Chemical and electrochemical oxidative coupling of N,N-dialkyl-p- phenylenediamines and arylsulfinic acids. Synthesis of sulfonamide derivatives

Article abstract of DOI:10.1016/j.tetlet.2010.10.014

Electrochemical and chemical oxidation of N,N-dialkyl-p-phenylenediamines have been studied in the presence of arylsulfinic acids as nucleophiles in aqueous solutions for the synthesis of sulfonamide derivatives. The results indicate that the electrochemi

Full text of DOI:10.1016/j.tetlet.2010.10.014

Tetrahedron Letters 51 (2010) 6447–6450
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Chemical and electrochemical oxidative coupling of
N,N-dialkyl-p-phenylenediamines and arylsulfinic acids.
Synthesis of sulfonamide derivatives
D. Nematollahi a, , E. Mehdipour b, A. Zeinodini-Meimand b, A. Maleki a
⇑
a Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Zip Code 65178-38683, Iran
b Department of Chemistry, Faculty of Science, Lorestan University, Khoramabad, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Electrochemical and chemical oxidation of N,N-dialkyl-p-phenylenediamines have been studied in the
presence of arylsulfinic acids as nucleophiles in aqueous solutions for the synthesis of sulfonamide deriv-
atives. The results indicate that the electrochemically or chemically generated quinone-diimines partic-
ipate in Michael-type addition reactions with arylsulfinic acids and are converted into the corresponding
sulfonamide derivatives.
Received 6 August 2010
Revised 17 September 2010
Accepted 1 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
N,N-Dialkyl-p-phenylenediamine
Arylsulfinic acid
Sulfonamides
Michael-type addition
Cyclic voltammetry
1. Introduction
amide derivatives,11and following the valuable works of Compton
et al. on the electrochemical oxidation of N,N-dialkyl-p-phenylen-
The development of efficient, simple, and straightforward
chemical and electrochemical processes for the synthesis of widely
used organic compounds from readily available reagents are major
challenges for chemists in organic synthesis. Sulfonamide deriva-
tives are of considerable interest and have been used extensively
as antibacterial,1 anti-carbonic anhydrase,2 diuretic3 and hypogly-
cemic reagents,4 and as pharmaceutical agents for the treatment of
different diseases such as infections,5 Alzheimer’s disease,6 HIV,7
and cancer.8 Besides clinical uses, a number of sulfonamides have
been synthesized and employed in various organic transforma-
tions, for example as organocatalysts for Michael and aldol reac-
tions9 and as chelate extraction reagents for divalent metal
cations.10
ediamines and subsequent 1,4-Michael addition,19–25 herein we de-
scribe convenient chemical and electrochemical methods for the
synthesis of sulfonamides by oxidation of N,N-dialkyl-p-phenylen-
ediamines in the presence of arylsulfinic acids. This work has led
to the development of facile and environmentally friendly electro-
chemical and chemical methods for the synthesis of sulfonamides.
We performed the electrochemical oxidation of N,N-dialkyl-p-
phenylenediamines 1a,b in the presence of 4-chlorobenzenesulfi-
nic acid (3a) and the chemical oxidation of N,N-dialkyl-p-pheny-
lenediamines 1a,b in the presence of arylsulfinic acids 3a–c in
aqueous solution using potassium ferricyanide as the oxidizing
agent.
A literature survey revealed that only our previous Letter has re-
ported an electrochemical synthesis of sulfonamides,11 but in the
vast number of chemical methods reported for the synthesis of sul-
fonamides, various catalysts and harsh conditions have been
used.1,12–14 Consequently, there is an opportunity for further devel-
opment toward mild conditions, increased variation of the substitu-
ents in the substrates and improved yields. Based on our own
experience in the synthesis of organic compounds via electrochem-
ical routes,15–18 and our previous study on the synthesis of sulfon-
2. Results and discussions
A cyclic voltammogram of a 1.0 mM solution of N,N-diethyl-p-
phenylenediamine (1a) in aqueous solution containing 0.2 M phos-
phate buffer, pH 7.5, is shown in Figure 1, curve a. One anodic peak
(A1) and the corresponding cathodic peak (C1) were evident, which
correspond to the transformation of 1a into the quinone-diimine
2a and vice versawithin a two-electron process (Scheme 1).11,16,19–25
In the presence of 1.0 mM 4-chlorobenzenesulfinic acid (3a),
the cathodic peak (C1) decreased and a new anodic peak (A2) ap-
peared at a more positive potential (Fig. 1, curve b). This indicated
the reactivity of the electrochemically generated quinone-diimine
⇑
Corresponding author. Tel.: +98 811 8282807; fax: +98 811 8257407.
E-mail addresses: nemat@basu.ac.ir, dnematollahi@yahoo.com (D. Nematollahi).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.014

6448
D. Nematollahi et al. / Tetrahedron Letters 51 (2010) 6447–6450
A1
IpC1/IpA1
A1
4.2
3.2
15
0.8
A2
A2
0.7
0.6
0.5
b
a
11
7
d
c
2.2
b
a
1.2
0
25 50 75 100
3
v/mVs-1
c
0.2
-1
-5
-9
-0.8
-1.8
-2.8
C1
0.1
C1
-0.25
-0.15
-0.05
0.05
0.15
0.25
0.35
-0.1
0.0
0.2
0.3
0.4
E/V vs. SCE
E/V vs. SCE
Figure 2. Typical cyclic voltammograms of 1.0 mM N,N-diethyl-p-phenylenedi-
amine (1a) in the presence of 3.0 mM 4-chlorobenzenesulfinic acid at a glassy
carbon electrode, in aqueous solution containing 0.2 M phosphate buffer (pH 7.5).
Scan rates from (a) to (d) are 10, 25, 50, and 100 mV sÀ1, respectively. Inset:
variation of peak current ratio (IpC1/IpA1) versus scan rate.
Figure 1. Cyclic voltammograms of 1.0 mM N,N-diethyl-p-phenylenediamine (1a):
(a) in the absence, (b) in the presence of 1.0 mM 4-chlorobenzenesulfinic acid (3a)
and, (c) 1.0 mM 3a in the absence of 1a, at a glassy carbon electrode, in aqueous
solution containing 0.2 M phosphate buffer (pH 7.5). Scan rate: 10 mV sÀ1
.
R1
cyclic voltammetry (Fig. 3). It was shown that, in proportion to
the progress of the coulometry, the anodic peaks (A1 and A2) de-
crease. All the anodic and cathodic peaks disappeared when the
charge consumption became about 2eÀ per molecule of 1a.
These observations allow us to propose the pathway outlined in
Scheme 1 for the electrooxidation of 1a in the presence of 3a. Gen-
eration of quinone-diimine 2a is followed by a Michael-type addi-
tion reaction of 3a to quinone-diimine 2a, producing sulfonamide
H2N
N
R1
1a,b
2a,b
+
-2e
-H
R1
HN
N
R1
A1
IpA1
/
µ
A
A2
8
6
IpA1 = -0.42Q +
7.98
R2 = 0.9985
7.5
6
O
S
O
Cl
R1=C2H5
R1=CH3
3a
4.5
3
a
R1
O
S
4
H
1.5
0
Cl
N
N
R1
O
0
5
10 15 20
4e,f
Charge/C
2
Scheme 1. Electrochemical oxidation of 1a and 1b in the presence of 4-chloro-
benzenesulfinic acid (3a).
g
0
2a toward 3a. Additional voltammetric studies were performed by
varying the potential scan rate. Figure 2 shows the cyclic voltam-
mograms of N,N-diethyl-p-phenylenediamine (1a) in the presence
of 3a at various scan rates. The voltammograms show that propor-
tional to the augmentation of the potential sweep rate, the peak
current ratio (IpC1/IpA1) increases and the current of peak A2 de-
C1
0.1
-2
-0.1
0.0
0.2
0.3
0.4
E/V vs. SCE
creased. Furthermore, the current function for peak A1, (IpA1/v1/2
)
Figure 3. Cyclic voltammograms of 0.1 mmol N,N-diethyl-p-phenylenediamine
(1a) in the presence of 0.1 mmol 4-chlorobenzenesulfinic acid (3a) during
controlled potential coulometry at 0.20 V versus the SCE after consumption of (a)
0, (b) 2, (c) 4, (d) 7, (e) 9, (f) 14, and (g) 17 C. Inset: variation of anodic peak current
changes only slightly with increasing scan rate.
Controlled-potential coulometry was performed in aqueous
solution containing 0.1 mmol of 1a and 0.1 mmol of 3a at 0.20 V
versus the SCE. The electrolysis progress was monitored using
(IpA1) versus charge consumed. Scan rate: 20 mV sÀ1
.

D. Nematollahi et al. / Tetrahedron Letters 51 (2010) 6447–6450
6449
Table 1
4e as the final product. Oxidation of 4e is more difficult than oxi-
Synthesis of sulfonamide derivatives 4a–f via chemical oxidation
Entry Product R1 R2
C2H5 CH3 15
dation of the parent starting molecule 1a by virtue of the presence
of the electron-withdrawing p-tolylsulfonyl group as well as by the
insolubility of 4e in the phosphate buffer (pH 7.5) solution.
According to our results, the anodic peaks of the voltammo-
grams presented in Figure 1 (A1 and A2) pertain to the oxidation
of N,N-diethyl-p-phenylenediamine (1a) and sulfonamide 4e,
respectively. Obviously, the cathodic peak C1 corresponds to the
reduction of quinone-diimine 2a. Similar results were obtained
for the electrochemical oxidation of N,N-dimethyl-p-phenylenedi-
amine (1b) in the presence of 3a.
Time (min) Mp (°C)
Isolated yield (%)
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
154–156 92
C2H5
CH3
CH3
H
15
122–124 88
147–149 75
136–137 78
148–150 85
112–114 80
CH3 35
H
30
25
35
C2H5 Cl
CH3 Cl
was interrupted during electrolysis and the carbon anode was
washed in acetone in order to reactivate it. On completion of elec-
trolysis, the cell was placed in a refrigerator overnight. The solid
which precipitated was collected by filtration and was washed
with H2O. The products were purified by column chromatography
[silica gel, EtOAc/n-hexane (40/60) for 4e and (75/25) for 4f]. The
isolated yields of products 4e and 4f were 75% and 78%, respec-
tively. All products were characterized by IR, 1H NMR, 13C NMR
and MS.
In chemical oxidation, a suitable oxidizing agent is one that only
oxidizes N,N-dialkyl-p-phenylenediamines 1a,b to the quinone-dii-
mines without any side effects on the arylsulfinic acids 3a–c.
Potassium ferricyanide is a stable, easily handled and commer-
cially available oxidizing agent. Recently, we demonstrated the
suitability of potassium ferricyanide with an oxidation potential
of 0.24 V versus a SCE, for the oxidation of catechols.26,27 Several
aqueous media with different pHs were investigated during the
course of this study. The best results were achieved using an aque-
ous phosphate buffer (pH 7.5). When N,N-dialkyl-p-phenylenedi-
amines (1a,b) were treated with potassium ferricyanide in the
presence of arylsulfinic acids 3a–c in an aqueous solution contain-
ing 0.2 M phosphate buffer (pH 7.5), sulfonamides 4a–f were ob-
tained in good yields (Scheme 2, Table 1).
4. Chemical synthesis of 4a–f
To a vigorously stirred solution of a phosphate buffer (pH 7.5, c
0.2 M) was added a solution of N,N-dialkyl-p-phenylenediamines
1a,b (1.0 mmol) and arylsulfinic acid 3a–c (1.0 mmol). A solution
of potassium ferricyanide (2.0 mmol) (40 ml) was added dropwise
over a period of 15–35 min. The reaction mixture became dark in
color and precipitates were formed. At the end of the reaction,
the mixture was placed in a refrigerator overnight. The solid mate-
rials were collected by filtration. Products 4a and 4b were washed
with H2O and recrystallized from acetone/n-hexane. The other
products were purified by column chromatography [silica gel,
EtOAc/n-hexane (40/60) for 4e, (75/25) for 4f and (35/65) for 4c
and 4d]. The products were characterized by IR, 1H NMR, 13C
NMR and MS.
As shown in Table 1, treatment of N,N-dialkyl-p-phenylenedi-
amines 1a,b and arylsulfinic acids 3a–c in the presence of potas-
sium ferricyanide afforded the corresponding sulfonamide
derivatives in good yields.
3. Electrochemical syntheses of 4e and 4f18
An aqueous solution of phosphate buffer (70 ml) (pH 7.5,
c = 0.2 M) containing 1.0 mmol of N,N-diethyl-p-phenylenediamine
(1a) [or N,N-dimethyl-p-phenylenediamine (1b)] and 1.0 mmol of
4-chlorobenzenesulfinic acid (3a) was electrolyzed at 0.20 V versus
the SCE, in an undivided cell equipped with a carbon rod as the an-
ode and a stainless steel cathode. The electrolysis was terminated
when the current decay became greater than 95%. The oxidation
5. Characterization data11
5.1. 4-Chloro-N-[4(diethylamino)phenyl]benzenesulfonamide
(C16H19ClN2O2S) (4e)
NH2
NH
Mp 148–150 °C. IR (KBr): 3236, 2974, 1611, 1517, 1399, 1334,
1267, 1157 cmÀ1 1H NMR (90 MHz, CDCl3): d = 1.2 (t, 6H, J = 7),
.
2 mmol [Fe(CN)6]3-
3.3 (q, 4H, J = 7), 6.5 (d, 2H, J = 8), 6.7 (d, 2H, J = 9), 7.4 (d, 2H,
J = 8), 7.7 (d, 2H, J = 9). 13C NMR (22.5 MHz, CDCl3): d = 12.4, 44.3,
112.0, 123.5, 126.5, 128.9, 138.1, 138.7, 146.7. MS (EI): m/z (rela-
tive intensity); 338 (M+Å) (5), 175 (22), 163 (100), 133 (55), 119
(90), 111 (87), 91 (55), 75 (85), 50 (42), 29 (53), 27 (50).
N+
N
R1 R1
R1 R1
2a,b
1a,b
5.2. 4-Chloro-N-[4(dimethylamino)phenyl]benzenesulfonamide
(C14H15ClN2O2S) (4f)
R2
Mp 112–114 °C. IR (KBr): 3258, 2796, 1611, 1519, 1476, 1397,
O
1335, 1227, 1161, 1092 cmÀ1 1H NMR (90 MHz, CDCl3): d = 2.9
.
R2
S
(s, 6H), 6.6 (d, 2H, J = 8), 6.8 (d, 2H, J = 7), 7.4 (d, 2H, J = 8), 7.6 (d,
2H, J = 7). 13C NMR (22.5 MHz, CDCl3): d = 40.4, 112.8, 124.6,
125.9, 128.9, 138.1, 138.9, 149.4 ppm. MS (EI): m/z (relative inten-
sity); 310 (M+.) (2), 163 (18), 135 (100), 119 (52), 111 (47), 75 (38),
65 (32), 50 (32), 42 (28), 41 (23), 18 (17).
In conclusion, we have described facile, convenient and versa-
tile protocols for the electrochemical and chemical syntheses of
sulfonamides using commercially available starting materials in
aqueous solution. Mild reaction conditions, short reaction times
and good to excellent yields are attractive features of the proce-
dures. We believe that the experimental simplicity and use of
O
3a-c
O S
HN
O
R1
N
R1
4a-f
Scheme 2. Chemical oxidation of 1a,b in the presence of 3a–c.

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D. Nematollahi et al. / Tetrahedron Letters 51 (2010) 6447–6450
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Acknowledgments
The authors acknowledge Bu-Ali Sina University Research
Council and the Center of Excellence in Development of Chemical
Methods (CEDCM) for supporting this work.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.10.014.
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