Novel synthesis of mafenide and other amino sulfonamides by electrochemical reduction of cyano sulfonamides

Article abstract of DOI:10.1002/hlca.200690123

Both aliphatic and aromatic amino sulfonamides such as mafenide (1a) were synthesized in good yields (80-86%) by direct electrochemical hydrogenation of the corresponding nitriles in an undivided cell containing a Ni cathode, a Pt anode, and Raney Ni as catalyst (Table 1). The reaction can be performed without external supply of pressurized gas by in situ generation of H2. Slightly elevated temperatures (45°) and low current densities (10 mA/cm²) are favorable conditions for this type of electrochemical nitrile hydrogenation. Our synthetic protocol does not require high-pressure equipment or chemical hazards, is environmentally very friendly, and more economical than traditional methods. The concentration of adsorbed H^. radicals on the catalyst surface can be easily controlled by adjusting the electric potential, which may lead to improved product selectivity and, at the same time, reduces the risk of explosion and fire.

Full text of DOI:10.1002/hlca.200690123

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Helvetica Chimica Acta – Vol. 89 (2006)
Novel Synthesis of Mafenide and Other Amino Sulfonamides by
Electrochemical Reduction of Cyano Sulfonamides
by Shaik Lateef, Srinivasulu Reddy Krishna Mohan, Rudraraju Rameshraju, and Srinivasulu Reddy
Jayarama Reddy*
Electrochemical Research Laboratory, Department of Chemistry, Sri Venkateswara University,
Tirupati-517502, India
(fax: +91-877-2249611; e-mail: profjreddy_s@yahoo.co.in)
Both aliphatic and aromatic amino sulfonamides such as mafenide (1a) were synthesized in good
yields (80–86%) by direct electrochemical hydrogenation of the corresponding nitriles in an undivided
cell containing a Ni cathode, a Pt anode, and Raney Ni as catalyst (Table 1). The reaction can be per-
formed without external supply of pressurized gas by in situ generation of H2. Slightly elevated temper-
atures (458) and low current densities (10 mA/cm2) are favorable conditions for this type of electrochem-
ical nitrile hydrogenation. Our synthetic protocol does not require high-pressure equipment or chemical
hazards, is environmentally very friendly, and more economical than traditional methods. The concentra-
tion of adsorbed HC radicals on the catalyst surface can be easily controlled by adjusting the electric
potential, which may lead to improved product selectivity and, at the same time, reduces the risk of explo-
sion and fire.
Introduction. – Amino sulfonamides are important synthetic organic compounds
that often exhibit antibacterial and antifungal activities [1][2]. Therefore, some of
these compounds are called ‘sulfa medicines’, one example being mafenide (1a),
which is being used in the treatment of acute burns [3]. The synthesis of amino sulfon-
amides from the corresponding nitriles by (catalytic) reduction is very important. In
this process, primary amines are obtained, which form a large group of compounds
widely used in pharmaceuticals and agrochemicals [4]. Nitrile reduction is also very
important both in synthetic [5] and industrial [6] chemistry. Miller et al. have synthe-
sized several amino sulfonamides by catalytic reduction of cyano compounds, nitro sul-
fonamides, or N-acyl derivatives [1].
One great advantage of electrochemical reduction is the fact that they are ecologi-
cally very friendly. Since there is a ‘mass-free’ electron transfer between an electrode
and a substrate, there is typically no need for waste disposal [7]. So, Krishnan et al.
[8][9], and Song and Pintauro [10] have studied the electrochemical reduction of
nitriles with different metal-block electrodes in a divided cell. However, the use of a
divided cell substantially increased production costs, and the system was impractical
© 2006 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 89 (2006)
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to be further developed for commercial applications. To develop a more-convenient
and commercially useful synthetic method for the preparation of amino sulfonamides
from nitriles, it would, thus, be highly desirable to find a high-yielding system based
on an undivided cell for performing electrochemical hydrogenation.
In this paper, we present, for the first time, an electrochemical technique that
involves a combination of in situ electrochemical generation of pure H2 adsorbed on
Raney Ni as the catalyst in an undivided cell equipped with a Ni cathode and a Pt anode.
Results and Discussion. – Electrolysis was carried out under anhydrous conditions
in MeOH/MeONa to avoid nitrile hydrolysis [11]. The use of compressed H2 gas was
circumvented by electrolytic generation of H2 as reducing agent. The selective reduc-
tion of the biologically relevant nitriles 2a–f was performed in an undivided cell con-
taining a Ni cathode, a Pt anode, and Raney Ni as catalyst at various temperatures
(Table 1) and current densities (Table 2). In the absence of catalyst, the electrochemical
hydrogenation of compounds 2 resulted in only poor yields (15–20%) of the amines 1
due to non-productive evolution of H2 gas.
The best conditions in terms of yield were slightly elevated temperature (458) and
low current density (10 mA/cm2). The reactions at the cathode mainly include hydro-
genation and H2 evolution, which alters the product yield. These results suggest that
elevated temperatures accelerate the reduction of nitriles to a greater extent than
the formation and evolution of H2 from electrochemically generated, adsorbed HC rad-
icals. In turn, with increasing current density, H2 evolution increased; hence, low cur-
rent densities are favorable.
Table 1. Influence of Temperature on the Yield of Electrochemically Generated Amino Sulfonamides. All
reactions were performed at a current density of 10 mA/cm2.
Series
Product (1)
Isolated yield [%]
H2NꢀCH2ꢀR
58
158
258
358
458
a
60
69
75
81
85
b
59
67
71
80
83
c
62
61
71
65
77
72
81
74
86
80
d
e
f
57
61
67
69
74
71
78
76
81
83

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Helvetica Chimica Acta – Vol. 89 (2006)
Table 2. Influence of Current Density on the Yield of Electrochemically Generated Amino Sulfonamides.
All reactions were performed at 258.
Entry
Current density
[mA/cm2]
Isolated yield [%]
1
a
1
b
1
c
1
d
1
1
2
3
10
25
50
75
70
63
71
64
59
77
71
63
72
67
60
74
70
62
71
64
56
From a mechanistic point of view, the observed increase in product yields is the
result of the competition between the two above reactions. Electrochemical hydroge-
nation of an organic substance proceeds via the formation of adsorbed HC interacting
with the organic substrate approaching from solution. When reductions are carried
out in the presence of Raney Ni as catalyst, H+ is abstracted from MeOH, and then
takes up one electron. The resulting atomic HC gets adsorbed on the catalyst surface,
and then reacts with a CN group to form the desired CH2NH2 function according to
Eqns. 1 and 2:
MeOH+eꢀ ! Haꢁ ds +MeOꢀ
(1)
(2)
4 Hꢁads +RꢀCꢂN ! RꢀCH2NH2
According to the above mechanism, we assume that the actual reduction of the CN
function takes place by the adsorbed, electrochemically generated, catalyst-activated
H-atoms, rather than by direct electron transfer between the substrate and the elec-
trode.
Experimental Part
Electrochemical Hydrogenation. All reactions were carried out in an undivided cell containing a Ni
cathode and a Pt anode (2×2 cm each). Through a soln. of the nitrile 2 (10 mmol) [1][12][13] in anh.
MeOH (40 ml) containing MeONa (0.1 mol) and freshly prepared Raney Ni (1.0 g) [14], O2-free N2
gas was bubbled for 10–15 min. Then the soln. was electrolyzed at const. current density (10 mA/cm2)
until 4 F/mol of electricity were consumed. Then, the mixture was transferred to a round-bottom flask,
and the solvent was evaporated. The residue was treated with 10% aq. HCl, and the aq. layer was
extracted with Et
A
with Et2O (3×25 ml). The combined org. extract was dried (Na2SO4) and concentrated under reduced
AHCTREUNG
pressure to afford the appropriated amino sulfonamides 1. For yields, see Table 1.
4-(Aminomethyl)benzenesulfonamide (1a). M.p. 147–1498 (lit. m.p. 151–1528 [1]). IR (KBr): 1124,
1
1335, 2231, 3327 cmꢀ1. H-NMR (CDCl3): d=3.36 (s, CH2); 3.9 (br. s, NH2); 6.41 (br. s, SO2NH2); 7.26
(d, 2 arom. H); 7.73 (d, 2 arom. H). Anal. calc. for C7H10N2O2S (186.23): C 45.15, H 5.40, N 15.04;
found: C 45.17, H 5.38, N 15.07.
1-[4-(Aminomethyl)phenyl]methanesulfonamide (1b). M.p. 159–1618 (lit. m.p. 160.5–162.08 [1]). IR
(KBr): 1127, 1337, 3325 cmꢀ1
.
1H-NMR (CDCl3): d=3.18 (s, ArCH2
G
G
ArCH2
ACHTREUNG

Helvetica Chimica Acta – Vol. 89 (2006)
1257
4-(2-Aminoethyl)benzenesulfonamide (1c). M.p. 145–1478 (lit. m.p. 147.5–149.08 [1]). IR (KBr):
1136, 1341, 3331 cmꢀ1 1H-NMR (CDCl3): d=2.77 (t, ArCH2); 2.91 (t, CH2N); 3.6 (br. s, CH2
NH2);
.
ACHTREUNG
6.24 (br. s, SO2NH2); 7.29 (d, 2 arom. H); 7.74 (d, 2 arom. H). Anal. calc. for C8H12N2O2S (200.26): C
47.98, H 6.03, N 13.98; found: C 48.01, H 6.01, N 13.95.
2-[4-(Aminomethyl)phenyl]ethane-1-sulfonamide (1d). M.p. 172–1748. IR (KBr): 1129, 1331, 3329
cmꢀ1. 1H-NMR (CDCl3): d=3.23 (t, ArCH2
N
G
ACHTREUNG
1
1119, 1334, 3328 cmꢀ1. H-NMR (CDCl3): d=2.04 (m, SCH2
G
N
3.30 (t, SCH2); 6.36 (br. s, SO2NH2). Anal. calc. for C3H10N2O2S (138.19): C 26.07, H 7.29, N 20.27;
found: C 26.09, H 7.27, N 20.29.
4-Aminobutane-1-sulfonamide (1f). M.p. (HCl salt) 124–1258 (lit. m.p. 127–1298 [1]). IR (KBr):
1121, 1329, 3342 cmꢀ1 1H-NMR (CDCl3): d=1.59 (m, CH2CH2N); 1.79 (m, CH2CH2S); 2.4 (br. s,
.
CH
A
31.56, H 7.95, N 18.40; found: C 31.59, H 7.93, N 18.38.
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Received April 5, 2006