A green approach for the electrochemical synthesis of 4-morpholino-2- (arylsulfonyl)benzenamines

Article abstract of DOI:10.1016/j.tetlet.2010.07.053

Electrochemical synthesis of 4-morpholino-2-arylsulfonyl-benzamines was carried out by the electrochemical oxidation of 4-morpholinoaniline in the presence of arenesulfinic acids at a carbon electrode, in aqueous solution. Our voltammetric data indicate that electrochemically generated p-quinone-diimine participates in Michael type addition reaction with arenesulfinic acids and via an EC mechanism converts to the title products. This method provides a green, one-pot procedure for the synthesis of 4-morpholino-2-(arylsulfonyl)benzenamines of potential biological significance.

Full text of DOI:10.1016/j.tetlet.2010.07.053

Tetrahedron Letters 51 (2010) 4862–4865
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A green approach for the electrochemical synthesis of
4-morpholino-2-(arylsulfonyl)benzenamines
*
D. Nematollahi , R. Esmaili
Faculty of Chemistry, Bu-Ali Sina University, Hamedan 65178-38683, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Electrochemical synthesis of 4-morpholino-2-arylsulfonyl-benzamines was carried out by the electro-
chemical oxidation of 4-morpholinoaniline in the presence of arenesulfinic acids at a carbon electrode,
in aqueous solution. Our voltammetric data indicate that electrochemically generated p-quinone-diimine
participates in Michael type addition reaction with arenesulfinic acids and via an EC mechanism converts
to the title products. This method provides a green, one-pot procedure for the synthesis of 4-morpholino-
2-(arylsulfonyl)benzenamines of potential biological significance.
Received 1 May 2010
Revised 26 June 2010
Accepted 9 July 2010
Available online 14 July 2010
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
4-Morpholinoaniline
Electrochemical synthesis
Cyclic voltammetry
p-Quinone-diimine
Sulfinic acid
1. Introduction
In acidic media, the cyclic voltammograms show one anodic (A1)
and a corresponding cathodic peak (C1), which correspond to the
Electrochemistry provides a versatile means for the selective
reduction and oxidation of organic compounds.1 Unique selectivity
due to in situ formation of an active species at the interface, inver-
sion in polarity by transfer of an electron and variability, in product
formation by the control of the electric potential are some of the
advantages of electrosynthesis.2 Organosulfones have been used
as drugs due to their strong in vitro and in vivo anti-bacterial
and anti-fungicidal activity.3 Further, diphenylsulfone derivatives
were found to possess anti-bacterial activity.4 The incorporation
of a diphenylsulfone moiety into various heterocyclic systems
was found to increase their biological activity.5 For example,
diphenylsulfone is used as an intermediate for the synthesis of
4,40-diaminodiphenylsulfone (dapsone) (Fig. 1) which is an anti-
leprotic and anti-inflammatory drug.6
We anticipated that the synthesis of new diphenylsulfone
derivatives would be useful from the point of view of pharmaceu-
tical properties (Fig. 1). This idea prompted us to investigate the
electrochemical oxidation of 4-morpholinoaniline (1) in the pres-
ence of arenesulfinic acids 2a–c as nucleophiles. This method rep-
resents a facile and one-pot electrochemical process for the
synthesis of new diphenylsulfone derivatives in good yields and
purities.
transformation of 4-morpholinoaniline (1) into p-quinone-diimine
(1ox) and vice versa within a quasi-reversible two-electron process
(Fig. 2, pH 2 and 5).7 Under these conditions, the peak current ratio
(IpC1/IpA1) of nearly unity, can be considered a criterion for the sta-
bility of p-quinone-diimine (1ox) produced at the surface of the
electrode under the experimental conditions. In other words, the
side reactions are too slow to be observed on the cyclic voltamme-
try time scale. In neutral and basic solutions, the peak current ratio
(IpC1/IpA1) is less than unity and decreases with increasing pH
(Fig. 2, pH 7 and 10). The electrochemical oxidation of aromatic
amines is quite complex, depending on their structure and the
electrolysis conditions leading to a variety of products. The prod-
ucts may vary largely by using aqueous or non-aqueous, neutral,
acidic, or basic conditions.8 Therefore, in this study in order to min-
imize side reactions, a solution containing phosphate buffer (pH
2.0, 0.2 M) was selected as a suitable medium for the electrochem-
ical study and the synthesis of new diphenylsulfone derivatives
4a–c (Scheme 1).
NH2
O
S
O
S
H2N
NH2
R
Cyclic voltammograms of 1 mM solutions of 4-morpholinoani-
line (1) in aqueous solutions at various pHs are shown in Figure 2.
O
O
N
A
B
O
* Corresponding author. Tel.: +98 811 8282807; fax: +98 811 8257407.
E-mail address: nemat@basu.ac.ir (D. Nematollahi).
Figure 1. The structure of dapsone (A) and compounds reported here (B).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.053

D. Nematollahi, R. Esmaili / Tetrahedron Letters 51 (2010) 4862–4865
4863
A1
A1
10
8
9
pH= 2
pH= 5
7
5
6
4
3
2
1
0
-1
-3
-5
-7
-2
-4
-6
-8
C1
C1
-0.1
0
0.1 0.2 0.3 0.4 0.5 0.6
E/V vs. SCE
0.18 0.28 0.38 0.48 0.58 0.68
E/V vs. SCE
A1
A1
13
10
7
22
18
14
10
6
pH= 10
pH= 7
A2
A0
4
1
A0
-2
-5
-8
2
-2
C0
C0
C1
-6
-0.15
0
0.15 0.3 0.45 0.6
E/V vs. SCE
-0.4
-0.2
0
0.2
0.4
E/V vs. SCE
Figure 2. First (green lines) and second (orange lines) cyclic voltammograms of 1 mM 4-morpholinoaniline (1) at a glassy carbon electrode, in buffered solutions (various
pHs, same ionic strength). Scan rate: 100 mV sꢀ1; t = 25 1 °C.
Cyclic voltammograms of a 1 mM solution of 4-morpholinoani-
line (1) in an aqueous solution containing 0.2 M phosphate buffer
(pH 2), in the presence of 1 mM toluenesulfinic acid (2a) are shown
in Figure 3 curve b. As can be seen, the cathodic peak (C1) disap-
peared completely and a new anodic peak (A2) appeared at more
positive potentials. Also, the potential of peak A1 (EpA1) shifted
toward a less positive potential. The occurrence of a chemical reac-
tion is supported by the decrease in the current of peak C1 during
the reverse scan, which could indicate that p-quinone-diimine 1ox
formed at the surface of the electrode is consumed by a chemical
reaction with 2a.9 The current of peak C1 strongly depends on
the potential scan rate. At lower scan rates, the peak current ratio
(IpC1/IpA1) is less than one and increases when the sweep rate
increases.9 A similar situation was observed when the 2a to 4-mor-
pholinoaniline (1) concentration ratio was decreased.
Controlled-potential coulometry was performed in an aqueous
solution containing 0.25 mmol of 1 and 0.25 mmol of 2a at 0.4 V
versus saturated calomel electrode (SCE). The electrolysis progress
was monitored using cyclic voltammetry (Fig. 4). It was found that,
proportional to the advancement of coulometry, the anodic peaks
(A1 and A2) decreased. All the anodic and cathodic peaks disap-
peared when the charge consumption was about 2eꢀ per molecule
of 1. These observations allow us to propose the pathway shown in
Scheme 1 for the electrooxidation of 1 in the presence of 2a.
The generation of p-quinone-diimine (1ox) is followed by a
Michael type addition reaction of 2a on p-quinone-diimine (1ox),
16.0
13.5
11.0
8.5
A2
A1
b
a
6.0
3.5
c
1.0
-1.5
-4.0
-6.5
-9.0
C1
0.18 0.28 0.38 0.48 0.58 0.68
E/V vs. SCE
Figure 3. Cyclic voltammograms of 1 mM 4-morpholinoaniline (1): (a) in the
absence and (b) in the presence of 1 mM toluenesulfinic acid (2a) and, (c) 1 mM 2a
in the absence of 1, at a glassy carbon electrode, in aqueous solution containing
0.2 M phosphate buffer (pH 2). Scan rate: 100 mV sꢀ1; t = 25 1 °C.

4864
D. Nematollahi, R. Esmaili / Tetrahedron Letters 51 (2010) 4862–4865
A1
A2
55
45
35
25
15
5
a
60
50
40
30
20
10
0
IpA1 = -1.4Q + 60
R2 = 0.9826
e
f
-5
0
10
20
30
40
0.15 0.25 0.35 0.45 0.55
0.65
Charge/C
E/V vs. SCE
Figure 4. Cyclic voltammograms of 0.25 mmol 4-morpholinoaniline (1) in the presence of 0.25 mmol toluenesulfinic acid (2a) during controlled potential coulometry at 0.4 V
versus SCE. After consumption of: (a) 0, (b) 10, (c) 20, (d) 30 and, (e) 38 coulombs. Curve f: variation of peak current (IpA1) versus charge consumed. Scan rate: 100 mV sꢀ1
t = 25 1 °C.
;
-2e-, -H+
producing the diphenylsulfone 4a as the final product. The oxida-
tion of 4a is more difficult than the oxidation of the starting mol-
ecule 1 by virtue of the presence of the electron-withdrawing
tolylsulfonyl group on 4a. Therefore, over-oxidation of 4a was cir-
cumvented during the reaction because of the presence of the elec-
tron-withdrawing group as well as by the insolubility of the final
product 4a in the phosphate buffer (pH 2) solution.
O
N
NH2
O
N
NH
O
O
S
S
O
O
4a-c
5a-c
R
R
According to our results, the anodic peaks of the voltammo-
grams presented in Figure 3 (A1 and A2) pertain to the oxidation
of 4-morpholinoaniline (1) and diphenylsulfone 4a, to p-quinone-
diimines 1ox and 5a, respectively (Schemes 1 and 2). Obviously,
the cathodic peak C1 corresponds to the reduction of p-quinone-
diimine 1ox into 1.
In contrast to 4-morpholinoaniline (1), the presence of a tolu-
enesulfinic group with electron-withdrawing character results in
an increase in the reactivity of p-quinone-diimine 5a toward fast
side reactions. Therefore, on the time scale of our experiments,
the cathodic counterpart of oxidation of 5a was not observed.
Scheme 2.
The results of this work show that 4-morpholinoaniline (1) is
oxidized to p-quinone-diimine 1ox which is then attacked by
arenesulfinic acid 2a–c. The final products are obtained via an EC
mechanism, after consumption of 2eꢀ per molecule of 1. According
to our results, the Michael type reaction of these nucleophiles with
the p-quinone-diimine leads to the formation of new diphenylsulf-
one derivatives in good yields and high purities. The presented
work represents
a
facile, reagent-less, and environmentally
-2e- -H+
(1)
O
N
NH
O
N
NH2
1
1ox
O
N
NH
O
N
NH2
H
O
O
S
O
O
S
S
(2)
R
O
N
NH
+
O
O
1ox
2a-c
4a-c
R
3a-c
R
mp (oC)
155-157
141-142
Yield (%)
90
R
4a Cl
4b
4c
80
85
H
CH3
165-166
Scheme 1.

D. Nematollahi, R. Esmaili / Tetrahedron Letters 51 (2010) 4862–4865
4865
friendly method with high atom economy, for the synthesis using a
carbon electrode.
2.3. 2-(4-Chlorophenylsulfonyl)-4-morpholinobenzenamine
(4c, C16H17N2O3SCl)
The reaction equipment was used as described in earlier
papers.10
1H NMR (300 MHz, DMSO-d6): d = 2.95 (4H, s), 3.71 (4H, d,
J = 3.8 Hz), 5.7 (br s, ꢁ2H), 6.76 (1H, d, J = 9.6 Hz), 7.14 (2H, d,
J = 6.3 Hz), 7.66 (2H, d, J = 8.3 Hz), 7.96 (2H, d, J = 8.3 Hz). 13C
NMR (75 MHz, CDCl3): d = 50.3, 66.6, 114.3, 119.3, 126.4, 129.2,
129.9, 132.0, 138.8, 140.5, 141.8, 142.6. IR (KBr): 3426, 3350,
2964, 2866, 2814, 1628, 1502, 1450, 1311, 1298, 1277, 1232,
1150, 1117, 1088, 820, 770, 584 cmꢀ1. MS (EI): m/z (relative inten-
sity); 352 (100), 294 (64), 229 (23), 111 (26), 91 (48), 65 (24).
2. General procedure for the synthesis of 4a–c
Phosphate buffer solution (50 ml, 0.2 M, pH 2) containing
0.25 mmol of 4-morpholinoaniline (1) and 0.25 mmol of toluene-
sulfinic acid (benzensulfinic acid or 4-chlorobenzenesulfinic acid)
was subjected to electrolysis at 0.4 V versus SCE, in an undivided
cell. The electrolysis was terminated when the current decayed
to 5% of its original value. The precipitated solid was collected by
filtration and was washed several times with water. After drying,
the products were characterized by IR, 1H NMR, 13C NMR, and
MS. The average current yield is more than 89%. In this method
the electrochemical process involved in cathode is the reduction
of protons.
Acknowledgments
The authors acknowledge the Bu-Ali Sina University Research
Council and Center of Excellence in Development of Chemical
Methods (CEDCM) for support of this work.
References and notes
1. Fotouhi, L.; Mosavi, M.; Heravi, M. M.; Nematollahi, D. Tetrahedron Lett. 2006,
47, 8553–8557.
2. Shono, T. Electroorganic Synthesis; Academic Press: San Diego, 1991.
3. (a) Huang, F.; Batey, R. A. Tetrahedron 2007, 63, 7667–7672; (b) Wolf, W. M. J.
Mol. Struct. 1999, 474, 113–124.
2.1. 4-Morpholino-2-(4-methylphenylsulfonyl)benzenamine
(4a, C17H20N2O3S)
1H NMR (300 MHz, CDCl3): d = 2.42 (s, 3H), 3.10 (s, 4H), 3.91 (s,
4H), 4.90 (br s, ꢁ2H), 6.65 (1H, d, J = 8.7 Hz), 7.10 (1H, s), 7.29 (2H,
d, J = 8.9 Hz), 7.47 (1H, s), 7.83 (2H, d, J = 8.1 Hz). 13C NMR (75 MHz,
CDCl3): d = 21.6, 51.2, 66.5, 116.7, 119.1, 122.8, 125.4, 127.0, 129.7,
138.5, 144.1, 145.9. IR (KBr): 3418, 3345, 2975, 2920, 2860, 2816,
1626, 1500, 1450, 1284, 1232, 1144, 1117, 951, 814, 661, 586 cm
ꢀ1. MS (EI): m/z (relative intensity); 332 (100), 274 (53), 209 (44),
91 (59), 65 (20).
4. (a) Mavrodin, A.; Zotta, V.; Stoenescu, V. M.; Oteleanu, D. Pharm. Zentralhalle
Dtsch. 1956, 95, 353–361; (b) Elslager, E. F.; Gavrilis, Z. B.; Phillips, A. A.; Worth,
D. F. J. Med. Chem. 1969, 12, 357–363.
5. Almajan, G. L.; Barbuceanu, S. F.; Almajan, E. R.; Draghici, C.; Saramet, G. Eur. J.
Med. Chem. 2009, 44, 3083–3089.
6. (a) Repichet, S.; Le Roux, C.; Hernandez, P.; Dubacjean-Roger, J. J. Org. Chem.
1999, 64, 6479–6482; (b) Coleman, M. D.; Tingle, M. D. Drug Dev. Res. 1992, 25,
1–16.
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689–694; (b) White, P. C.; Lawrence, N. S.; Davis, J.; Compton, R. G. Anal. Chim.
Acta 2001, 447, 1–10; (c) Kershaw, J. A.; Nekrassova, O.; Banks, C. E.; Lawrence,
N. S.; Compton, R. G. Anal. Bioanal. Chem. 2004, 379, 707–713; (d) Giovanelli, D.;
Lawrence, N. S.; Klymenko, O. V.; Jiang, L.; Jones, T. G. J.; Compton, R. G.
Electroanalysis 2003, 15, 961–968; (e) Maleki, A.; Nematollahi, D. Electrochem.
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3405–3414; (b) Steckan, E. In Organic Electrochemistry, an Introduction and a
Guide; Baizer, M. M., Lund, H., Eds.; Marcel Dekker: New York, 1991. Chapter
15; (c) Bacon, J.; Adams, R. N. J. Am. Chem. Soc. 1968, 90, 6596–6599.
9. Bard, A. J.; Faulkner, L. R. Electrochemical Methods, 2nd ed.; Wiley: New York,
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Nematollahi, D.; Tammari, E.; Esmaili, R. J. Electroanal. Chem. 2008, 621, 113–
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79–86.
2.2. 4-Morpholino-2-(phenylsulfonyl)benzenamine (4b,
C16H18N2O3S)
1H NMR (300 MHz, CDCl3): d = 3.04 (4H, d, J = 12.4 Hz), 3.85 (4H,
d, J = 12.3 Hz), 4.88 (br s, ꢁ2H), 6.64 (1H, m), 7.05 (1H, d, J = 8.6 Hz),
7.49 (4H, m), 7.93 (2H, m). 13C NMR (75 MHz, CDCl3): d = 50.8, 66.7,
116.5, 119.1, 122.2, 125.3, 126.9, 129.0, 133.1, 140.6, 141.5, 143.0.
IR (KBr): 3458, 3362, 2962, 2854, 2818, 1634, 1616, 1500, 1446,
1315, 1290, 1230, 1146, 1117, 1095, 947, 866, 818, 754, 723,
690, 590, 550 cmꢀ1. MS (EI): m/z (relative intensity); 318 (100),
260 (69), 195 (36), 167 (35), 91 (41), 77 (40).