Microwave-assisted efficient methylation of alkyl and arenesulfonamides with trimethylsulfoxonium iodide and KOH

Article abstract of DOI:10.1080/00397910802045600

A solvent-free synthesis of N-methyl and N,N-dimethylsulfonamides has been achieved by treating the primary and secondary sulfonamides with Me3S+OI- and KOH under microwave irradiation on alumina support. Copyright Taylor & Francis Group, LLC.

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Microwave-Assisted Efficient
Methylation of Alkyl and
Arenesulfonamides with
Trimethylsulfoxonium Iodide
and KOH
Sarika Malik a , Upender K. Nadir a & Pramod S.
Pandey a
a Department of Chemistry, Indian Institute of
Technology, Delhi, India
Version of record first published: 09 Sep 2008.
To cite this article: Sarika Malik , Upender K. Nadir & Pramod S. Pandey (2008):
Microwave-Assisted Efficient Methylation of Alkyl and Arenesulfonamides with
Trimethylsulfoxonium Iodide and KOH, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 38:18, 3074-3081
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Synthetic Communications1, 38: 3074–3081, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802045600
Microwave-Assisted Efficient Methylation
of Alkyl and Arenesulfonamides with
Trimethylsulfoxonium Iodide and KOH
Sarika Malik, Upender K. Nadir, and Pramod S. Pandey
Department of Chemistry, Indian Institute of Technology, Delhi, India
Abstract: A solvent-free synthesis of N-methyl and N,N-dimethylsulfonamides
has been achieved by treating the primary and secondary sulfonamides with
Me3Sþ OIꢀ and KOH under microwave irradiation on alumina support.
Keywords: Microwave, solvent-free synthesis, sulfonamide, trimethylsulfoxonium
iodide
INTRODUCTION
N,N-Dimethylsulfonamides are useful as photopolymerizable catalysts,
fillers in dental materials, herbicides, and mildew- and rot-resisting mate-
rials for paper. Besides this, they are important constituents of volatile
components of oakmass oleoresin and fresh yellow mobin fruits. They
also form part of the catalyst used in Suzuki and amination cross-
coupling reactions.[1] Most commonly, aromatic dimethylsulfonamides
are synthesized through the condensation of arenesulfonyl chloride with
dimethyl amine.[2] Several other approaches have also been used for prep-
aration of N-mono- and N,N-dimethylsulfonamides, such as pseudomo-
lecular rearrangement,[3] phase transfer catalyzed (PTC) N-alkylation,[4]
electrophilic substitution of arene with ClSO2NR2,[5] and intramolecular[6]
and intermolecular[1,7–9] displacement reactions. Although these appro-
aches gave N-mono- and N,N-dimethylsulfonamides, they generally
suffer from drawbacks such as long reaction times, formation of
Received January 9, 2008.
Address correspondence to Pramod S. Pandey, Department of Chemistry,
Indian Institute of Technology, Delhi, Hauz Khas, New Delhi 110016, India.
E-mail: pramod@chemistry.iitd.ac.in
3074

Microwave-Assisted Methylation of Sulfonamides
3075
by-products, unsatisfactory yields, cumbersome experimental proce-
dures, and use of hazardous solvents and expensive catalysts.
We have shown previously[10] that methylene transfer from dimethyl-
sulfoxonium methylide to N-arenesulfonylimines leads to a one-pot
synthesis of 2-aryl-N-arenesulfonylazetidines. In these reactions, how-
ever, yields were modest because of solvent-phase conformational
mobility.
The demand for increasingly clean and efficient chemical synthesis is
important from both economic and environmental points of view. One
commonly used method is a combination of microwave irradiation and
solid support. This offers a number of advantages such as environmen-
tally friendliness, shorter reaction times, efficiency, high yields and easy
workups.[11,12]
RESULTS
During the course of our investigations pertaining to microwave-assisted
reactions on solid supports,[13] we tried synthesis of 2-aryl-N-arenesulfo-
nylazetidines by using N-arenesulfonylimines 1, trimethylsulfoxonim
iodide 2, and potassium hydroxide (KOH) under microwave irradiation.
To our surprise, however, the only product obtained on workup was the
corresponding N,N-dimethylarenesulfonamide (Scheme 1).
We surmised that the product arises from hydrolysis of the imines to
the corresponding sulfonamide, which then gets methylated. Although
Nddaka et al.[14] previously reported the synthesis of N,N-dimethylated
sulfonamides from N-sulfonyltellurimides, the formation of these com-
pounds from its carbon analog is not known. To test these ideas, several
arenesulfonamides 3a–j were treated with trimethylsulfoxonium iodide 2
and KOH under microwave irradiation on solid support to get the corre-
sponding N,N-dimethylated products. Thus, herein we report a facile,
Scheme 1. Formation of N,N-dimethylarenesulfonamides from N-arenesulfonyli-
mines under microwave irradiation.

3076
S. Malik, U. K. Nadir, and P. S. Pandey
Scheme 2. Synthesis of N-mono- and N,N-dimethyl alkyl and arenesulfonamides
by trimethylsulfoxonium iodide and KOH under microwave irradiation.
noncatalytic, solvent-free method for the synthesis of N-mono- and N,N-
dimethyl alkyl and arenesulfonamides 4a–j under microwave irradiation
using trimethylsulfoxonium iodide and KOH as methylating agent
(Scheme 2).
Some of the results we obtained for the preparation of N-mono and
N,N-dimethylated alkyl and arenesulfonamides are summarized in Table 1.
All products (reported in Table 1) are known in literature, except 4e, 4i,
and 4j. It is remarkable that the reaction time is very short, and yields of
the products are excellent. The primary sulfonamides can be monomethy-
lated or dimethylated by an appropriate amount of Me3Sþ OI- and KOH
(Entries a–g). Entries 4c–g show that the reaction times and yields of the
products are not affected significantly by the nature of the substituent
(electron donating or electron withdrawing). Entries 4h–j show that
Table 1. Various N-mono- and N,N-dimethylsulfonamides synthesized by
trimethylsulfoxonium iodide and KOHa
Time Temp. Power
(ꢁC)
Yieldc
(%)
Sr. nob
R1
R2
(min)
(W)
Ref.
4a
4b.
4c
4d
4e
4f
4g
4h
4i
ꢀCH3
ꢀC6H5
ꢀCH3
ꢀCH3
4
4
4
4
4
4
4
4
4
4
130
130
130
130
130
130
130
130
130
130
640
640
640
640
640
640
640
640
640
640
8a
8a
2b
3
—
2b
2b
7a
—
—
85
90
88
88
86
87
90
81
91
92
4ꢀClC6H4
ꢀCH3
4ꢀCH3C6H4
4ꢀNO2C6H4
4ꢀNH2C6H4
4ꢀOCH3C6H4
ꢀCH3
ꢀCH3
ꢀCH3
ꢀCH3
ꢀCH3
ꢀCOC6H5
4ꢀNH2C6H4 ꢀC4H4NOd
4j
4ꢀNH2C6H4 ꢀC6H7N2d
aSulfonamide: 1 mmol; trimethylsulfoxonium iodide: 2 mmol; KOH: 2 mmol.
bProducts were characterized by IR, NMR, elemental analysis, and HRMS.
cIsolated, unoptimized yields.
d
ꢀC4H4NO and ꢀC6H7N2 are

Microwave-Assisted Methylation of Sulfonamides
3077
reaction works equally well with secondary sulfonamides. The reaction
proceeds cleanly, and workup is simple, involving only filtration of solid
support and removal of solvent to obtain the product in high purity.
Attempts to carry out these reactions with aniline, acrylamide, benza-
mide, and benzoic acid afforded no mono- or dimethylated products,
hereby showing that the method is applicable to sulfonamides only. It
should be noted that efficacy of this dry synthetic method was evaluated
by comparison with the same reaction in prolonged refluxing conditions
where the reactants were completely recovered. It may also be noted that
the reaction was successful only when alumina was used as the solid sup-
port; it failed when silica gel or montmorillonite K-10 or KSF were used
as the solid support.
CONCLUSION
In conclusion, we have described an experimentally simple and con-
venient process for the synthesis of N-methyl and N,N-dimethyl alkyl
and arenesulfonamides by trimethylsulfoxonium iodide and KOH under
microwave irradiation.
This protocol is fairly general and applicable to a wide variety of sulfo-
namides. The yields are excellent. Reaction times are short, and the workup
procedure is simple. The advantages of this method over reported ones
include simplicity, generality, rapidity, and avoidance of toxic or expensive
catalysts and solvents. Moreover, to the best of our knowledge, there is no
reference on the synthesis of N-mono- and N,N-dimethylsulfonamides,
which works equally well for primary and secondary sulfonamides.
EXPERIMENTAL
1H and 13C NMR spectra were recorded on a DPX-300 Bruker spectrometer.
Data are reported are as follows: Integration, chemical shift in parts per
million (ppm) from tetramethylsilane (TMS) on the d scale, multiplicity
(s ¼ singlet, bs ¼ broad singlet, d ¼ doublet, t ¼ triplet, dd ¼ doublet
doublet, and m ¼ multiplet), and coupling constant in Hertz (Hz).
Mass spectra were recorded on QSTAR Excel Applied Biosystem spec-
trometer. Melting points were determined using an Electron Bombay
micro-melting-point apparatus and are uncorrected. For all microwave-
induced reactions, a focused Pelco laboratory microwave oven was used.
IR absorption spectra were recorded on a Nicolet 5DX FTIR instrument,
and values are reported in centimetersꢀ1. Monitoring of reactions was carried
out using silica-gel thin-layer chromatograpic (TLC) plates (Silica Merck 60

3078
S. Malik, U. K. Nadir, and P. S. Pandey
F254). Spots were visualized by UV light at 254 nm. Where required, column
chromatography was performed using silica gel (60–120 mesh).
General Procedure for Preparation of N-Mono- and N,N-
Dimethylsulfonamides
A mixture of appropriate sulfonamide (1 mmol), trimethylsulfoxonium
iodide (2 mmol), and KOH (2 mmol) was loaded on alumina
(0.5 mmol). This mixture was irradiated with microwaves for the speci-
fied time (Table 1) to get N,N-dimethylsulfonamides. For the synthesis
of N-monomethylsulfonamides the reactant ratio used was 1:1:1. Only
a single product (as shown by TLC) was formed. The reaction was
quenched by the addition of cold H2O. The product was extracted
with ethyl acetate, and removal of the solvent gave the product in
high purity.
Data
N,N-Dimethylmethanesulfonamide 4a: White crystalline solid; mp 46–48
ꢁC; yield ¼ 85%; IR: nmax (cmꢀ1): 1334, 1154; H (300 MHz, CDCl3):
1
d ¼ 2.78 (s, 3H), 2.86 (s, 6H); 13C NMR (75 MHz, CDCl3): d ¼ 37.76,
34.34.
ꢁ N,N-Dimethylbenzenesulfonamide 4b: Brown crystalline solid; mp 50–
1
51 C; yield ¼ 90%; IR: nmax (cmꢀ1): 1346, 1163; H (300 MHz, CDCl3):
d ¼ 2.71 (s, 6H), 7.53 (m, 3H), 7.76 (m, 2H); 13C NMR (75 MHz, CDCl3):
d ¼ 135.35, 132.66, 128.95, 127.64, 37.87.
N,N-Dimethyl-4-chlorobenzenesulfonamide 4c: Yellow crystalline
solid; mp 76–77 ꢁC; yield ¼ 88%; IR: nmax (cmꢀ1): 1315, 1136;
1H (300 MHz, CDCl3): d ¼ 2.71 (s, 6H), 7.54 (m, 2H), 7.75 (m, 2H);
13C NMR (75 MHz, CDCl3): d ¼ 139.20, 134.02, 129.30, 129.05, 37.81.
N,N-Dimethyl-4-methylbenzenesulfonamide 4d: White crystalline
solid; mp 79–81 ꢁC; yield ¼ 88%; IR: nmax (cmꢀ1): 1333, 1160;
1H (300 MHz, CDCl3): d ¼ 2.40 (s, 3H), 2.68 (s, 6H), 7.32 (m, 2H),
7.64 (m, 2H); 13C NMR (75 MHz, CDCl3): d ¼ 143.47, 135.68, 129.69,
127.22, 37.26, 22.48.
N,N-Dimethyl-4-nitrobenzenesulfonamide 4e: Yellow crystalline solid;
ꢁ
1
mp 154–155 C; yield ¼ 86%; IR: nmax (cmꢀ1): 1346, 1163; H NMR
(300 MHz, CDCl3): d ¼ 2.78 (s, 6H), 7.97 (m, 2H), 8.41 (m, 2H);
13C NMR (75 MHz, CDCl3): d ¼ 150.11, 141.73, 128.78, 113.33, 37.76;
CHN found (calcd.): 41.17 (41.73), 4.56 (4.34), 12.77 (12.17).
C8H10N2O4SNa: 253.0259 [M þ Na]þ : found: 253.0258.
N,N-Dimethyl-4-aminobenzenesulfonamide 4f: White crystalline solid;
mp 170–172 ꢁC; yield ¼ 87%; IR: nmax (cmꢀ1): 1333, 1160; 1H (300 MHz,

Microwave-Assisted Methylation of Sulfonamides
3079
CDCl3): d ¼ 2.61 (s, 6H), 4.91 (bs, 2H) 7.23 (m, 2H), 7.67 (m, 2H);
13C NMR (75 MHz, CDCl3): d ¼ 143.84, 127.46, 127.11, 118.88, 37.94.
N,N-Dimethyl-4-methoxybenzenesulfonamide 4g: Brown crystalline
solid; mp 71–72 ꢁC; yield ¼ 90%; IR: nmax (cmꢀ1): 1335, 1154;
1H (300 MHz, CDCl3): d ¼ 2.74 (s, 6H), 3.82 (s, 3H), 7.01 (m, 2H),
7.72 (m, 2H); 13C NMR (75 MHz, CDCl3): d ¼ 162.90, 132.90, 129.83,
114.13, 55.57, 37.95.
N-Benzoyl-N-methyl-4-methylbenzenesulfonamide 4h: White crystal-
line solid; mp 65–66 ꢁC; yield ¼ 81%; IR: nmax (cmꢀ1): 1693, 1331,
1
1159; H (300 MHz, CDCl3): d ¼ 2.42 (s, 3H), 2.63 (s, 3H), 7.34 (m,
3H), 7.52 (m, 4H), 7.74 (m, 2H); 13C NMR (75 MHz, CDCl3): 200.01,
150.01, 128.88, 127.49, 127.11, 123.44, 114.67, 38.12, 23.22.
4-Amino-N-(5-methyl-3-isoxazolyl)-N-methylbenzenesulfonamide 4i:
Yellow brown crystalline solid; mp 82–84 ꢁC; yield ¼ 91%; IR
1
n
max(cmꢀ1): 3477, 3334, 3201, 1343, 1158; H NMR (300 MHz, CDCl3):
d ¼ 2.31 (s, 3H), 3.16 (s, 3H), 4.42 (bs, 2H), 6.42 (s, 1H), 6.51 (d,
J ¼ 8.1 Hz, 2H), 7.42 (d, J ¼ 8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d ¼ 170.03, 161.03, 151.36, 129.30, 124.52, 113.94, 97.55, 34.86, 12.59;
CHN found (calcd.): 49.91 (49.43), 4.56 (4.86), 15.55 (15.73).
C11H14N3O3S: 268.0756 [M þ H]þ : found: 268.0755.
4-Amino-N-(4,6-dimethyl-2-pyrimidinyl)-N-methylbenzenesulfonamide
4j: Yellow brown crystalline solid; mp 215–217ꢁC; yield ¼ 92%; IR
1
n
max(cmꢀ1): 3471, 3375, 3249, 1365, 1149, H NMR (300 MHz, CDCl3):
d ¼ 2.31 (s, 6H), 3.62 (s, 3H), 4.09 (bs, 2H), 6.61 (d, J ¼ 6.9 Hz, 2H),
7.26 (s, 1H), 7.82 (d, J ¼ 7.2 Hz, 2H), 13C NMR (75 MHz, CDCl3): d ¼
167.06, 150.46, 131.14, 114.08, 113.03, 33.73, 23.66; CHN found (calcd.):
54.12 (53.97), 4.56 (4.49), 19.01 (19.37). C13H16N4O2SNa: 315.0892
[M þ Na]þ : found: 315.0890.
ACKNOWLEDGMENT
We are thankful to the Council of Scientific and Industrial Research
(CSIR), New Delhi, for the fellowship for S. M.
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