Microwave-assisted synthesis of some substituted sulfamides

Article abstract of DOI:10.1080/10426507.2013.819868

Microwave-assisted synthesis of some substituted open-chain and cyclic sulfamides, by amine-exchange reaction, was studied in a modified domestic microwave oven. Reaction times and yields under microwave radiation were compared with classical heating. Synthesis of the sulfamides under microwave irradiation gave better yields with the desired compounds, and in considerably reduced reaction times, than those obtained by classical heating. [Supplementary materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfer, and Silicon and the Related Elements for the following free supplemental files: Additional figures.]

Full text of DOI:10.1080/10426507.2013.819868

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Microwave-Assisted Synthesis of Some
Substituted Sulfamides
Aliye Gediz Erturk a & Yunus Bekdemir b
a Faculty of Science and Arts, Department of Chemistry , Ordu
University , Ordu , Turkey
b Canik Basari University, Department of Molecular Biology,
Gurgenyatak Campus , 55080 , Canik/ Samsun , Turkey
Accepted author version posted online: 02 Sep 2013.Published
online: 03 Dec 2013.
To cite this article: Aliye Gediz Erturk & Yunus Bekdemir (2014) Microwave-Assisted Synthesis of Some
Substituted Sulfamides, Phosphorus, Sulfur, and Silicon and the Related Elements, 189:2, 285-292,
DOI: 10.1080/10426507.2013.819868
To link to this article: http://dx.doi.org/10.1080/10426507.2013.819868
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Phosphorus, Sulfur, and Silicon, 189:285–292, 2014
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2013.819868
MICROWAVE-ASSISTED SYNTHESIS OF SOME
SUBSTITUTED SULFAMIDES
Aliye Gediz Erturk1 and Yunus Bekdemir2
1Faculty of Science and Arts, Department of Chemistry,
Ordu University, Ordu, Turkey
2Canik Basari University, Department of Molecular Biology,
Gurgenyatak Campus 55080, Canik/ Samsun, Turkey
GRAPHICAL ABSTRACT
Abstract Microwave-assisted synthesis of some substituted open-chain and cyclic sulfamides,
by amine-exchange reaction, was studied in a modified domestic microwave oven. Reaction
times and yields under microwave radiation were compared with classical heating. Synthesis
of the sulfamides under microwave irradiation gave better yields with the desired compounds,
and in considerably reduced reaction times, than those obtained by classical heating.
[Supplementary materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfer, and Silicon and the Related Elements for the following free supplemental
files: Additional figures.]
Keywords Sulfamides; amine-exchange reactions; microwave irradiation
Received 3 April 2013; accepted 24 June 2013.
We would like to thank the Ondokuz Mayis University (Grant No: F-286) for financial support of this work.
Address correspondence to Aliye Gediz Erturk, Faculty of Science and Arts, Department of Chemistry, Ordu
University, Ordu, Turkey. E-mail: aerturk@att.net
285

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A. G. ERTURK AND Y. BEKDEMIR
INTRODUCTION
There are very striking similarities between the structure of sulfamide, which is an
important member of organosulfur compounds, and urea.1 The pharmacological proper-
ties of the sulfamides have commanded the interest of organic and medicinal chemists.
Compounds bearing this functionality have been investigated as agonists of the 5-HTID
receptor, for their active components in epinephrine analogues, their nonhydrolizable com-
ponents of peptide-mimetics and as carbonic anhydrase inhibitors.2 In addition, previous
research has considered alkyl/aryl sulfamides as new candidates for antiepileptic drugs.3
Molecular structures with the sulfamide function are used as oral antidiabetic agents,4
diuretics and antiglaucoma agents and it has recently emerged that they also have poten-
tial as anticonvulsant, antiobesity, anticancer, antipain, and anti-infective drugs.5 Cyclic
sulfamides, in particular, are used as components of insecticide mixtures and as myorelax-
anti-inflammatory agents.6 Aryl-substituted seven and eight-membered cyclic sulfamides
inhibit HIV-1 protease, serine protease and metalloprotease.7,8
The synthesis of sulfamide derivatives have been summarized into two main synthetic
routes in the literature9: (a) from the reaction of primary amines (alkyl or aryl) with
thionyl and sulfuryl halides (very reactive and corrosive chemicals) in an inert solvent at
low temperatures. Parnell has used this route extensively to obtain aromatic sulfamides.4
(b) from the reaction of primary amines with sulfamides by means of amine exchange.
Kirsanov and Spillane have synthesized a number of sulfamides in extremely dry diglyme
or dry pyridine, in this way.10 These two synthetic routes needed very long reaction times
and the derivatives obtained were in much lower yields than desired (such as 6% and
4% for the synthesis of 5-chloro- and 5-nitro- 1H,3H-2,1,3-benzothiadiazole 2,2-dioxides,
respectively).11
Recently, the use of microwave heating has become an area of increasing interest
in both academic and industrial laboratories because it can dramatically enhance the rate
of reaction and, in many cases, increase product purity and yields.12,13 Therefore, high-
speed synthesis by microwaves provides the technology for rapid optimization of reactions,
efficient synthesis of new chemical entities, and for the discovery and probing of new
chemical reactivity.14 Especially, the combination of solvent-free conditions and microwave
irradiation, leads to enhancement in conversions and selectivity, use of inexpensive reagents
and simple product isolation procedures,15 which are compatible with features of the
environmentally-friendly technique, the so-called green chemistry.16
Herein, we report the facile synthesis of cyclic and acyclic substituted sulfamides
by an amine exchange reaction, producing high yield using a microwave approach which
proceeds more rapidly than conventional heating. Aryl, alkyl amines and diamines and also
aldehydes were reacted in a modified domestic microwave with sulfamide in the presence
of a solvent under reflux or solvent-free medium at 360, 900 W (2450 MHz) of microwave
irradiation, resulting in shorter reaction times with higher yields when compared to classical
heating.
RESULTS AND DISCUSSION
Microwave-assisted amine exchange reactions of sulfamide with substituted o-
phenylenediamines were carried out in the presence of commercial diglyme under reflux.
The reaction was performed at 900 W of microwave power and atmospheric pressure within

MICROWAVE SYNTHESIS OF SOME SULFAMIDES
287
Table 1 Reaction times and yields for classical and microwave procedures in the preparation of 5-Substituted
1H, 3H-2,1,3-benzothiadiazole 2,2-dioxides
Conventional heating17,18
Microwave irradiationa
Time (min) Yield (%)
80
Product
Time (min)
45
Yield (%)
64
2a
2b
8
45
34
7
75
2c
45
45
6
4
7
5
74
55
2d
aMW power = 900 W.
5–8 min. Under conventional heating, when the reaction is completed, the diglyme is re-
moved in the work-up by distillation from the filtrate at 55◦C/15 mmHg. However, this
was not needed since the microwave reactions were carried out using the diglyme as a neat
solvent. Results and experimental conditions are summarized in Table 1.
Reactions of sulfamide with open-chain diamines in a microwave oven were carried
out in the presence of diglyme under reflux. The reaction was performed at 360 W of
microwave power and atmospheric pressure for 20 min. Results and experimental conditions
are summarized in Table 2. It has been pointed out that when the methylene chain exceeds
eight carbon atoms in the reaction of the sulfamides with the diamines, the product formed
will be polymeric in nature.9 Microwave syntheses of compounds (4b) and (4c) were
performed in diglyme to reduce formation of the polymeric by-product and shorten the
reaction time.
The microwave-assisted amine exchange reactions of sulfamide with substituted aro-
matic and aliphatic amines were carried out in the presence of pyridine. The reaction was
performed at 900–360 W of microwave power for 4–15 min. For example, in the literature,
compounds (6a–c) and (8c) were not synthesized with amine exchange reactions before-
hand. These compounds were obtained either from reaction of the corresponding amine
with SO2Cl2 at –78◦C4 or from reaction of their sulfamyl chlorides1 with their correspond-
ing amines, respectively. Both methods include highly corrosive starting materials and take
a long time. Spillane and coworkers have synthesized some sulfamides by amine exchange

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A. G. ERTURK AND Y. BEKDEMIR
Table 2 Reaction times and yields for classical and microwave procedures in the preparation of substituted of
1,2,6-thiadiazinane 1,1-dioxides
Conventional heating19
Time (min) Yield (%)
Microwave irradiationa
Time (min) Yield (%)
Product
4a
4b
120
23b
20
45
360
32
20
64
4c
360
13
20
18
aMW power = 360 W, bReaction was performed in triethylenediamine.
reaction in ultra-dried diglyme which was not enough to get the expected amount of the
sulfamides. In our approach we used commercial diglyme (99.5%) without drying and the
yields were considerably higher. Results and experimental conditions are summarized in
Table 3.
In Table 4, the results and experimental conditions are given for 3-Imino-4-substituted
phenyl-1,2,5-thiadiazolidine 1,1-dioxides, which were obtained from reactions of a series
of benzaldehyde derivatives with sulfamide in the presence of NaCN in an aqueous ethanol
mixture. In Table 5, the results are given for the preparation of 3,4-Diphenyl-1,2,5-thiadiazol
1,1-dioxide. When microwave-assisted heating was used, each product was obtained in
shorter reaction times and with higher yields than with conventional heating.
In conclusion, a microwave-assisted protocol for the facile, rapid and “green” synthe-
sis of substituted sulfamide derivatives has been developed which proceeds expeditiously
through the amine exchange method at atmospheric pressure. Although catalysts or addi-
tives were not involved in the reaction, and yields of 65–90% of sulfamide derivatives were
achieved, the reaction times were dramatically reduced from 45 (to 360) min by traditional
heating to 3 (to 15) min under suitable conditions of microwave irradiation. The reaction not
only accelerates upon exposure to microwave irradiation, thus shortening its reaction time
and work-up procedure, but also eliminates the formation of any byproduct when compared
to the traditional methods involving conventional heating. Furthermore, the reactions can
be achieved without using dry reaction solvents.

MICROWAVE SYNTHESIS OF SOME SULFAMIDES
289
Table 3 Reaction times and yields for classical and microwave procedures in the preparation of substituted of
N,N’-diphenylsulfamides and N,N’-dialkyldulfamides
Conventional
heating20–22
Microwave irradiationa,b
Product
Time (min) Yield (%) Time (min)
Yield (%)
87a
6a
330
84
13
6b
6c
330
330
20
15
5
75a
40a
15
8a
8b
330
330
70
79
8
4
97b
93b
8c
330
330
21
73
15
7
52b
93b
8d
MW Power: a900 W, with pyridine; b360 W, without solvent.
EXPERIMENTAL
Chemicals were purchased from Aldrich, Acros, Merck, and Fluka and purified by
crystallization or distillation before use. Thin layer chromatography (TLC) was performed
using Merck aluminum-backed plates (Kieselgel 60 F254), and visualization was achieved
by ultraviolet (UV) light. During the experiments to find the optimal conditions for each
reaction, we took TLC of the reaction mixtures at one minute intervals in each case, until
we were sure that the reaction did not proceed under prolonged microwave radiation,
even with higher power. So, when the starting materials consumed, we determined the
reaction time and convenient energy level. All products were characterized by comparison
1
of their physical data with samples prepared by conventional heating. The H and 13C
NMR spectra were recorded on a Varian Mercury–400 MHz Spectrometer at 400 and
100 MHz, respectively, in CDCl3 and DMSO-d6 using TMS as the internal standard. IR
Spectra were recorded with a MATTSON 1000 FTIR Spectrophotometer. Melting points
were determined on an Electrothermal Digital Melting Point Apparatus. Experiments were
carried out under microwave irradiation by using a domestic microwave oven (Bosch model
HMT 812C 2450 MHz) that was modified by fitting a reflux system and internal camera.
The domestic microwave oven operated at a frequency of 2450 MHz with power ranging

290
A. G. ERTURK AND Y. BEKDEMIR
Table 4 Reaction times and yields for classical and microwave procedures in the preparation of 3-Imino-4-
substituted phenyl-1,2,5-thiadiazolidine 1,1-dioxides
Conventional heating23,24
Microwave irradiationa
Product
Time (min)
360
Yield (%)
35
Time (min)
4
Yield (%)
10a
10b
92
360
360
62
41
2.5
3
95
10c
10d
96
47
360
11
2
aMW power = 90 W
from 90 to 900 W. Elemental analysis was performed by Midwest Microlabs in Indianapolis,
USA.
General Procedure for the Preparation of 5-Substituted 1H,3H-2,1,3-
benzothiadiazole 2,2-dioxides (2a–d):17,18 o-Phenylenediamine (280 mg, 2.6 mmol) and
sulfamide (250 mg, 2.6 mmol) were dissolved in diglyme. Diglyme was used as a neat
solvent. The resulting solution was placed inside a modified domestic microwave oven at
900 W and irradiated for 8 min. under reflux. The reaction was completed as determined
by TLC monitoring, using ether/petroleum ether (3:1) as the eluent. The reaction mixture
was then removed from the oven, cooled in ice, and filtered. The residue was dissolved
in ether (20 mL) and washed successively with HCl (2 N, 3 × 5 mL) and with saturated
brine (3 mL). The ether solution was dried and benzylamine (1 mL) was added. The
sulfamide salt was precipitated: it was filtered off, washed with ether, and shaken with HCl
(2 N, 10 mL). The acidic solution was extracted with ether (4 × 5 mL) and the combined
extracts were dried and evaporated to leave the product.

MICROWAVE SYNTHESIS OF SOME SULFAMIDES
291
Table 5 Reaction times and yields for classical and microwave procedures in the preparation of 3,4-Diphenyl-
1,2,5-thiadiazol 1,1-dioxide
Conventional heating25
Time (min) Yield (%)
1440 57
Microwave irradiationa,b
Time (min) Yield (%)
10 66
Product
12
aMW power = 360 W breflux in abs EtOH.
General Procedure for the Preparation of Substituted 1,2,6-thiadiazinane 1,1-
dioxide (4a–c):19 Trimethylenediamine (290 mg, 3.9 mmol) and sulfamide (125 mg,
1.3 mmol) were mixed in a 25 mL flask. The mixture was refluxed in a modified oven
(360 W) for 5 min. The reaction mixture was controlled by TLC at regular intervals on
silica gel with a mixture of chloroform and petroleum ether (9:1) as the eluent. After cooling
to room temperature, HCl (4 N, 5 mL) was added and the liquid phase was extracted using
ethyl acetate. The combined extracts were dried and evaporated to product.
General Procedure for the Preparation of Substituted N,Nꢀ-diphenylsulfamides
(6a–c)20–22 and N,N’-dialkyldulfamides (8a–d):20 Aniline (240 mg, 2.6 mmol), sulfamide
(125 mg, 1.3 mmol), and pyridine (1 mL) were mixed in a 25 mL flask. The mixture was
refluxed in a modified oven (360 W) for 20 min. The reaction mixture was controlled by
TLC at regular intervals on silica gel with a mixture of ether and petroleum ether (4:1) as
the eluent. After cooling, HCl (2 N, 5 mL) was added to obtain a mixture and was extracted
with chloroform. The chloroform phase was then dried and evaporated to form the product
(6a–c). Synthesis of N,N’-dialkylsulfamides (8a–d) was realized without using pyridine,
under similar conditions.
General Procedure for the Preparation of 3-Imino-4-substituted phenyl-1,2,5-
thiadiazolidine-1,1-dioxide (10a–d):23,24 Sodium cyanide (35 mg, 0.72 mmol) was added
to 70% aqueous alcohol solution involving benzaldehyde (70 mg, 0.66 mmol) and sulfamide
(125 mg, 1.3 mmol) in a 25 mL flask. The mixture was refluxed in a modified microwave
oven (90 W) for 3 min. 1 N NaOH (0.6mL) was added to the obtained mixture. The reaction
mixture was monitored throughout the experiment with TLC on silica gel with a mixture
of ethyl acetate and ether (4:1) as the eluent. An aqueous mixture was extracted with ethyl
acetate (2 × 1.3 mL) and diethyl ether (0.7 mL). The aqueous phase was acidified with 1 N
HCl (pH∼2). Precipitated solids were recrystallized with ethyl alcohol.
General Procedure for the Preparation of 3,4-Diphenyl-1,2,5-thiadiazol-1,1-
dioxide (12):25 Benzil (274 mg, 1.3 mmol), sulfamide (125 mg, 1.3 mmol), and triethy-
lamine (0.05 mL) were mixed with absolute ethyl alcohol (3 mL) in a 25 mL flask. The
mixture was refluxed in a modified microwave oven (360 W) for 120 min. Progress of the

292
A. G. ERTURK AND Y. BEKDEMIR
reaction was monitored by TLC, and the eluent was acetone and petroleum ether (4:1). The
reaction mixture was concentrated, washed and recrystallized with acetone. The combined
extracts were dried and evaporated to form product (12). In order to increase the yield, the
water which was formed was removed and then the reaction was renewed in a medium
with anhydrous Na2SO4. Finally, product (12) was synthesized (0.118 g, 66%) at 360W for
10 min.
3-Imino-4-(4-(dimethylamino)phenyl)-1,2,5-thiadiazolidine 1,1-dioxide
(10d)
1
Mp 208–210◦C; IR (KBr): 3429, 3262, 3062, 2923, 1339, 1146 cm−1; H-NMR
(400 MHz, DMSO-d6, 25 ◦C); δ = 2.88 (s, 6H), 5.16 (s, 1H), 6.71 (d, J = 8.00 Hz, 2H), 7.21
(d, J = 8.00 Hz, 2H), 7.44 (s, 2H), 8.18 (s, 1H); 13C-NMR (100 MHz, DMSO-d6, 25 ◦C);
δ = 40.1, 64.3, 112.1, 124.9, 128.3, 150.4, 170.2 ppm; Anal. Calcd. For C10H14N4O2S: C
47.23, H 5.55, N 22.03, S 12.61. Found: C 47.48, H 5.51, N 21.80, S 12.63%.
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