 3i
was obtained in 75% yield.
As previously mentioned, sulfonamides can be used as
protecting groups for amino acids. In this context, glycine was
used as substrate and the corresponding sulfonamide 3j was
obtained in 48% yield. It is noteworthy that the reaction can be
carried out without the need to convert the amino acid into the
corresponding ester. When (S)-(-)-α-methylbenzylamine was
submitted to the reaction conditions using two different
sulfinate salts, the corresponding sulfonamides, 3k and 3l were
obtained with 98% and 95% yields, respectively, without any
observable racemization. A similar result was observed when
Table 2. Molar ratio optimization for sulfonamide 3a.a
i = 20 mA, t = 1 h
LiClO4 (0.1 mol.L-1
p-TolSO2Na
+
NH2
Ph
Ph
NHSO2p-Tol
+
Ph
N
Ph
)
1a
2a
3a
4a
(%)b
Entry
1a (mmol)
2a (mmol)
3a
46
78
95
91
48
49
26
-
4a
20
13
5
1
2
3
4
5
6
7
8
9c
0.5
0.5
0.5
0.5
1.0
1.5
2.0
0.5
-
2.0
1.5
1.0
0.5
0.5
0.5
0.5
-
7
10
40
64
54
-
1.0
-
aReaction conditions: The appropriate amount of 2a and graphite powder (300 mg) were
mixed and then transferred to the macroelectrode cavity (anode). The appropriate
amount of 1a was added to the macroelectrode cavity containing the graphite powder
and 2a, and submitted to a constant current (i = 20 mA) for 1 h. 0.1 mol.L-1 LiClO4 solution
b
was used as supporting electrolyte (Fig. 1). A graphite rod was used as cathode.
Determined by GC with respect to 1a. c Only traces of 5a were observed.
Once the best conditions for the electrosynthesis of
sulfonamides were determined, they were applied to different
substrates in order to verify the versatility of the new method
(Scheme 1).
i = 20 mA, t = 1h
R1
R2
R1NHR2
R3SO2Na
+
N
SO2R3
3a-s
LiClO4 (0.1 mol.L-1
)
1a-s
2a-e
NHSO2p-Tol
NHSO2p-Tol the (R)-isomer was used, where 3m was also obtained without
NHSO2p-Tol
racemization.
Me
MeO
3c
(75%)
3b
(96%)
3a
(95%)
When aniline was used as the starting material, the
corresponding sulfonamide 3n was not observed. Only
nitrobenzene, the corresponding oxidation product, was
observed. The use of aqueous ammonium hydroxide solution
did not give the corresponding product 3o being only the by-
product 5a observed in the reaction.
SO2p-Tol
NHSO2p-Tol
N
NHSO2p-Tol
F
3f
(90%)
3e
3h
(79%)
3d
(95%)
NHSO2p-Tol
HO
NHSO2p-Tol
NHSO2p-Tol
O
3i
(75%)
(30%)
3g
(90%)
The use of non-aromatic sodium sulfinates did not lead to the
desired products. When sodium methanesulfinate was used,
the corresponding product 3p was not obtained. The same
behavior was observed when rongalite and sodium triflinate
were used, where the corresponding products 3q and 3r were
not obtained. These results indicated that the species
electrochemically generated from the sodium salts of sulfinic
acids must be sufficiently stable for the subsequent reaction
with amines. This effect was confirmed by the reaction of
benzylamine 1a and benzenesulfinic acid sodium salt, where the
corresponding product 3s was obtained in 83% yield. Some
reports in the literature describe the formation of aryl sulfinyl
radicals by a one-electron oxidation of the respective sodium
sulfinate salts.30 However, this reaction strategy requires the
use of metals as catalytic oxidizing agents. Thus, for a better
NHSO2Ph
NHSO2p-Tol
HO2C
NHSO2p-Tol
3j
(48%)
3l
(95%)
3k
(98%)
NHSO2p-Tol
3n
SO2p-Tol
NHSO2p-Tol
H2N
3m
3o
(-)
(90%)
(-)
NHSO2CH2OH
NHSO2Me
NHSO2CF3
(Trace)
3r
3q
(-)
3p
(-)
NHSO2Ph
(83%)
3s
Scheme 1. Electrosynthesis of different sulfonamides in cavity cell.
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understanding about the reactions occurring in the
electrochemical cavity cell, linear sweep voltammetries were
carried out to determine the oxidation peak potentials for 1a
and 2a, separately. A linear sweep voltammetry (Fig. 2) of 1a (50
Sodium p-toluene sulfinate
Benzylamine
Blank
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DOI: 10.1039/D0GC01360A
0.5
0.4
0.3
0.2
0.1
0.0
mmol.L-1) was carried out in LiClO4 (0.1 mol.L-1) in
a
MeCN/water (7:3) solution, using a glassy carbon anode,
Ag/AgCl, KCl (sat.) as reference and stainless steel grid as
cathode. Scan rate was 100 mV.s-1 and the potential ranged
from zero to 1.8 V in a standard cell of three electrodes (Fig. S5).
Thus, it was observed a one-electron oxidation peak at 1.45 V,
which is in accordance with previously described data,31 leading
to the formation of the benzylamine cation radical [BnNH]+
(1a’) (Eq. 1). The same procedure was applied to the linear
sweep voltammetry of 2a (50 mmol.L-1) solution (Fig 2). It was
observed a peak at 1.04 V, due to the one-electron oxidation of
p-TolSO2Na to give the corresponding [p-TolSO2] radical (2a’)
(Eq. 2).25,32
0.0
0.3
0.6
0.9
1.2
1.5
1.8
E vs. Ag/AgCl, KCl(sat.) / V
Figure 2. Linear sweep voltammetry of 50 mmol.L-1 1a, and 50 mmol.L-1
2a in 0.1 mol.L-1 LiClO4 MeCN/water (7:3) solution, using a glassy carbon
anode, Ag/AgCl, KCl(sat.) as reference, stainless steel grid as cathode,
and scan rate = 100 mV.s-1.
BnNH2
BnNH2 + 1e
(1)
Electrochemical reactions allow the electron transfer control by
following the experimental charge (Qexp) passed during the
electrolysis [Qexp = i x t, where i = current (A) and t = reaction
time (s)]. The Qexp can be associated to theoretical charge Qt =
n x z x F, where n = number of mols (mol), z = number of
electrons, and F = 96,485 C.mol-1 (Faraday constant). In the
heterocoupling reaction (Eq. 5), 1 e-/equivalent is necessary for
the oxidation of 1a (limiting reagent, 0.5 mmol), and 1 e-
/equivalent for the oxidation of 2a. Thus, the charge necessary
for oxidation of 1a and 2a should be Qt = 96.5 C, which is higher
than the Qexp passed during the electrolysis carried out for 1 h
(Qexp = 0,02 A x 3600 s = 72.0 C). Therefore, only 75% of the total
charge was necessary for the consumption of reagents (1a + 2a),
giving 95% of 3a and 5% of 4a (Table 1, entry 3).
As observed in linear voltammograms (Fig. 1), the oxidation
peak potentials of 1a and 2a are not close (E = 410 mV), thus,
the oxidation of 1a is more difficult than 2a. In addition, the
current peak intensity for the oxidation of 2a (i = 0.504 mA) is
3.7 times higher than 1a (i = 0.137 mA), thus, showing a higher
electron transfer rate for 2a. As described in Table 1, the ideal
reaction conditions require 2 equivalents of 2a vs. 1 equivalent
of 1a, which also favours the formation of 2a’ radical. Therefore,
in agreement to linear voltammetry experiments, 1a and 2a
homocoupling products obtained (Table 2, entries 8 and 9), and
the lower charge (75%) necessary for total consumption of
reagents 1a and 2a (Table 1, entry 3), it can be proposed
another mechanism for the N-S heterocoupling occurring on the
graphite powder macroelectrode surface, according to Eqs. 6
and 7.
1a
1a'
p-TolSO2Na
p-TolSO2 + 1e + Na
(2)
2a
2a'
Thus, during electrolysis carried out in the electrochemical
cavity cell, homo and heterocoupling reactions would be
expected (Eqs. 3 to 5).
+ NH3 + 2 H+
Ph
2 BnNH2
Ph
N
(3)
1a'
4a
O2
+
p-TolSSO2p-Tol
+
2 p-TolSO2
(4)
(5)
5a
2a'
p-TolSO
+
H
BnNHSO2p-Tol
BnNH2
2
1a'
2a'
3a
The homocoupling product 4a (Eq. 3) was identified in most
reaction conditions described in Table 1, reaching 40% yield
when 200 mg of graphite powder was used as reaction medium
(Table 1, entry 2). On the other hand, only traces of the 5a, the
homocoupling product, were observed (Eq. 4). The formation of
the homocoupling product 4a was evidenced by an electrolysis
carried out using only 1a, under the standard reaction
conditions: i = 20 mA and t = 1 h (Table 2, entry 8), giving 4a in
54% yield. When the same electrolysis was carried out using
only 2a as reagent, under the experimental conditions, only
traces of 5a, the homocoupling product was observed (Table 2,
entry 9). The heterocoupling product 3a was also observed in
most reactions described in Table 1, reaching 95% by using 300
mg of graphite powder as reaction medium (Table 1, entry 3).
BnNH2
1a
+
p-TolSO2
BnNH2SO2p-Tol
(6)
(7)
2a'
3a'
2 BnNHSO2p-Tol + H2
2 BnNH2SO2p-Tol
3a'
3a
The electrochemical and reaction conditions favor the oxidation
of 2a: lower oxidation potential (1.04 V), higher electron
transfer rate, higher concentration of 2a (2 eq.) and low yield of
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10 X. Tang, L. Huang, C. Qi, X. Wu, W. Wu and H.ViJeiwanArgti,clCe hOenlmine.
the by-product 5a (S-S homocoupling). Thus, 2a’ radical should
be formed in high concentrations and reacts with the amino
group of 1a to give the intermediate specie [BzNH2SO2p-Tol]+
(3a’) (Eq. 6), which is not stable and loses H which combines to
give H2 (Eq. 7). This mechanism was confirmed by an electrolysis
carried out under the standard reaction conditions at constant
potential E = 0.8 V vs. Ag/AgCl, KCl (sat.). At this potential, 2a
was selectively oxidized to give 2a’ radical as the major product.
The electrolysis gave 77% yield of 3a, 8% of 4a, and 15% of
unreacted 1a (Table 1, entry 11). Thus, the electrochemical
heterocoupling reaction between sodium sulfinates and amines
can occur through the coupling of the respective radicals
generated from the 1F.mol-1 oxidation (Eq. 5), at the same time
that the heterocoupling reaction can occur from the single
sulfinate oxidation (0.5 F.mol-1).
Commun. 2013, 49, 6102-6104.
DOI: 10.1039/D0GC01360A
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Soc. 2006, 128, 15423–15431.
Conclusions
The electrochemical generation of sulfinyl radicals from
commercially available and non-expensive sodium salts of aryl
sulfinic acids was carried out in graphite powder
macroelectrode, using an electrochemical cavity cell. The
formation of the arylsulfinyl radical was evidenced by the
oxidation potential determined by voltammetry experiments.
The lower theoretical charge consumption can be explained by
simultaneous 2e-/1e- equivalent mechanisms. Further reactions
with different amines gave the corresponding sulphonamides in
good to moderate yields, depending on the structure of the
amine used. The methodology is simple, fast, efficient, and it
could be applied for the synthesis of more complex
sulfonamides.
Acknowledgements
31 A. Thirumoorthi and K. P. Elango, J. Chem. Sci., 2007, 119,
289–294.
32 P. Qian, M. Bi, J. Su, Z. Zha and Z. Wang, J. Org. Chem., 2016,
81, 4876–4882.
We gratefully acknowledge CAPES, CNPq (401541/2016-9) and
FACEPE (APQ-0549-1.06/17/INCT 2014) for financial support.
P.H.M (309778/2018-2), M.N. (PQ2-306132/2017-6), D.A.V. and
D.G. are also thankful to CNPq and CAPES for their fellowships.
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