Microwave-induced rapid access to aromatic and heteroaromatic sulfonamides under solvent-free conditions without using external base

Article abstract of DOI:10.1081/SCC-200032530

Microwave-induced syntheses of sulfonamides, without using base under solvent-free conditions, have been developed. The process finds its utility because of its simple operational procedure and high yields. Moreover, the process is fast and accommodative to different substituents on aromatic as well as heteroaromatic rings rendering sulfonamides (28 examples).

Full text of DOI:10.1081/SCC-200032530

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Microwave‐Induced Rapid
Access to Aromatic and
Heteroaromatic Sulfonamides
Under Solvent‐Free
Conditions Without Using
External Base
Ashwani Kumar Sharma a & Saibal Kumar Das a
a Discovery Chemistry, Dr. Reddy's Laboratories
Ltd., Discovery Research, Bollaram Road, Miyapur,
Hyderabad, 500049, India
Published online: 19 Apr 2010.
To cite this article: Ashwani Kumar Sharma & Saibal Kumar Das (2004):
Microwave‐Induced Rapid Access to Aromatic and Heteroaromatic Sulfonamides
Under Solvent‐Free Conditions Without Using External Base, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 34:20, 3807-3819
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 20, pp. 3807–3819, 2004
Microwave-Induced Rapid Access
to Aromatic and Heteroaromatic
Sulfonamides Under Solvent-Free
Conditions Without Using
External Base#
*
Ashwani Kumar Sharma and Saibal Kumar Das
Discovery Chemistry, Dr. Reddy’s Laboratories Ltd.,
Discovery Research, Bollaram Road, Miyapur, Hyderabad 500049, India
ABSTRACT
Microwave-induced syntheses of sulfonamides, without using base under
solvent-free conditions, have been developed. The process finds its utility
because of its simple operational procedure and high yields. Moreover, the
process is fast and accommodative to different substituents on aromatic as
well as heteroaromatic rings rendering sulfonamides (28 examples).
Key Words: Aromatic; Heteroaromatic; Solvent-free; Sulfonamide.
#DRL-Publication No. 327.
*
Correspondence: Saibal Kumar Das, Discovery Chemistry, Dr. Reddy’s Laboratories
Ltd., Discovery Research, Bollaram Road, Miyapur, Hyderabad 500049, India; Tel.:
þ91-40-23045439 ; Fax: þ 91-40-23045438; E-mail: saibalkumardas@drreddys.com.
3807
DOI: 10.1081/SCC-200032530
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

3808
Sharma and Das
INTRODUCTION
Sulfonyl groups have been widely used to protect amines and other
nitrogenous functionality in organic syntheses.[1] Sulfonamides are also an
important class of compounds in organic chemistry. Research is going on in
drug development, where the sulfonamides are proved to be a separate class
of therapeutic agents used in different areas as cholesterol modulator,[2] anti-
arrhythmic drug and b–adrenergic blocker,[3] antitumor agents against multi-
drug resistant tumors,[4] selective Cox-II inhibitors,[5] endothelin receptor
antagonists,[6] etc. Although there are a number of methods[3,7] available to
prepare sulfonamides, one often uses a base, and the reactions take a long
time for completion. Our interest in the total synthesis of biologically signifi-
cant molecules containing sulfonamide moiety in general has opened the
avenue for newer methodologies for the introduction of sulfonyl groups.
Herein, we report some of our investigational findings in the microwave-
assisted sulfonamide synthesis without using base and solvent, as shown in
Sch. 1 and 2, which could be an attractive alternative to hitherto reported
methods.
The benefits of microwave-assisted reactions in the field of organic chem-
istry are increasingly making the technique more established worldwide, as is
evident from the number of reviews that have appeared in the literature since
1991.[8] Microwave irradiation has proved its efficiency in rate enhancement
over classical heating methods, and there has been tremendous advance in
the synthesis of organic compounds using microwave irradiation.[9]
RESULTS AND DISCUSSION
Although there are several methods available in the literature[3,7] to make
these kinds of sulfonamides, at our hands, all those methods did not work well.
Either low or no yields and even disulfonamide formation were observed.
The compound in entry 1 (Table 1) was reported in 59.7% yield based on
benzene sulfonyl chloride (0.8 equivalent with respect to the substrate)
used.[2b] Using classical techniques, we could not even achieve 50% yields
Scheme 1.

Microwave-Induced Synthesis of Sulfonamides
3809
Scheme 2.
for the compounds in entries 2 and 3, Table 1. For the compound in entry 2, we
also obtained disulfonamide when the reaction was performed using triethyl
amine in dichloromethane. Because we are using microwave techniques for
other organic reactions, we wanted to explore this possibility.
To our surprise, the reactions afforded the products easily under solvent-
free conditions in the absence of an external base. But, the use of even a stoi-
chiometric amount of sulfonyl chlorides afforded a loss in yields. The
optimum condition ultimately determined was the use of 0.65 equivalents of
sulfonyl chlorides. The yields were calculated based on the amount of sulfonyl
chlorides used. In most of the cases, we could achieve high yields, although
where the anilines were very high melting, the yields were relatively low. If
there were electron-withdrawing groups (EWGs) or no group at p-position
of the substrate, the yields were high in contrast to the presence of electron-
donating groups (EDGs) at the same position. This may be because the
EWG lowers the availability of lone pairs on nitrogen, thereby reducing the
probability of forming salts; instead, it reacts with the sulfonyl group under
forced conditions. Bulky molecules showed the same deviations. Steric
hindrance was prominent in entries 12, 13, 14, and 16 (Table 1); although,
moderate yields were observed in entries 11 and 15. In general, poor yields
have been observed for the free carboxylic acid substituents at the ortho-
position. This observation was also reflected in reactions with 3-amino
thiophene-2-carboxylic acid. Very low yields (20–30%) were observed with
free acids against very high yields in case of esters (Table 2). Typically,
both the reactants were placed in an open vessel and irradiated with micro-
waves for an appropriate time (Tables 1 and 2) without any solvent. All the
compounds were characterized based on their hydrogen nuclear magnetic
resonance (1H-NMR), infrared (IR), and liquid chromatography-mass spec-
trometry (LC-MS) data.
To conclude, the present methodology is operationally simple and
requires no external base; the reactions are clean with no appreciable side
product being detected; and it is cost effective and high yielding. In some

Table 1. Preparation of various sulfonamides using six-membered ring scaffold (Sch. 1).
Time
(min)
Entry
1
R1
R2
X
R3
Product
%Yield
92
Ref.
[2b]
p-C(CF3)2OH
H
H
CH
6
2
p-C(CF3)2OH
CH
6
84
—
[10a]
[7b]
3
4
5
6
H
H
H
H
H
CH
CH
CH
CH
5
6
6
6
88
76
68
92
H
[10b]
H
p-CF3
—
[10c]
7
p-CF3
H
CH
6
66

[10d]
[10e]
[10e]
8
9
p-CF3
H
H
CH
N
6
6
92
29
H
10
11
H
H
N
2
6
56
62
p-OMe
o-COOH
CH
—
—
12
p-OMe
o-COOH
CH
6
31
13
14
H
o-Cl
CH
CH
5
7
46
30
—
—
m-F
o-COOH
(continued)

Table 1. Continued.
Time
(min)
Entry
15
R1
R2
X
R3
Product
%Yield
68
Ref.
—
m-Cl
m-Cl
o-COOEt
CH
8
16
o-COOEt
CH
8
45
—
[7a]
[7c]
17
18
p-OMe
p-OMe
H
H
CH
CH
6
6
78
88
[7d]
19
p-OMe
H
CH
6
90

[7a]
20
m-Br
H
CH
6
88
[10f]
21
22
m-Br
m-Br
H
H
CH
CH
6
6
85
94
[7a]
[10h]
23
24
25
p-COOH
p-COOH
H
H
H
CH
CH
CH
6
8
8
63
60
54
—
[10i]
p-COOH

3814
Sharma and Das
Table 2. Preparation of various sulfonamides using thiophene ring structure (Sch. 2).
Time
(min)
Entry
1
R
Product
%Yield
75
Ref.
[10g]
5
2
3
10
10
75
80
—
[10g]
cases, yields are higher than those obtained through existing methods.
The absence of catalyst and solvent, easy workup procedure, and short
reaction time impart greater merit to this procedure over those existing.
EXPERIMENTAL
The 1H-NMR spectra were recorded with tetramethylsilane (TMS, d 0.00)
as internal standards on a Varian Gemini 200 MHz FT NMR spectrometer.
Mass spectra were measured on Hewlet Packard-5989A mass spectrometer
(CI, 20 eV). The IR spectra were recorded using Perkin–Elmer 1650
Fourier transform-infrared (FT-IR) spectrophotometer. Melting points were
measured in a glass capillary on a digital melting point apparatus model
No. Bu¨chi-535, and they are uncorrected. All the chromatography solvents
were distilled before use. Silica gel (100–200 mesh, SRL, India) was used
for column purification.
General Procedure
Aniline derivative (100 mg) and aryl (or methyl) sulfonyl chloride
(0.65 equiv) were placed in an open vessel, and the mixture was irradiated

Microwave-Induced Synthesis of Sulfonamides
3815
with microwaves (LG model: MC-804AAR) for the appropriate time (see
Tables 1 and 2). The reaction mixture was then treated with ethyl acetate to
remove the solid particles (mostly salts of remaining starting material). The
supernatant was evaporated to dryness. The residue was purified on silica
gel (100–200 mesh) using ethyl acetate-pet ether to afford the desired
products as summarized in Tables 1 and 2.
Table 1, entry 2
Mp. 185–1878C; 1H-NMR (CDCl3 þ DMSO-d6, 200 MHz): d 2.37
(s, 3H, CH3), 7.16 (d, 2H, J ¼ 8.6 Hz, Ph), 7.30 (d, 2H, J ¼ 8.1 Hz, Ph),
7.54 (d, 2H, J ¼ 8.3 Hz, Ph), 7.68 (d, 2H, J ¼ 7.8 Hz, Ph); IR (KBr): nmax
(cm21) 3390, 3241, 1615, 1517, 1467, 1228, 1165; LC-MS (CI): m/z 414
(Mþ þ 1). Anal calculated for C16H13F6NO3S: C 46.49; H 3.17; N 3.39.
Found: C 46.48; H 3.42; N 3.23.
Table 1, entry 6
1
Mp. 70–728C; H-NMR (CD3OD, 200 MHz): d 2.37 (s, 3H, CH3), 7.25
(d, 2H, J ¼ 8.8 Hz, Ph), 7.31 (d, 2H, J ¼ 8.6 Hz, Ph), 7.50 (d, 2H,
J ¼ 8.3 Hz, Ph), 7.71 (d, 2H, J ¼ 8.3 Hz, Ph); IR (Neat): nmax (cm21) 3264,
1619, 1517, 1328, 1162; LC-MS (CI): m/z 316 (Mþ þ 1). Anal calculated
for C14H12F3NO2S: C 53.32; H 3.95; N 4.44. Found: C 53.20; H 4.21; N 4.41.
Table 1, entry 11
1H-NMR (CDCl3, 200 MHz): d 2.32 (s, 3H, CH3), 3.76 (s, 3H, CH3),
7.01–7.23 (m, 3H, Ph), 7.64 (d, 4H, J ¼ 8.1 Hz, Ph); IR (Neat): nmax
(cm21) 3424, 3222, 2926, 1682, 1498, 1241, 1229, 1164, 1039; LC-MS
(CI): m/z 321 (Mþ), 322 (Mþ þ 1). Anal calculated for C15H15NO5S: C
56.06; H 4.70; N 4.36. Found: C 55.80; H 4.88; N 4.66.
Table 1, entry 12
1H-NMR (CDCl3 þ DMSO-d6, 200 MHz): d 3.75 (s, 3H, CH3), 7.03 (dd,
1H, J ¼ 8.9 and 2.9 Hz, Ph), 7.40 (d, 1H, J ¼ 2.7 Hz, Ph), 7.41–7.54 (m, 3H,
Ph), 7.69 (d, 1H, J ¼ 5.5 Hz, Ph), 7.73 (d, J ¼ 7.3 Hz, Ph); IR (Neat): nmax
(cm21) 3419, 1659, 1499, 1027, 1006; LC-MS (CI): m/z 308 (Mþ þ 1).
Anal calculated for C14H13NO5S: C 54.72; H 4.26; N 4.56. Found: C 54.49;
H 3.97; N 4.85.

3816
Sharma and Das
Table 1, entry 13
1
Mp. 100–1028C; H-NMR (CDCl3, 200 MHz): d 2.38 (s, 3H, CH3),
6.92–7.08 (m, 1H, Ph), 7.15–7.28 (m, 4H, Ph), 7.65 (d, 3H, J ¼ 8.3 Hz,
Ph); IR (KBr): nmax (cm21) 3440, 3265, 1595, 1482, 1396, 1167; LC-MS
(CI): m/z 282 (Mþ þ 1 with 35Cl), 284 (Mþ þ 1 with 37Cl). Anal calculated
for C13H12ClNO2S: C 55.42; H 4.29; N 4.97. Found: C 55.08; H 4.42; N 5.23.
Table 1, entry 14
Mp. 140–1428C; 1H-NMR (CDCl3, 200 MHz): d 2.36 (s, 3H, CH3), 6.80
(t, 1H, J ¼ 8.8 Hz, Ph), 7.22 (d, 2H, J ¼ 7.8 Hz, Ph), 7.35–7.54 (m, 2H, Ph),
7.73 (d, 2H, J ¼ 8.1 Hz, Ph), 10.34 (br s, D2O exchangeable); IR (KBr): nmax
(cm21) 3437, 2927, 1667, 1613, 1467, 1259, 1164; LC-MS (CI): m/z 310
(Mþ þ 1). Anal calculated for C14H12FNO4S: C 54.36; H 3.91; N 4.53.
Found: C 54.28; H 3.79; N 4.43.
Table 1, entry 15
Mp. 116–1188C; 1H-NMR (CDCl3, 200 MHz): d 1.37 (t, 3H, J ¼ 7.1 Hz,
CH2CH3), 2.38 (s, 3H, CH3), 4.33 (q, 2H, J ¼ 7.2 Hz, CH2CH3), 6.99 (dd, 1H,
J ¼ 8.8 and 2.0 Hz, Ph), 7.25 (d, 2H, J ¼ 7.8 Hz, Ph), 7.70–7.79 (m, 3H, Ph),
7.85 (d, 1H, J ¼ 8.6 Hz, Ph), 10.77 (br s, D2O exchangeable); IR (KBr): nmax
(cm21) 3438, 1687, 1595, 1491, 1253, 1157; LC-MS (CI): m/z 354 (Mþ þ 1
with 35Cl), 356 (Mþ þ 1 with 37Cl). Anal calculated for C16H16ClNO4S: C
54.31; H 4.56; N 3.96. Found: C 54.58; H 4.48; N 3.72.
Table 1, entry 16
Mp. 110–1128C; 1H-NMR (CDCl3, 200 MHz): d 1.35 (t, 3H, J ¼ 7.2 Hz,
CH2CH3), 4.33 (q, 2H, J ¼ 7.1 Hz, CH2CH3), 6.99 (dd, 1H, J ¼ 8.6 and
1.9 Hz, Ph), 7.40–7.56 (m, 3H, Ph), 7.72 (d, 1H, J ¼ 1.6 Hz, Ph), 7.80–
7.96 (m, 3H, Ph), 10.80 (br s, D2O exchangeable); IR (KBr): nmax (cm21
)
3424, 2925, 1691, 1574, 1492, 1248, 1160; LC-MS (CI): m/z 340 (Mþ þ 1
with 35Cl), 342 (Mþ þ 1 with 37Cl). Anal calculated for C15H14ClNO4S: C
53.02; H 4.15; N 4.12. Found: C 53.38; H 3.92; N 4.43.
Table 1, entry 24
Mp. 128–1308C; 1H-NMR (CD3OD, 200 MHz): d 7.17 (d, 2H,
J ¼ 8.6 Hz, Ph), 7.45–7.58 (m, 3H, Ph), 7.80–7.88 (m, 4H, Ph); IR (KBr):
nmax (cm21) 3424, 3279, 1681, 1606, 1337, 1291, 1090; LC-MS (CI): m/z

Microwave-Induced Synthesis of Sulfonamides
3817
278 (Mþ þ 1). Anal calculated for C13H11NO4S: C 56.31; H 4.0; N 5.15.
Found: C 56.04; H 4.10; N 4.85.
Table 2, entry 2
1
Mp. 88–908C; H-NMR (CD3OD, 200 MHz): d 3.80 (s, 3H, CH3), 6.57
(d, 1H, J ¼ 5.4 Hz, thiophene), 7.39 (t, 1H, J ¼ 4.6 Hz, Ph), (d, 2H,
J ¼ 7.8 Hz, Ph), 7.59 (d, 1H, J ¼ 7.3 Hz, Ph), 7.64 (d, 1H, J ¼ 5.4 Hz, thio-
phene), 7.83 (d, 2H, J ¼ 7.3 Hz, Ph); IR (KBr): nmax (cm21) 3453, 2951,
1700, 1682, 1550, 1447, 1374, 1242, 1174, 1091; LC-MS (CI): m/z 238
(Mþ- COOMe). Anal calculated for C12H11NO4S2: C 48.47; H 3.73; N
4.71. Found: C 48.08; H 3.55; N 5.00.
ACKNOWLEDGMENTS
We express our esteemed gratitude to Professor J. Iqbal and
Dr. R. Rajagopalan for their continuous encouragement to this work.
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Received in the UK June 20, 2004