Electrochemical synthesis of sulfonamide derivatives based on the oxidation of 2,5-diethoxy-4-morpholinoaniline in the presence of arylsulfinic acids

Article abstract of DOI:10.1021/jo500812d

Some new sulfonamide derivatives were synthesized in aqueous solutions via anodic oxidation of 2,5-diethoxy-4-morpholinoaniline in the presence of arylsulfinic acids using a commercial carbon anode. In addition, the formation mechanism of the products was discussed. The obtained data show that the electrogenerated quinone diimine undergoes a Michael-type addition reaction with arylsulfinic acids to yield the respective sulfonamide derivatives. In this work, two different types of products (mono- and disulfone derivatives) in the same precursor could be isolated just by controlling the exerted potentials.

Full text of DOI:10.1021/jo500812d

Note
pubs.acs.org/joc
Electrochemical Synthesis of Sulfonamide Derivatives Based on the
Oxidation of 2,5-Diethoxy-4-Morpholinoaniline in the Presence of
Arylsulfinic Acids
Hadi Beiginejad† and Davood Nematollahi*,‡
†Department of Chemistry, Faculty of Science, Malayer University, P.O. Box 65719, Malayer, I. R. Iran
‡Faculty of Chemistry, Bu-Ali-Sina University, Hamedan 65178-38683, I. R. Iran
S
* Supporting Information
ABSTRACT: Some new sulfonamide derivatives were
synthesized in aqueous solutions via anodic oxidation of 2,5-
diethoxy-4-morpholinoaniline in the presence of arylsulfinic
acids using a commercial carbon anode. In addition, the
formation mechanism of the products was discussed. The
obtained data show that the electrogenerated quinone diimine
undergoes a Michael-type addition reaction with arylsulfinic
acids to yield the respective sulfonamide derivatives. In this
work, two different types of products (mono- and disulfone
derivatives) in the same precursor could be isolated just by
controlling the exerted potentials.
On the other hand, the presence of alkyl groups in the
ulfonamides are a class of antibacterial compounds, all of
Swhich contain the sulfonamido group, −SO NH (Figure structures of drugs increases their hydrophobicity and makes it
2
easier for them to cross the gut wall. One of the properties of
such drugs is their lack of rapid excretion. Accordingly, we
expected that the synthesis of new sulfonamide derivatives with
one or two arylsulfinic groups might lead to the above-
mentioned properties. To implement this idea, we synthesized
some new sulfonamide derivatives by means of the anodic
oxidation of 2,5-diethoxy-4-morpholinoaniline (DEM) in the
presence of arylsulfinic acids (Figure 1).
The cyclic voltammogram of a solution of DEM in an
aqueous solution containing perchloric acid (c = 0.1 M) is
shown as curve a in Figure 2. As can be seen, one anodic peak
(A1) and two cathodic peaks (C1 and C0) were obtained.
Anodic peak A1 and cathodic peak C1 are counterparts and
correspond to the transformation of DEM to p-quinone
diimine QDI, and vice versa within a reversible two-electron
process.6 In addition, cathodic peak C0 corresponds to the
reduction of 2,5-diethoxy-4-iminocyclohexa-2,5-dienone
(formed from the hydrolysis of QDI) to 4-amino-2,5-
diethoxyphenol.6 The oxidation of DEM in the presence of
p-toluenesulfinic acid (TSA) as a nucleophile was studied in
some detail. As can be seen, IpC1 and IpC0 decrease and a new
anodic peak (A2) and corresponding cathodic peak (C2) appear
1). These compounds are used in both human and veterinary
medicine. In human medicine they are widely used to treat
various conditions including urinary tract infections, eye
lotions, gut infections, and mucous membrane infections.
Sulfonamides are classified in veterinary medicine as standard
use, highly soluble, potentiated, and topical sulfonamides.1,2
These drugs are preferred because of their wide spectrum of
antimicrobial activity and noninterference with the host defense
mechanism. Thus, the synthesis of new sulfonamide derivatives
is a fascinating and informative area in medicinal chemistry.2
Such properties have motivated a greater number of researchers
to develop new methods for the synthesis of sulfonamide
derivatives. In this way, many of these compounds have been
synthesized and investigated against various protozoal, bacterial,
and viral diseases.2,3
On the other hand, because of the high selectivity due to the
in situ formation of the reactants at the electrode−electrolyte
interface, the change of polarity using electron transfer
reactions, and the formation of different types of products by
control of the potential, electrochemistry can be considered as a
powerful tool for the synthesis of complex organic molecules.4
A literature review shows that contrary to the large number of
reports on chemical synthesis, only a few papers on the
electrolytic synthesis of the sulfonamide derivatives have been
published.5
Received: April 10, 2014
Published: June 13, 2014
© 2014 American Chemical Society
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Figure 1. Structures of some available sulfonamides and sulfonamides synthesized in this work (P1, P2, and DSDEM).
results show that anodic peak A1 disappeared when the charge
consumption was about two electrons per molecule of DEM.
The cyclic voltammetry and controlled-potential coulometry
data accompanied by the spectroscopic data of the final product
(see the Supporting Information) allow us to propose the
mechanism shown in Scheme 1 for the electrochemical
oxidation of DEM in the presence of TSA at 0.40 V vs Ag/
AgCl.
Scheme 1. Proposed Mechanism for the Electrochemical
Oxidation of DEM in the Presence of TSA and BSA
Figure 2. Cyclic voltammograms of (a) DEM (1.0 mM), (b) DEM
(1.0 mM) in the presence of TSA (2.0 mM), and (c) TSA (2.0 mM)
in the absence of DEM in aqueous solutions containing perchloric acid
(0.1 M) at a glassy carbon electrode. Scan rate = 100 mV s−1; t = 25
1 °C.
According to our results, it seems that the 1,4-addition
(Michael addition) reaction of TSA to QDI leads to new
derivative of 2,5-diethoxy-4-morpholinoaniline (P1) as a final
product. The oxidation of P1 is more difficult than the
oxidation of DEM by virtue of the presence of the electron-
withdrawing tolylsulfonyl group on P1 as well as the insolubility
of P1 in aqueous solution. Our data also confirm that the new
peaks A2 and C2 are related to oxidation of P1 to its related p-
quinone diimine (P1ox) and vice versa within a reversible two-
electron process (E1/2 = 0.51 V; see Scheme 2).
at more positive potentials (Figure 2, curve b). It should be
noted that, under these conditions, no anodic or cathodic peaks
were observed in the cyclic voltammogram of TSA (Figure 2,
curve c).
The effect of the TSA concentration on the cyclic
voltammogram of DEM was also studied. Our data show that
when the TSA concentration is increased, (a) IpA1 remains
constant, (b) IpC1 and IpC0 decrease, and (c) IpA2 and IpC2
increase (see Figure S1 in the Supporting Information).
The effect of the potential scan rate on the cyclic
voltammogram of DEM in the presence of TSA was also
studied. The obtained data show that with increasing scan rate,
the peak current ratios (IpC1/IpA1 and IpA1/IpA2) increase.
The time scale of a cyclic voltammetry experiment is
determined by the scan rate, as increasing the scan rate
decreases the experimental time scale and removes the effects
In the EC mechanism, the peak current ratios (IpA1/IpC1 and
pA2/IpA1) are indications of the homogeneous reaction rate. An
I
increase in the peak current ratio is an indicator of a high
reaction rate. Comparison of the cyclic voltammogram of DEM
in the presence of TSA with that of benzenesulfinic acid (BSA)
shows that the rates of the reactions between arylsulfinic acids
and QDI vary in the order TSA > BSA (Figure S2 in the
Supporting Information). The observed trend is expected since
TSA is much better nucleophile than BSA because of the
presence of a methyl group with electron-donating character in
the structure of TSA.5b,c
In order to synthesize the disulfone derivatives of DEM,
electrochemical oxidation of DEM was studied in a 50/50 (v/v)
water (phosphate buffer, pH 3.2)/acetonitrile mixture.
Acetonitrile as a cosolvent was added to dissolve P1. Under
these conditions, the cyclic voltammogram shows one anodic
peak (A1) and two cathodic peaks (C1 and C0) at 0.34, 0.21,
and 0.08 V vs Ag/AgCl, respectively. In the presence of TSA,
of the following chemical reaction (the reaction of QDI with
7
TSA) appearing as an increase in IpC1/IpA1 and IpA1/IpA2
.
Furthermore, the current function for peak A1, IpA1/v1/2
,
changes only slightly with increasing scan rate, and such
behavior is also adopted as indicative of the EC mechanism.7
Controlled-potential coulometry was performed in an aqueous
solution containing perchloric acid (c = 0.1 M), DEM (0.25
mmol), and TSA (0.25 mmol) at 0.40 V vs Ag/AgCl. Our
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the cathodic peaks (C1 and C2) decreased and a new anodic/
cathodic couple peak (A2/C2) appeared at 0.43 and 0.40 V vs
Ag/AgCl, respectively. Controlled-potential coulometry was
performed in a 50/50 (v/v) water (phosphate buffer, pH 3.2)/
acetonitrile mixture containing DEM and TSA at 0.50 V vs Ag/
AgCl. Monitoring the electrolysis progress by cyclic voltam-
metry synchronously during controlled-potential coulometry
showed that as the coulometry progresses, IpA1 and IpA2
decrease (Figure 3). These peaks (A1 and A2) disappear
when the charge consumption becomes about four electrons
per molecule of DEM.
economy (>99%), and selective synthesis of mono- or disulfone
derivatives of DEM (P1 or DSDEM) just by controlling the
exerted potential during electrolysis. Finally, although one-pot
reactions are performed potentiostatically on a millimolar scale
in divided cells, there is little difficulty in producing larger
quantities by using larger cells.
EXPERIMENTAL SECTION
■
Apparatus and Reagents. The working electrode used in the
voltammetry experiments was a glassy carbon disc (1.8 mm diameter),
and a platinum wire was used as the counter electrode. The working
electrode used in controlled-potential coulometry and macroscale
electrolysis was an assembly of four ordinary soft carbon rods (6 mm
in diameter and 4 cm in length), placed as single rods at the edges of a
square with a distance of 3 cm. A large platinum gauze cylinder (25
cm2 in area) constituted the counter electrode. The electrochemical
oxidations were performed under constant-potential conditions in a
cell with two compartments separated by an ordinary porous fritted-
glass diaphragm (a tube with 1.5 cm diameter) and equipped with a
magnetic stirrer. DEM, TSA, BSA, perchloric acid, and other solvents
were obtained from commercial sources and used without further
purification. More details are described in the previous paper.8
Electroorganic Synthesis of P1 and P2. In a typical procedure,
70 mL of 0.1 M perchloric acid solution containing DEM (0.25 mmol)
and TSA or BSA (0.25 mmol) was subjected to electrolysis at 0.40 V
vs Ag/AgCl in a divided cell. The electrolysis was terminated when the
current decayed to 5% of its original value. The precipitated solid was
collected by filtration and washed several times with water.
N-(2,5-Diethoxy-4-morpholinophenyl)-4-methylbenzenesulfona-
mide (C21H28N2O5S, P1). Isolated yield: 62% (0.065 g). Mp: 211−212
1
Figure 3. Cyclic voltammograms of DEM (0.30 mmol) in the
presence TSA (0.60 mmol) during controlled-potential coulometry at
0.50 V vs Ag/AgCl in a 50/50 (v/v) water (phosphate buffer, pH
3.2)/acetonitrile mixture after the consumption of (a) 0 C, (b) 20 C,
°C (dec). H NMR (300 MHz, acetone-d6): δ 1.23 (t, 3H), 1.44 (t,
3H), 2.38 (s, 3H), 3.89 (t, 4H), 3.95 (q, 2H), 4.00 (t, 4H), 4.15 (q,
2H), 7.39 (m, 4H), 7.76 (d, J = 8.2 Hz, 2H), 8.79 (NH, 1H). 13C
NMR (75 MHz, CDCl3): δ 14.6, 21.4, 55.4, 64.9, 66.2, 66.4, 107.4,
107.6, 125.1, 128.0, 130.2, 130.5, 137.9, 144.2, 145.0, 145.3. IR (KBr):
553.8, 576.0, 621.0, 709.7, 812.7, 908.6, 1043.1, 1089.5, 1122.0,
1210.5, 1265.7, 1340.2, 1399.5, 1453.0, 1511.2, 1598.8, 2989.8, 3243.1
cm−1. MS: m/z (relative intensity) 420 (63, [M]+), 265 (52), 246
(90), 172 (20), 155 (23), 139 (23), 123 (49), 107 (18), 91 (52), 45
(20). Anal. Calcd for C21H28N2O5S: C, 59.98; H, 6.71; N, 6.66; S,
7.63. Found: C, 59.82; H, 6.67; N, 6.64; S, 7.59.
N-(2,5-Diethoxy-4-morpholinophenyl)benzenesulfonamide
(C20H261N2O5S, P2). Isolated yield: 57% (0.058 g). Mp: 213−214 °C
(dec). H NMR (300 MHz, acetone-d6): δ 1.23 (t, 3H), 1.46 (t, 3H),
3.88 (m, 6H), 4.15 (t, 4H), 4.25 (q, 2H), 7.39 (s, 2H), 7.39 (m, 3H),
7.87 (d, J = 8.6 Hz, 2H), 8.76 (NH, 1H). 13C NMR (75 MHz,
CDCl3): δ 13.8, 53.1, 64.3, 65.2, 106.0, 108.4, 127.0, 129.2, 133.3,
144.1, 144.6. IR (KBr): 627.0, 692.6, 727.7, 764.7, 909.9, 1034.2,
1121.1, 1169.5, 1217.3, 1269.1, 1334.8, 1394.0, 1450.8, 1526.8, 2986.6,
3273.2 cm−1. MS: m/z (relative intensity) 406 (100, [M]+), 265 (98),
237 (58), 181 (25), 143 (58), 125 (72), 94 (35), 77 (86), 43 (35).
Anal. Calcd for C20H26N2O5S: C, 59.09; H, 6.45; N, 6.89; S, 7.89.
Found: C, 58.88; H, 6.76; N, 6.70; S, 7.63.
(c) 41 C, (d) 60 C, and (e) 110 C. Scan rate = 100 mV s−1; t = 25
°C.
1
Under these conditions, the generation of P1ox is followed by
a Michael-type addition reaction of TSA to produce disulfone
derivative DSDEM as a final product (Scheme 2). The
structure of DSDEM was further confirmed by single-crystal
X-ray diffraction analysis, as shown in Figure 4.
The presented electrochemical method has some important
advantages, including the use of electricity as the energy source
instead of oxidative reagents, the ability to work at room
temperature and pressure, technical feasibility, high atom
Scheme 2. Proposed Mechanism for the Electrochemical
Synthesis of DSDEM
Electroorganic Synthesis of DSDEM. A 50/50 (v/v) water
(phosphate buffer, c = 0.2 M, pH 3.2)/acetonitrile mixture (70 mL)
containing DEM (0.25 mmol) and TSA (0.5 mmol) was subjected to
electrolysis at 0.50 V vs Ag/AgCl. The electrolysis was terminated
when the current decayed to 5% of its original value. The precipitated
solid was collected by filtration and washed several times with water.
N-(2,5-Diethoxy-4-morpholinophenyl)-N-(4-methylbenzenesul-
fonyl)-4-methylbenzenesulfonamide (C28H34N2O7S2, DSDEM). Iso-
1
lated yield: 63% (0.090 g). Mp: 184−185 °C (dec). H NMR (300
MHz DMSO-d6): δ 0.94 (t, 3H), 1.2 (t, 3H), 2.43 (s, 6H), 3.08 (t,
4H), 3.74 (m, 8H), 6.36 (s, 1H), 6.46 (s, 1H), 7.42 (d, J = 8.2 Hz,
4H), 7.68 (d, J = 8.3 Hz, 4H). 13C NMR (75 MHz DMSO-d6): δ 14.1,
14.7, 21.1, 50.0, 63.8, 64.3, 66.3, 103.2, 113.6, 118.0, 128.3, 129.4,
136.6, 143.6, 144.5, 144.8, 151.9. IR (KBr): 489.8, 546.4, 607.3, 662.9,
689.7, 812.7, 902.1, 971.0, 1044.8, 1085.7, 1116.2, 1173.0, 1205.0,
1347.1, 1372.4, 1390.7, 1407.7, 1451.1, 1514.4, 1597.8, 2810.2, 2850.6,
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Note
Figure 4. ORTEP view of the X-ray crystal structure of DSDEM.
2886.0, 2927.3, 2976.0 cm−1. Anal. Calcd for C28H34N2O7S2: C, 58.52;
H, 5.96; N, 4.87; S, 11.16. Found: C, 58.20; H, 5.75; N, 4.82; S, 11.27.
Org. Chem. 2005, 70, 7769−7772. (e) Davarani, S. S.; Nematollahi, D.;
Shamsipur, M.; Najafi, N. M.; Masoumi, L.; Ramyar, S. J. Org. Chem.
2006, 71, 2139−2142.
(5) (a) Nematollahi, D.; Maleki, A. Electrochem. Commun. 2009, 11,
488−491. (b) Varmaghani, F.; Nematollahi, D.; Mallakpour, S.;
Esmaili, R. Green Chem. 2012, 14, 963−967. (c) Nematollahi, D.;
Sayadi, A.; Varmaghani, F. J. Electroanal. Chem. 2012, 671, 44−50.
(6) Beiginejad, H.; Nematollahi, D. Electrochim. Acta 2013, 114,
242−250.
ASSOCIATED CONTENT
* Supporting Information
■
S
Cyclic voltammograms of DEM in the presence of TSA at
various concentrations; cyclic voltammograms of DEM in the
presence of TSA and BSA; FT-IR, H NMR, 13C NMR, and
1
MS spectra for compounds P1, P2, and DSDEM; and
crystallographic data for DSDEM (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
(7) Bard, A. J.; Faulkner, L. R. Electrochemical Methods, 2nd ed.;
Wiley: New York, 2001; p 497.
(8) Nematollahi, D.; Dehdashtian, S.; Niazi, A. J. Electroanal. Chem.
2008, 616, 79−86.
AUTHOR INFORMATION
Corresponding Author
*E-mail: nemat@basu.ac.ir.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the Bu-Ali Sina University Research Council
and the Center of Excellence in Development of Environ-
mentally Friendly Methods for Chemical Synthesis (CE-
DEFMCS) for their support of this work.
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