Electrosynthesis of sulfonamides from DMSO and amines under mild conditions

Article abstract of DOI:10.1039/d1cc00026h

With DMSO as the solvent and the precursor of a -SO₂Me unit at room temperature, a novel electrochemical oxidization and amination of DMSO with amines was developed for the synthesis of sulfonamides. Our investigations reveal that this transformation may involve a radical process and an electrochemical oxidization of DMSO.

Full text of DOI:10.1039/d1cc00026h

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Electrosynthesis of sulfonamides from DMSO and
amines under mild conditions†
Cite this: Chem. Commun., 2021,
57, 3579
Zhiguan Lin, Liangbin Huang * and Gaoqing Yuan
*
Received 4th January 2021,
Accepted 3rd March 2021
DOI: 10.1039/d1cc00026h
rsc.li/chemcomm
With DMSO as the solvent and the precursor of a –SO2Me unit at –SO2Me,12 and –O13 units. Herein, we reported a novel and
room temperature, a novel electrochemical oxidization and amina- practical sulfonamide synthesis from DMSO and amines under
tion of DMSO with amines was developed for the synthesis of electrochemical conditions.
sulfonamides. Our investigations reveal that this transformation
Electrosynthesis, which employs electrons as traceless redox
may involve a radical process and an electrochemical oxidization reagents, has been recognized as a green technology. In recent
of DMSO.
years, an electrochemical organic synthesis has attracted more
and more attention due to its tunability over electron-transfer
Sulfonamide is an important structural motif, which widely processes and friendliness to the environment.14 Following our
exists in pharmaceuticals and bioactive compounds, such as continuous interest on using DMSO as a synthon for organic
anticonvulsants, HIV protease inhibitors, antiviral, antibacterial, transformations,11,12,15 herein, we disclosed a novel and effi-
anti-inflammatory and antitumor agents, and herbicides cient electrochemical method to synthesize sulfonamides using
(Scheme 1).1 Besides, sulfonamide, an easy removable protecting DMSO as the starting material to provide the source of –SO2Me
groups of amines, has played a significant role in the transfor- at room temperature (Scheme 2). To the best of our knowledge,
mation of amines.2 Until now, many methods have been developed this is the first example of the synthesis of sulfonamides using
to synthesize sulfonamides, including the direct reaction of amino DMSO as the sulfur source.
compounds with sulfonyl chlorides3 and metal catalyzed cross-
N-Methyl-1-phenylmethanamine (1a) was chosen as a model
coupling of sulfonamides with organic electrophiles,4 or with substrate to examine the reaction conditions. Using KI as the
arylboronic acids under oxidative conditions (Scheme 2).5 Jiang supporting electrolyte, DMSO as the solvent and substrate, Pt plate
and coworkers reported a direct aerobic oxidative coupling between as an anode and Ni plate as a cathode, N-methyl-N-benzyl-
sulfinate salts with amines to prepare sulfonamides.6 Recently, methanesulfonamide 3a was obtained in 81% isolated yield under
Willis and Wu reported an elegant method to construct sulfona- 30 mA constant current for 8 h in an undivided cell (Table 1,
mides from cheap and commercially available amines and aryl- entry 1). IÀ ions were found to be crucial since no desired product
boronic acids in the presence of DABCO-bis(sulfur dioxide) or was observed when KI was replaced by NH4Br or n-Bu4NBF4
DABSO as a source of sulfur dioxide.7 Though great progress had (Table 1, entries 2 and 3). In addition, Using NH4I instead of KI,
been made in this aera, there were still some drawbacks in the the yield of 3a dropped significantly (Table 1, entry 4). Replacing
current methods, such as hazardous or expensive starting materials, DMSO with DMSO/H2O (v/v = 4 : 1) or DMF/DMSO (v/v = 4 : 1), we
stoichiometric amount of base or chemical oxidants, using a transi- could not detect the desired product 3a, and a majority of dimers of
tion metal catalyst and so on. Therefore, a practical and eco-friendly 1a was obtained (Table 1, entries 5 and 6). A Ni cathode was found to
method to synthesize sulfonamides under mild conditions was be important because no target product 3a could be detected when
highly desirable.
the Ni electrode was replaced by a C cathode, with a low conversion
DMSO can serve as not only a common solvent but also a of 1a (Table 1, entry 7). Furthermore, using an inexpensive C plate
multipurpose precursor for –Me,8 –CN,9 –CHO,10 –SMe,11
Key Laboratory of Functional Molecular Engineering of Guangdong Province,
School of Chemistry and Chemical Engineering, South China University of
Technology, Guangzhou 510640, P. R. China. E-mail: gqyuan@scut.edu.cn,
huanglb@scut.edu.cn
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Drug with sulfonamide structure motif.
d1cc00026h
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Table 2 Scope of amine substratesa
Scheme 2 Synthetic methods for sulfonamides.
Table 1 Optimization of the reaction conditionsa
Entry
Variation from the standard conditions
Yieldb
1
2
None
NH4Br instead of KI
86 (81%)c
n.d.
3
4
5
6
7
8
9
10
11
12
n-Bu4NBF4 instead of KI
NH4I instead of KI
n.d.
Trace
n.d.
n.d
n.r.
71%
63%
42%
24%
n.r.
DMSO/H2O (v/v = 4 : 1) instead of DMSO
DMF/DMSO (v/v = 4 : 1) instead of DMSO
Pt(+)7C(À) instead of Pt(+)7Ni(À)
C(+)7Ni(À) instead of Pt(+)7Ni(À)
20 mA instead of 30 mA
10 mA instead of 30 mA
5 mA instead of 30 mA
No electricity
a
Pt plate (10 mm  10 mm  0.1 mm) anode, Ni plate (10 mm  10 mm Â
0.1 mm) cathode, constant current = 30 mA, 1a (0.5 mmol), KI (0.2 mol LÀ1),
DMSO (5.0 mL), room temperature, 8 h, under air and an undivided cell.
b Yield was analyzed by GC-MS with n-dodecane as an internal standard,
n.d. = not detected, n.r. = no reaction. c Isolated yield.
a
Conditions: 1 (0.5 mmol), DMSO (5 mL), 8 h, isolated yield based on
amines.
anode showed slightly reduced yield compared with the platinum
plate anode (Table 1, entry 8). Moreover, a decreased current leads to aryl rings all gave moderate yields of the corresponding
lower reaction yields (Table 1, entries 9–11). Besides, the reaction products (3f–3h). Cyclic secondary amines such as tetrahydro-
could not take place without electricity (Table 1, entry 12).
isoquinoline, pyrrolidine, morpholine, and thiomorpholine
Under the optimized reaction conditions, we further studied etc., were compatible with those reactions, and were trans-
the scope of the reaction with different amines and the results formed into the corresponding products (3n–3u) in good yields.
are summarized in Table 2. Different aliphatic amines all show Aromatic amines such as 2-bromoaniline were suitable
a good activity in those transformations. Steric hindrance on substrates to undergo this reaction in a good yield (3z1).
the nitrogen of benzylamine had a neglectable influence on this Notably, 3-methoxyaniline and 4-methoxyaniline could also be
transformation (3b, 3c). Besides, phenethylamine gave an transformed into the corresponding products (3z2–3z3) in moderate
excellent yield of the corresponding product (3d). A moderate yields.
yield of N-benzylmethanesulfonamide (3e) was obtained when
In order to explore the reaction mechanism, several control
benzylamine was used, which was due to its dimerization. experiments were carried out. The desired product 3a was
Benzylamine with methyl, fluoro, and chloro groups on the obtained in a good yield under the protection of N2 gas
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(Scheme 3, eqn (1)), which indirectly indicated that the oxygen
atom of the sulfone group in 3a did not come from air. No 18
O
labeled product 3a was obtained in the presence of H218O
(Scheme 3, eqn (2)), suggesting that the oxygen atom of the
sulfonamides 3a did not originate from H2O. Based on these
experimental results, we deduced that DMSO provided all the
oxygen atom of the sulfone group in 3a. In addition, the desired
product 3a could only be obtained in a trace amount when
adding radical inhibitor 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) or 2,6-di-tert-butyl-4-methylphenol (BHT) to the electro-
lytic system (Scheme 3, eqn (3)), indicating that the formation of
3a presumably underwent a radical pathway. Within a reaction
time of 40 minutes, N-benzyl-N,S-dimethylthiohydroxylamine (4a)
and N-benzyl-N-methylmethanesulfinamide (5a) were detected by
GC-MS (Scheme 3, eqn (4)). The intermediate 5a could be isolated
and its characterization was given in the ESI.† In addition, 5a
could be transformed to N-methyl-N-benzylmethanesulfonamide
(3a) smoothly under the optimized conditions (Scheme 3, eqn (5)).
This implies that 4a and 5a may be the intermediates in this
conversion. Just DMSO in this standard reaction for 2 h,
methyl((methylsulfonyl)methyl)sulfane (6a) can be detected,
which means that DMSO can be transformed to CH3SH under
electrochemical conditions (Scheme 3, eqn (6)).16
Fig. 1 Cyclic voltammograms of DMSO (10 mL) at room temperature.
(a) Blank experiment; (b) KI (0.2 mol LÀ1); (c) KI (0.2 mol LÀ1) and N-methyl-
N-benzylmethanesulfonamide 1a (1 mmol); (d) DMSO (10 mL) and
n-Bu4NBF4 (0.2 mol LÀ1); with a GC disk working electrode, Pt counter
electrode and Ag/AgCl reference electrode at 100 mV sÀ1 scan rate.
Cyclic voltammetric (CV) experiments were executed to gain
insight into the reaction process. In the blank experiment
(Fig. 1a), no oxidation peak was observed. Adding KI, an
obvious oxidation peak was observed at 1.47 V vs. Ag/AgCl
(Fig. 1b). In the presence of 1a and KI at the same time, a
similar oxidation peak was observed (Fig. 1c), which was due to
the electro-oxidation of IÀ ions. Adding n-Bu4NBF4 to DMSO
solvent, two obvious oxidation peaks were observed at 0.9 V and
1.5 V vs. Ag/AgCl, which were due to the electro-oxidations of
Scheme 4 Proposed reaction mechanism.
DMSO (Fig. 1d). This result strongly indicated that DMSO could
be oxidized under the electrochemical conditions.
According to the above results, a plausible reaction mecha-
nism was proposed in Scheme 4. Initially, the iodide ion was
oxidized to an iodine radical in the Pt anode. Meanwhile,
DMSO was electro-oxidized at the anode to form radical cation
2b, which reacted with another molecule of DMSO to form
dimethyl sulfoxonium cation 2c and dimethyl sulfoxide radical
2e.17 The 2c was rearranged to sulfenate ester 2d, followed by
decomposing to CH3SH, CH2O and H+ ions.17 Meanwhile 1a
was attacked by 2e or an iodine radical to generate N-methyl-1-
phenylmethanamine radical 1b. In addition, the iodine radical
attacked CH3SH to give HI and MeSꢀ.18 And then, 1b was captured
by MeSꢀ to generate N-benzyl-N,S-dimethylthiohydroxylamine
(4a), which was further oxidized by DMSO to form N-benzyl-N-
methylmethanesulfinamide (5a).12,19 And 5a was further oxidized
by DMSO to give the target product 3a.18 In the cathode, the
cathodic reduction of H+ ions led to hydrogen evolution.
Scheme 3 Control experiments.
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In conclusion, a novel and efficient protocol for the synthesis
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of DMSO was developed. The procedure presented a convenient
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We thank the National Natural Science Foundation of China
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Conflicts of interest
There are no conflicts to declare.
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