A facile electrochemical method for the synthesis of new sulfonamide derivatives of potential biological significance

Article abstract of DOI:10.1016/j.cclet.2014.01.005

The electrochemical synthesis of some new sulfonamide derivatives was carried out via the electrochemical oxidation of 2,3-dihydrophthalazine-1,4- dione (1) in the presence of arylsulfinic acids (2a and 2b) as nucleophiles. The results show that, the electrogenerated phthalazine-1,4-dione (1ox) participates in a Michael type addition reaction with 2a or 2b and via an EC mechanism to produce the corresponding sulfonamide derivatives. This method provides a one-pot procedure for the synthesis of new sulfonamide derivatives of potential biological significance in good yields without using toxic reagents at a carbon electrode in an environmentally friendly manner.

Full text of DOI:10.1016/j.cclet.2014.01.005

Chinese Chemical Letters 25 (2014) 593–595
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
A facile electrochemical method for the synthesis of new sulfonamide
derivatives of potential biological significance
b
c
Davood Nematollahi a, , Saied Saeed Hosseiny Davarani , Pari Mirahmadpour ,
*
Fahimeh Varmaghani a
a Faculty of Chemistry, Bu-Ali Sina University, Hamedan 65178-38683, Iran
b Department of Chemistry, Faculty of Science, University of Shahid Beheshti, Tehran 19835389, Iran
c Department of Chemistry, Faculty of Science, Arak Branch, Islamic Azad University, Arak, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
The electrochemical synthesis of some new sulfonamide derivatives was carried out via the
electrochemical oxidation of 2,3-dihydrophthalazine-1,4-dione (1) in the presence of arylsulfinic acids
(2a and 2b) as nucleophiles. The results show that, the electrogenerated phthalazine-1,4-dione (1ox)
participates in a Michael type addition reaction with 2a or 2b and via an EC mechanism to produce the
corresponding sulfonamide derivatives. This method provides a one-pot procedure for the synthesis of
new sulfonamide derivatives of potential biological significance in good yields without using toxic
reagents at a carbon electrode in an environmentally friendly manner.
Received 29 July 2013
Received in revised form 23 December 2013
Accepted 26 December 2013
Available online 9 January 2014
Keywords:
2,3-Dihydrophthalazine-1,4-dione
Cyclic voltammetry
Electrochemical synthesis
Sulfonamide
ß 2014 Davood Nematollahi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Arylsulfinic acid
1. Introduction
electrochemical oxidation of 2,3-dihydrophthalazine-1,4-dione (1)
in the presence of p-toluenesulfinic acid (2a) and benzensulfinic
The therapeutic and pharmaceutical features of sulfonamides
have been reported for many years. These derivatives were
intensively investigated as the first effective antibacterial agents
[1]. Sulfonamides are still widely used for conditions such as acne
and urinary tract infections caused by bacteria resistant to other
antibiotics [2]. Sulfonamides can be carbonic anhydrase inhibitors,
diuretic and hypoglycemic reagents, and pharmaceutical agents
for the treatment of different diseases such as infections,
Alzheimer, HIV, and cancer [3–5]. Among N-containing heterocy-
clic compounds, phthalazine has attracted scientific interest.
Phthalazine derivatives were found to possess multiple biological
activities such as antimicrobial, anticonvulsant, antifungal, anti-
cancer, and anti-inflammatory activities [6–8]. Phthalazine deri-
vatives synthesis provides an entrance to a variety of compounds
with pharmacological activities. Following our experiences in
electrochemical synthesis of sulfonamides based on the in situ
generation of Michael acceptors [9–11], we envisioned that
organic compounds containing both phthalazine and sulfonamide
moieties might possess enhanced pharmaceutical properties and
medicinal activities. This idea prompted us to investigate the
acid (2b) as nucleophiles and we have reported an easy and one-
pot electrochemical method for the synthesis of sulfonamide
derivatives (3a and 3b) in good yields and purity, using
environmentally friendly protocols with high atom economy.
2. Experimental
Reaction equipment was described in an earlier paper [12]. 2,3-
Dihydrophthalazine-1,4-dione, toluene and benzene derivatives of
sulfinic acid were obtained from commercial sources. A solution of
phosphate buffer (60 mL, c = 0.2 mol/L, pH 2.0) in a water/
acetonitrile (85/15%, v/v) solution containing 2,3-dihydrophtha-
lazine-1,4-dione (1) (0.25 mmol) and 4-toluenesulfinic acid (or
benzensulfinic acid) (0.25 mmol) was electrolyzed in a divided cell
equipped with a carbon anode (an assembly of four rods) and a
large stainless steel gauze as the cathode, at 0.85 V vs. Ag/AgCl, at
25 8C. The electrolysis was terminated when the current decreased
by more than 95%. The process was interrupted several times
during the electrolysis and the carbon anode was washed in
acetone in order to reactivate the anode. At the end of the
electrolysis, the cell was placed in a refrigerator overnight. The
precipitated solid was collected by filtration and was washed
several times with water. After drying, the products were
characterized by IR, NMR (1H and 13C) and MS.
*
Corresponding author.
E-mail address: nemat@basu.ac.ir (D. Nematollahi).
1001-8417/$ – see front matter ß 2014 Davood Nematollahi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2014.01.005

594
D. Nematollahi et al. / Chinese Chemical Letters 25 (2014) 593–595
2,3-Dihydro-2-tosylphthalazine-1,4-dione (C15H12N2O4S) (3a):
Isolated yield: 75%. Mp. >270 8C (dec.), yellow. IR (KBr, cmÀ1):
2512, 1738, 1672, 1495, 1298, 1255, 1208, 1115, 1073, 1022, 825,
784, 679, 618, 559, 380, 230. 1H NMR (300 MHz, DMSO-d6):
1.7 (s,
3H), 6.8 (d, 2H), 7.5 (d, 2H), 7.8 (d, 2H), 8.1 (d, 2H), 11.9 (NH, 1H).
13C NMR (75 MHz, DMSO-d6):
24.2, 120.1, 126.4, 126.5, 128.4,
A1
n
A2
270
160
50
d
d
128.5, 130.1, 135.6, 136.7, 153.1, 157.2. MS (m/z) (relative
˙
intensity): 317 [M+H]+ (80), 252 (50), 221 (25), 163 (100), 132
(25), 104 (75), 76 (35), 50 (20).
2-(Phenylsulfonyl)-2,3-dihydrophthalazine-1,4-dione
(C14H10N2O4S) (3b): Isolated yield: 70%. Mp. >270 8C (dec.),
yellow. IR (KBr, cmÀ1):
n
2906, 1659, 1493, 1335, 1308, 1241,
1208, 1083, 1030, 824, 778, 672, 619, 486, 440. 1H NMR (300 MHz,
DMSO-d6): 6.9 (d, 2H), 7.9 (m, 3H), 7.8 (d, 2H), 8.3 (d, 2H) 10.7
(NH, 1H). 13C NMR (75 MHz, DMSO-d6):
120.1, 126.3, 128.2,
d
-60
d
0.3
0.5
0.7
0.9
1.1
1.3
128.5, 128.7, 130.7, 131.1, 134, 156.1, 163.1. MS (m/z) (relative
˙
E vs. Ag/AgCl (V)
intensity): 303 [M+H]+ (35), 239 (30), 221 (100), 163 (100), 132
(20), 104 (60), 76 (35), 50 (20).
Fig. 2. Multi-cyclic voltammograms of 1 (1.0 mmol/L) in the presence of 2a
(1.0 mmol/L) at glassy carbon electrode in an aqueous phosphate buffer
(0.2 mol LÀ1, pH 2.0)/acetonitrile (85/15, v/v) solution. Scan rate: 800 mV sÀ1
,
3. Results and discussion
temperature = (25 Æ 1) 8C.
Cyclic voltammogram of a 1.0 mmol/L solution of 2,3-dihy-
drophthalazine-1,4-dione (1) in a water (0.2 mol/L phosphate
buffer, pH 2.0)/acetonitrile (85/15%, v/v) is shown in Fig. 1, curve a.
As can be seen, one anodic (A1) and a cathodic peak C1 were
obtained at 1.0 and 0.78 V (E1/2 = 0.89 V) versus Ag/AgCl. The
anodic and cathodic peaks are counterpart and correspond to the
transformation of 1 to phthalazine-1,4-dione (1ox) and vice versa
within a quasi-reversible two-electron process. The peak current
ratio (IpC1/IpA1) is less than unity and decreases with the reduction
of the potential sweep rate indicating that the generated
phthalazine-1,4-dione (1ox) is not stable. This instability is related
to the oxidative ring cleavage of 1, as discussed in details in our
previously published paper [12]. The oxidation of 1 in the presence
of p-toluenesulfinic acid (2a) as nucleophile was studied using
cyclic voltammetry. Fig. 1, curve b, shows the cyclic voltammo-
gram obtained for a 1.0 mmol/L solution of 1 in the presence of
1.0 mmol/L of 2a. It is clear that the cathodic peak (C1) disappeared
and a new anodic peak (A2) appeared with a more positive
potential. In this Figure, the cyclic voltammogram of 2a is shown in
curve c. A close analysis of these three voltammograms (curves a–
c) suggested that A2 corresponds to 1ox, which is bonded to 2a. A
similar observation was made in the case of 1 in the presence of 2b.
The multi-cyclic voltammograms of 1.0 mmol/L 1 in the
presence of 1.0 mmol/L 2a are shown in Fig. 2. The reduced height
of the anodic peak (A1) in the second scan is probably due to the
formation of a thin film of product at the surface of the electrode,
inhibiting to a certain degree the performance of the electrode
process that was enhanced during the repetitive cycling of the
potential.
Controlled-potential coulometry was performed in water
(0.2 mol/L phosphate buffer, pH 2.0)/acetonitrile (85/15, v/v)
containing 0.25 mmol of 1 and 0.25 mmol of 2a at 0.85 V versus
Ag/AgCl. The electrolysis progress was monitored using cyclic
voltammetry (Fig. 3). It was found that, proportional to the
advancement of electrolysis, the anodic peak A1 decreased.
Diagnostic criteria of cyclic voltammetry, accompanied by
spectroscopic data (IR, 1H NMR, 13C NMR and MS) of the final
products allow us to propose the mechanistic pathway in Scheme 1
for the electrochemical oxidation of 1 in the presence of 2a and 2b.
According to our results, it seems that a 1,4-Michael type addition
reaction of 2a and 2b with 1ox is faster than other secondary
reactions, leading to the formation of 3a and 3b. The oxidation of
A1
A1
Progress of
coulometry
300
A2
a
A2
90
50
b
200
100
0
c
10
C1
C1
-100
-30
0.2
0.6
E vs. Ag/AgCl (V)
1
1.4
0.2
0.5
0.8
1.1
1.4
E vs. Ag/AgCl (V)
Fig. 1. A cyclic voltammogram of 1 (1.0 mmol LÀ1) in the absence of 2a (a), in the
presence of 2a (1.0 mmol LÀ1) (b), 2a (1.0 mmol LÀ1) in the absence of 1, in a water/
acetonitrile (85/15%, v/v) solution containing phosphate buffer (c = 0.2 mol LÀ1, pH
2.0) (c). Scan rate: 800 mV sÀ1, temperature = (25 Æ 1) 8C.
Fig. 3. Cyclic voltammograms of 1 (0.25 mmol) in the presence of 2a (0.25 mmol), at
a glassy carbon electrode in an aqueous phosphate buffer (0.2 mol LÀ1, pH 2.0)/
acetonitrile (85/15, v/v) solution during controlled-potential coulometry at 0.85 V
versus Ag/AgCl. Scan rate: 100 mV sÀ1, temperature = (25 Æ 1) 8C.

D. Nematollahi et al. / Chinese Chemical Letters 25 (2014) 593–595
595
O
O
O
O
S
-2e- -2H+
NH
NH
NH
N
N
R = CH3 2a, 3a
R = H 2b, 3b
-O2S
R
R
N
O
O
1
2a, 2b
O
O
1ox
3a, 3b
Scheme 1. Proposed mechanism for the electrochemical oxidation of 1 in the presence of arylsulfinic acids (2a and 2b).
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starting molecule (1) by virtue of the presence of an electron-
withdrawing phenylsulfonyl group on 3a and 3b.
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4. Conclusion
The results of this work show that 2,3-dihydrophthalazine-1,4-
dione (1) is oxidized to phthalazine-1,4-dione (1ox), which is then
attacked by arylsulfinic acids (2a and 2b). The final products are
obtained via an EC mechanism after a Michael type addition of
arylsulfinic acids to the electro-generated 1ox. According to our
results, these processes lead to the formation of new sulfonamide
derivatives in good yields. The presented work represents a facile
and reagent-less method with high atom economy for the
synthesis of sulfonamides using a carbon electrode.
Acknowledgments
We acknowledge Bu-Ali Sina University Research Council and
Center of Excellence in Development of Environmentally Friendly
Methods for Chemical Synthesis (CEDEFMCS) for their support of
this work.
[10] D. Nematollahi, E. Mehdipour, A. Zeinodini-Meimand, A. Maleki, Chemical and
electrochemical oxidative coupling of N,N-dialkyl-p-phenylenediamines and
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