An efficient one-pot synthesis of N-(substituted phenyl)-1,2,5-thiadiazolidine-2-carboxamide 1,1-dioxide derivatives

Article abstract of DOI:10.1002/jhet.3767

1,2,5-Thiadiazolidine-1,1-dioxide carboxamide derivatives 3a-3n are novel heterocyclic compounds synthesized by multicomponent condensation reaction in one pot of aniline, chlorosulfonyl isocyanate, and 2-chloroethylamine hydrochloride which is used as a

Full text of DOI:10.1002/jhet.3767

Received: 15 December 2018
DOI: 10.1002/jhet.3767
Revised: 5 February 2019
Accepted: 12 September 2019
A R T I C L E
An efficient one-pot synthesis of N-(substituted phenyl)-
1,2,5-thiadiazolidine-2-carboxamide 1,1-dioxide derivatives
Sihem Hessainia1
| Abbes Boukhari1
| Zinelaabidine Cheraiet2
1Laboratory of Organic Synthesis,
Abstract
Modeling and Optimization of Chemical
Processes, Department of Chemistry, Badji
Mokhtar-Annaba University, Annaba, P.
O. Box 12, 23000, Algeria
1,2,5-Thiadiazolidine-1,1-dioxide carboxamide derivatives 3a-3n are novel het-
erocyclic compounds synthesized by multicomponent condensation reaction
in one pot of aniline, chlorosulfonyl isocyanate, and 2-chloroethylamine
hydrochloride which is used as a useful precursor under mild conditions. This
reaction is realized with high atom economy, at room temperature and in a
short reaction time. Series of these desired products are obtained from good to
excellent yields within 2 hours in all cases. All the synthesized compounds are
characterized by 1H, 13C NMR, MS, and HMBC/HSQC spectroscopy.
2Ecole Supérieure des Technologies
Industrielles, Annaba, Cité saf-saf BP-
21823000, Algeria
Correspondence
Sihem Hessainia, Laboratory of Organic
Synthesis, Modeling and Optimization of
Chemical Processes, Department of
Chemistry, Badji Mokhtar-Annaba
University, P.O. Box 12, 23000 Annaba,
Algeria.
Email: shessainia@gmail.com
Funding information
General Directorate for Scientific Research
and Technological Development
1 | INTRODUCTION
sulfonylureas
derivative
compound
1
shows
antituberculous,[15] the sufamoyl ureas 2 influences the
cancerous activity,[16] and the cyclosulfamides 3 shows
serine protease inhibitors[17] (Figure 1).
Heterocycles containing nitrogen and sulfur are very inter-
esting compounds in organic synthesis as well as in medic-
inal chemistry due to their significant biological and
pharmacological properties.[1–3] The sulfonylureas and
cyclosulfamoyl ureas are an important class of com-
pounds, the sulfonylureas derivatives are the first oral
hypoglycemic agents which are known of their use for the
treatment of type II diabetes.[4] In addition, these mole-
cules exhibited other therapeutic uses such as ACAT
inhibitors,[5] herbicidal,[6] antifungal,[7] antimicrobial,[8]
and anticancer activities.[9] Among heterocyclic com-
pounds, the 1,2,5-thiadiazolidine 1,1-dioxides deriva-
tives of cyclosulfamides containing nitrogen, oxygen and
sulfur exhibit multiple biological and pharmacological
activities,[10,11] because of their analogues of cyclosulfamoyl
ureas. They are used as diuretic agents,[12] potential
inhibitors of HIV-1 viral protease,[2] antidepressants,[13]
and reverse transcriptase inhibitors.[14] For example,
Cyclosulfamides[10] and cyclosulfamide carbamoyl[18]
derivatives have been already described in the literature
using different methods.[19] These methods present disad-
vantages, we quote the low afforded yield,[20] the long
reaction time,[21] heating,[22] or adding an activator factor
involving several steps.[23]
In this work, we report the synthesis of novel
thiadiazolidine carboxamide dioxides derivatives 3a-n
using multicomponent condensation reaction in one pot.
The reaction is carried out under certain environmentally
reaction conditions. The chlorosulfonyl isocyanate (CSI)
has been found to be versatile reagent in synthetic het-
erocyclic chemistry,[24] especially to introduce the sul-
famoyl moiety in sulfamide due to their dual
functionalities. The synthesis of all these thiadiazolidine
carboxamide dioxides derivatives has not been reported
J Heterocyclic Chem. 2019;1–7.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

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HESSAINIA ET AL.
SCHEME 2 Multicomponent condensation reaction in one
pot for the synthesis of novel cyclosulfamide carboxamide
derivatives
FIGURE 1 Sulfamoyl urea and cyclic sulfamides moieties
having biological activities
in situ in the presence of three equivalents of
triethylamine in acetonitrile as solvent at 0ꢀC
(Scheme 2); the results show that within 2 hours, the
intramolecular cyclization is realized and the desired
product 3a is obtained with a significantly improvement
of yield (up to 70%) (Table 1). So, this new methodology
of multicomponent condensation reaction in one pot is
able to promote the synthesis of N-(4-F-phenyl)
1,2,5-thiadiazolidine-2-carboxamide 1,1-dioxide only in
2 hours in eco-friendly conditions.
SCHEME 1 Synthesis of cyclosulfamide carboxamide via
intramolecular cyclization by two steps
In addition, to validate this new protocol and show
the effectiveness of the multicomponent reaction MCRs
for the preparation of novel cyclosulfamides ureas, we
apply this optimized reaction on series of variously
substituted aniline with electron-withdrawing and
electron-donating groups in order to access to N-
(substituted phenyl) 1,2,5-thiadiazolidine-2-carboxamide
1,1-dioxide derivatives with high yield. The results are
summarized in Table 1, and show that the reaction
between aniline is substituted by electron-withdrawing
or electron-donating groups, CSI and 2-chloroethylamine
in one pot provides from good to excellent yields
(60% < yield < 90%) for all compounds (3a-3n). These
results affirm the utility and efficiency of the mul-
ticomponent reaction MCRs which is developed for the
first time for the preparation of the new types of cyclo-
sulfamide carboxamide compounds. All the synthesized
yet neither by multicomponent reaction nor by other
methods.
2 | RESULTS AND DISCUSSION
In this work, we focused our attention on the develop-
ment of an efficient and simple protocol for the prepara-
tion of new thiadiazolidine carboxamide dioxides.
Initially, the 4-F-aniline was chosen due to its high reac-
tivity, then we attempted the synthesis of N-(4-F-phenyl)-
1,2,5-thiadiazolidine-2-carboxamide 1,1-dioxide through
two steps. The first one is the condensation of 4-F-aniline
1a with CSI using dichloromethane as solvent, after
30 minutes, the 2-chloroethylamine is added in situ in
the presence of triethylamine and the acetonitrile as sol-
vent at 0ꢀC to give the 1-(N-2-chloroethyl)sulfamoyl)-
3-N-(4-halogenophenyl)urea 2a after isolation by column
chromatography. In the second step, the intramolecular
cyclization of 2a compound is provided using the K2CO3
in acetonitrile within 3 hours at 60ꢀC to obtain the N-
(4-F-phenyl)-1,2,5-thiadiazolidine-2-carboxamide 1,1-
dioxide 3a (Scheme 1). The results show that the
desired product is obtained in a low yield (<30%).
Moreover, to provide the N-(substituted phenyl)
1,2,5-thiadiazolidine-2-carboxamide 1,1-dioxide deriva-
tives with high yield, we change the protocol and the
reaction conditions. We think about using the mul-
ticomponent condensation reaction in one pot as a new
approach to easily access the thiadiazolidine carboxamide
dioxides of original structures. The 4-F-aniline 1a and
CSI when are reacted within 30 minutes in the same con-
ditions of the first voice, the 2-chloroethylamine is added
1
compounds are well characterized by H and 13C NMR
spectroscopy.
Structure of 3a is characterized as N-(4-F-phenyl)-1,-
2,5-thiadiazolidine-2-carboxamide 1,1-dioxide from its
spectral data, in which the absence of carbamic protons
in 1H NMR confirms the formation of cyclosulfamide car-
boxamide bridge. The obtained compounds 2a and 3a-n
1
are characterized by H and 13C NMR spectroscopy. The
sulfamoyl urea 2a is characterized by a proton signal car-
ried by the nitrogen atom which is located between the
carbonyl group and the sulfonyl group (SO2) appearing
between 8.35 and 8.41 ppm, as well as, the presence of
the peaks of other protons of NH of 2a at (8.35 ppm
CONHSO2 and 6.93 ppm NHSO2). During the cyclization
of the product 2a, the absence of the carbamic proton sig-
nal is mentioned above and the appearance of two new
signals of methylene cyclosulfamides urea 3a-n at
3.65 ppm confirms the intramolecular cyclization.

HESSAINIA ET AL.
3
TABLE 1 Synthesis of cyclosulfamide urea 3a-n
reactant is generated from the addition of triethylamine
to 2-chloroethanaminium. This reaction then leads to the
compound 2a-n. The use of the excess of TEA allows the
removal of the labile proton which is fixed on nitrogen
atom ( NH ) or in the way (a) to end to five-membered
ring, more thermodynamically stable, by the intramolec-
ular nucleophilic substitution reaction, according to
(b) to give a seven-membered ring, thermodynamically
less stable and does not form (Scheme 3).
Cyclosulfamide urea 3(a-n), (yield %)[a], [b]
3 | CONCLUSION
To recapitilize, an efficient and reproducible procedure
for the synthesis of cyclosulfamide ureas derivative
through one-pot three-component condensation of vari-
ous anilines reacts with CSI and 2-chloroethylamine in
the presence of an excess of triethylamine is developed.
The important features of this procedure are the use of
available starting materials, the simplicity of reaction and
work-up, the high yield, and short reaction times.
4 | EXPERIMENTAL SECTION
Melting points were determined in open capillary tubes
with an electrothermal apparatus and are uncorrected.
1H, 13C NMR spectra were measured with a 300 WB or
with an AC 400 Bruker spectrometer using, acetone-d6
and DMSO-d6 as solvent and TMS as an internal stan-
dard. Chemical shifts are reported in δ units (ppm). All
coupling constants (J) are reported in Hertz (Hz). Multi-
plicity is indicated as s (singlet), d (doublet), t (triplet),
and m (multiplet). The reactions have been separated by
recrystallization. The masse spectra were recorded on a
DSQ Thermo Electron apparatus (70 eV) by chemical
ionization (gaseous ammonia) by direct introduction.
Elemental analysis was performed with a PerkinElmer
2400 C, H, N analyzer and determined values were
within the acceptable limits of the calculated values.
aAll reactions were carried out with 1 mmol of aniline, 1 mmol ICS, and
1 mmol of 2-chloroethylamine, TEA (3eq) in acetonitrile, at 0ꢀC.
bIsolated yield after crystallization with ethyl acetate/hexane.
However, the singlet signals that can be attributed to the
CONH protons of the urea fragments are observed at 8.49
to 10.50 ppm. In 13C NMR, the appearance of peaks
between 43 and 45 ppm characteristic of the two methy-
lene groups confirmed the presence ring of five-
membered 1,2,5-thiadiazolidine. The relative attribution
of proton-carbon on N-(2-methyl-4-nitrophenyl)-1,-
2,5-thiadiazolidine-2-carboxamide 1,1-dioxide is deter-
mined by series of 2D NMR, HSQC, and HMBC
experiments. 2D mode HSQC experiments confirm the
vicinal relationship (C H correlation 1-2). In the case
of N-(2-methyl-4-nitrophenyl)-1,2,5-thiadiazolidine-2-
carboxamide 1,1-dioxide, HSQC (C H correlation 1-2)
no coupling for both signals at 8.08 ppm (t) and
8.27 ppm, confirming that are protons of NH. In the same
product, HMBC (C H correlation 1-3) cross signals have
been observed between N C2 O and C2 N H with the
pair (8.27, 114.96). The doublet of the nitrogen atom of
the starting compound 1a-n attacks the carbonyl carbon
which happens to be the first electrophilic site of the CSI
reagent, to lead to the intermediate 10a-n and thus to the
urea group ( NH CO NH ). This intermediate then
reacts with the 2-chloroethylamine hydrochloride
4.1 | Typical procedure for the synthesis
of 1-(N-2-chloroethyl)sulfamoyl)-3-N-
(4-4-fluorophenyl)urea (2a)
Sulfamoyl urea derivative were obtained by slowly adding
the solution of 4-F-aniline 1a in dry dichloromethane
(10 mL) to a stirred solution of CSI (5.74 mmol, 0.5 mL)
in anhydrous DCM (10 mL) at −5ꢀC. The reaction mix-
ture was vigorously stirred at 0ꢀC for 30 min. The crude
solid was isolated by vacuum filtration, and then used
immediately in the next step. 2-Chloroethylamine

4
HESSAINIA ET AL.
SCHEME 3 Probable mechanism to explain the formation of N-(Substituted phenyl)-1,2,5-thiadiazolidine-2-carboxamide 1,1-dioxide
derivatives
hydrochloride was dissolved in dry acetonitrile at 0ꢀC
then triethylamine was added (5.73 mmol; 0.7 mL) and
stirred for 30 minutes followed by slow dropwise. Addi-
tion of the product dissolved in the same solvent was fur-
ther agitated for another 1 hours. The reaction mixture
was diluted with DCM (30 mL) and subsequently washed
with 0.1 N HCl (20 mL) and then with water (25 mL).
The organic layer was dried over anhydrous sodium sul-
fate and concentrated in vacuo to give the desired sulfon-
amide derivatives 1-(N-2-chloroethyl)sulfamoyl)-3-N-
(4-fluorophenyl)urea 2a after purification by silica gel
chromatography using ethyl acetate: hexane (5:5).
resulting reaction mixture, the solvent was evaporated in
vacuo. The product was purified by column chromatogra-
phy on silica gel using ethyl acetate: petroleum ether
(3:7) to give pure products 3a in 27% yields.
4.2.1 | N-(4-fluorophenyl)-
1,2,5-thiadiazolidine-2-carboxamide
1,1-dioxide 3a
C9H10FN3O3S, Rf = 0.46 (acetate/petroleum ether: 3/7),
1
white solid, yield 27%, Mp: 169ꢀC to 170ꢀC. H NMR
(400 MHz, DMSO-d6) δ: 8.74 (s, 1H, NHCO), 7.91 (t,
J = 5.7 Hz, 1H, NHcyc), 7.43 (dd, J = 9.0, 4.9 Hz, 2H, H-
Ar), 7.14 (t, J = 8.8 Hz, 2H, H-Ar), 3.66 (t, J = 6.4 Hz, 2H,
CH2cycN), 3.31 (q, 2H, CH2cycNH). 13C NMR (101 MHz,
DMSO-d6) δ 159.65 to 157.26 (1JC-F = 241.39Hz), 150.60,
135.11 to 135.09 (4JC-F = 2.02Hz), 121.37 to 121.29 (3JC-
4.1.1 | 1-(N-2-chloroethyl)sulfamoyl)-
3-N-(4-fluorophenyl)urea 2a
C9H11FN3O3SCl, Rf = 0.40 (CH2Cl2/MeOH: 9.9/0.1), yel-
low oil, yield 45%. 1H NMR (300 MHz, acetone-d6) δ: 9.35
(s, 1H, NHCO), 8.35 (s, 1H, CONHSO2), 7.56 to 7.50 (m,
2H, H-Ar), 7.15 to 7.06 (m, 2H, H-Ar), 6.93 (t, J = 6.2 Hz,
1H, NHSO2), 3.77 (t, J = 6.4 Hz, 2H, CH2Cl), 3.51 (q,
J = 6.2 Hz, 2H, CH2NH). 13C NMR (75 MHz, acetone) δ:
160.46, 150.08, 134.59, 121.26, 115.41, 45.29, 42.65. Ele-
mental Anal. (%), calculated: C, 36.56; H, 3.75; N, 14.21;
found: C, 36.51; H, 3.75; N, 14.24.
= 8.08 Hz), 115.99 to 115.77 (2JC-F = 22Hz), 45.28,
F
43.35. Elemental Anal. (%), calculated: C, 41.70; H,
3.89; N, 16.21; found: C, 41.72; H, 3.85; N, 16.23.
4.3 | General procedure for synthesis of
compounds 3a-n in one step
To a solution of CSI (5.74 mmol, 0.5 mL) in dry DCM
(10 mL) cooled to −5ꢀC, the solution of aniline 1a-n in
dry DCM (10 mL) was added dropwise. The reaction mix-
ture was stirred at 0ꢀC for 30 min. The crud solid was iso-
lated by vacuum filtration and then used immediately in
the next step. 2-Chloroethylamine hydrochloride was dis-
solved in dry acetonitrile and cooled to −5ꢀC, then exceed
triethylamine was added (17.2 mmol, 2.1 mL) and stirred
4.2 | General procedure for the
cyclization
1-(N-2-chloroethyl)sulfamoyl)-3-N-(4-fluorophenyl)urea
2a (1equivalent), and 3 equivalent of K2CO3 in 10 mL of
acetonitrile was stirred at 60ꢀC for 3 hours. From the

HESSAINIA ET AL.
5
for 30 minutes followed by slow dropwise. Addition of
the isolated product dissolved in the same solvent was
further stirred for another 2 hours. The solvent was evapo-
rated in vacuo; the obtained crud was dissolved in 40 mL
of DCM with HCl (0.1 N, 30 mL). The organic layer 3a-n
was separated and dried over magnesium sulfate and evap-
orated to in vacuum. Recrystallization of the crude product
from ethyl acetate: hexane (5:5) afforded pure N-(hal-
ogeno/alkylphenyl)-1,1,5-thiadiazolidine-2-carboxamide
1,1-dioxide 3a-n as white/yellow solids and were pre-
pared in excellent yield.
7.94 (t, J = 5.7 Hz, 1H, NHcyc), 7.48 (d, J = 8.8 Hz, 2H,
H-Ar), 7.39 (d, J = 8.8 Hz, 2H, H-Ar), 3.65 (t, J = 6.4 Hz,
2H, CH2cycN), 3.31 (q, J = 6.0 Hz, 2H, CH2cycNH). 13C
NMR (101 MHz, DMSO-d6) δ: 150.45, 138.26, 132.09,
121.34, 115.06, 116.42, 45.29, 43.36, 39.71. Elemental
Anal. (%), calculated: C, 33.76; H, 3.15; N, 13.12;
found: C, 33.74; H, 3.17; N, 13.14.
4.3.4 | N-(4-chlorophenyl)-
1,2,5-thiadiazolidine-2-carboxamide
1,1-dioxide 3d
4.3.1 | N-(4-fluorophenyl)-
1,2,5-thiadiazolidine-2-carboxamide
1,1-dioxide 3a
C9H10ClN3O3S, Rf = 0.50 (ethyl acetate/hexane: 5/5),
1
white solid, yield 73%, Mp: 171ꢀC to 172ꢀC. H NMR
(250 MHz, DMSO-d6) δ: 8.82 (s,1H, NHCO), 7.98 (t,
J = 5.8 Hz, 1H, NHcyc), 7.45 (d, J = 8.9 Hz, 2H, H-Ar),
7.35 (d, J = 8.9 Hz, 2H, H-Ar), 3.65 (t, J = 6.3 Hz,2H,
CH2cycN), 3.30 (q, J = 6.1 Hz, 2H, CH2cycNH).13C NMR
(63 MHz, DMSO-d6) δ: 150.46, 137.72, 129.18, 128.95,
127.17, 121.02, 115.80, 45.26, 43.36. MS (ESI+ 70 eV m/
z): LCMS: 274.3 [M H]-. Elemental Anal. (%), cal-
culated: C, 39.21; H, 3.66; N, 15.24; found: C, 39.16; H,
3.61; N, 15.21.
C9H10FN3O3S, Rf = 0.46 (ethyl acetate/hexane: 5/5),
white solid, yield 71%, Mp: 169ꢀC to 170ꢀC. H NMR
1
(400 MHz, DMSO-d6) δ: 8.74 (s, 1H, NHCO), 7.91 (t,
J = 5.7 Hz, 1H, NHcyc), 7.43 (dd, J = 9.0, 4.9 Hz, 2H, H-
Ar), 7.14 (t, J = 8.8 Hz, 2H, H-Ar), 3.66 (t, J = 6.4 Hz, 2H,
CH2cycN), 3.31 (q, 2H, CH2cycNH). 13C NMR (101 MHz,
DMSO-d6) δ 159.65 to 157.26 (1JC-F = 241.39Hz), 150.60,
135.11 to 135.09 (4JC-F = 2.02Hz), 121.37 to 121.29 (3JC-
= 8.08 Hz), 115.99 to 115.77 (2JC-F = 22 Hz), 45.28,
F
43.35. Elemental Anal. (%), calculated: C, 41.70; H,
3.89; N, 16.21; found: C, 41.72; H, 3.85; N, 16.23.
4.3.5 | N-(3-fluorophenyl)-
1,2,5-thiadiazolidine-2-carboxamide
1,1-dioxide 3e
4.3.2 | N-(4-idophenyl)-
1,2,5-thiadiazolidine-2-carboxamide
1,1-dioxide 3b
C9H10FN3O3S, Rf = 0.42 (ethyl acetate/hexane: 5/5),
1
white solid, yield 85%, Mp: 176ꢀC to 177ꢀC. H NMR
(250 MHz, DMSO-d6) δ: 8.91 (s, 1H, NHCO), 8.01 (t,
J = 5.9 Hz, 1H, NHcyc), 7.66 to 6.05 (m, 4H, H-Ar), 3.66
(t, J = 6.3 Hz, 2H, CH2cycN), 3.30 (q, J = 6.1 Hz, 2H,
CH2cycNH). 13C NMR (63 MHz, DMSO-d6) δ 152.17 to
150.47 (1JC-F = 245Hz), 140.68 to 140.50 (2JC-F = 20Hz),
131.05 to 130.89 (2JC-F = 19.8 Hz), 115.18, 110.11 to
109.78 (3JC-F = 20.79 Hz), 106.33 to 105.91 (3JC-
C9H10IN3O3S, Rf = 0.45 (ethyl acetate/hexane: 5/5), white
solid, yield 60%, Mp: 184ꢀC to 185ꢀC. 1H NMR (400 MHz,
DMSO-d6) δ: 8.75 (s, 1H, NHCO), 7.94 (t, J = 5.7 Hz, 1H,
NHcyc), 7.63 (d, J = 8.6 Hz, 2H, H-Ar), 7.26 (d,
J = 8.6 Hz, 2H, H-Ar), 3.65 (t, J = 6.4 Hz, 2H, CH2cycN),
3.31 (q, J = 6.2 Hz, 2H, CH2cycNH). 13C NMR (101 MHz,
DMSO-d6) δ: 150.40, 138.74, 137.92, 137.74, 121.61, 86.78,
45.29, 43.35, 40.65. Elemental Anal. (%), calculated: C,
29.44; H, 2.75; N, 11.44; found: C, 29.47; H,
2.77; N, 11.41.
= 26.46Hz), 45.25, 43.36. MS (ESI+ 70 eV m/z): LCMS:
F
282 ([M + Na]+. Elemental Anal. (%), calculated: C,
41.70; H, 3.89; N, 16.21; found: C, 41.73; H,
3.90; N, 16.21.
4.3.6 | N-(2-tolyl)-1,2,5-thiadiazolidine-
2-carboxamide 1,1-dioxide 3f
4.3.3 | N-(4-bromophenyl)-
1,2,5-thiadiazolidine-2-carboxamide
1,1-dioxide 3c
C10H13N3O3S, Rf = 0.44 (ethyl acetate/hexane: 5/5), white
solid, yield 70%, Mp: 186ꢀC to 187ꢀC. 1H NMR (400 MHz,
DMSO-d6) δ: 7.99 (s, 1H, NHCO), 7.94 (t, J = 5.8 Hz, 1H,
NHcyc), 7.71 (d, J = 8.0 Hz, 1H, H-Ar), 7.17 (dd, J = 16.7,
7.9 Hz, 2H, H-Ar), 7.01 (t, J = 7.4 Hz, 1H, H-Ar), 3.66
C9H10BrN3O3S, Rf = 0.39 (ethyl acetate/hexane: 5/5),
white solid, yield 65%, Mp: 180ꢀC to 181ꢀC. H NMR
(400 MHz, DMSO-d6) δ: 8.81 (s, J = 11.1 Hz, 1H, NHCO),
1

6
HESSAINIA ET AL.
(t, J = 6.4 Hz, 3H, CH2cycN), 3.33 (q, J = 6.1Hz, 2H,
CH2cycNH), 2.20 (s, 3H, CH3). 13C NMR (101 MHz,
DMSO-d6) δ: 150.47, 136.53, 130.79, 129.04, 126.74,
124.40, 122.05, 45.32, 43.37, 18.04. Elemental Anal. (%),
calculated: C, 47.05; H, 5.13; N, 16.46; found: C, 47.00; H,
5.13; N, 16.49.
(%), calculated: C, 44.27; H, 4.83; N, 15.49; found: C,
44.27; H, 4.88; N, 15.51.
4.3.10 | N-(4-methoxyphenyl)-
1,2,5-thiadiazolidine-2-carboxamide
1,1-dioxide 3j
4.3.7 | N-(3-tolyl)-1,2,5-thiadiazolidine-
2-carboxamide 1,1-dioxide 3g
C10H13N3O4S, Rf = 0.48 (ethyl acetate/hexane: 5/5), white
solid, yield 86%, Mp: 173ꢀC to 174ꢀC. 1H NMR (250 MHz,
DMSO-d6) δ: 8.49 (s, 1H, NHCO), 7.90 (t, J = 5.9 Hz, 1H,
NHcyc), 7.40 to 7.23 (m, 2H, H-Ar), 6.97 to 6.78 (m, 2H, H-
Ar), 3.71 (s, 3H, CH3O), 3.65 (t, J = 6.5 Hz, 2H, CH2cycN),
3.29 (q, J = 6.1 Hz, 2H, CH2cycNH).13C NMR (63 MHz,
DMSO-d6) δ: 155.75, 150.55, 131.56, 121.39, 114.48, 55.65,
45.25, 43.37. MS (ESI+ 70 eV m/z): LCMS: 294 [M + Na]+.
Elemental Anal. (%), calculated: C, 44.27; H, 4.83; N,
15.49; found: C, 44.22; H, 4.86; N, 15.52.
C10H13N3O3S, Rf = 0.43 (ethyl acetate/hexane: 5/5),
1
white solid, yield 72%, Mp: 183ꢀC to 184ꢀC. H NMR
(400 MHz, DMSO-d6) δ: 8.52 (s, 1H, NHCO), 7.90 (t,
J = 5.7 Hz, 1H, NHcyc), 7.24 (s, 1H, H-Ar), 7.22 to 7.14
(m, 2H, H-Ar), 6.89 to 6.82 (m, 1H, H-Ar), 3.66 (t,
J = 6.4 Hz, 2H, CH2cycN), 3.31 (q, J = 6.2.Hz, 2H,
CH2cycNH), 2.27 (s, 3H, CH3). 13C NMR (101 MHz,
DMSO-d6) δ: 150.40, 138.68, 138.60, 129.17, 124.23,
119.85, 116.51, 45.31, 43.36, 21.58. Elemental Anal. (%),
calculated: C, 47.05; H, 5.13; N, 16.46; found: C,
47.02; H, 5.10; N, 16.47.
4.3.11 | N-(3-(trifluoromethyl)phenyl)-
1,2,5-thiadiazolidine-2-carboxamide
1,1-dioxide 3k
4.3.8 | N-(4-tolyl)-1,2,5-thiadiazolidine-
2-carboxamide 1,1-dioxide 3h
C10H10F3N3O3S, Rf = 0.49 (ethyl acetate/hexane: 5/5), white
1
solid, yield 85%, Mp: 194ꢀC to 195ꢀC. H NMR (400 MHz,
DMSO-d6) δ: 8.99 (s, 1H, NHCO), 7.97 (d, J = 10.4 Hz, 1H),
7.56 (dt, J = 15.6, 8.2 Hz, 3H, NHcyc+ H-Ar), 7.39 (d,
J = 7.5 Hz, 1H, H-Ar), 3.67 (t, J = 6.3 Hz, 2H, CH2cycN),
3.32 (q, J = 6.2 Hz, 2H, CH2cycNH). 13C NMR (101 MHz,
C10H13N3O3S, Rf = 0.45 (ethyl acetate/hexane: 5/5), white
solid, yield 81%, Mp: 179ꢀC to 180ꢀC. 1H NMR (250 MHz,
DMSO-d6) δ: 8.56 (s, 1H, NHCO), 7.93 (t, J = 5.8 Hz, 1H,
NHcyc), 7.29 (d, J = 8.4 Hz, 2H,H-Ar), 7.11 (d, J = 8.4 Hz,
2H, H-Ar), 3.65 (t, J = 6.3 Hz, 2H, CH2cycN), 3.29 (q,
J = 6.1 Hz, 2H, CH2cycNH), 2.24 (s,3H, CH3).13C NMR
(63 MHz, DMSO-d6) δ: 150.42, 136.08, 132.58, 129.71,
119.51, 45.27, 43.37, 20.79. MS (ESI+ 70 eV m/z): LCMS:
278 [M + Na]+, 253.9 [M − H]-. Elemental Anal. (%), cal-
culated: C, 47.05; H, 5.13; N, 16.46; found: C, 47.05; H,
5.11; N, 16.44.
DMSO-d6)
δ
150.70, 139.74, 130.51 to 130.21(2JC-
= 30.3 Hz), 130.21 to 129.88 (2JC-F = 33.33Hz), 129.88 to
F
129.56 (2JC-F = = 32.32Hz), 125.89, 123.13, 119.82 to 119.78
(3JC-F = 4.04Hz), 117.89, 115.44 to 115.40 (3JC-F = 4.04Hz),
45.28, 43.32. Elemental Anal. (%), calculated: C, 38.84; H,
3.26; N, 13.59; found: C, 38.80; H, 3.22; N, 13.59.
4.3.12 | N-(2-methoxy-4-nitrophenyl)-
1,2,5-thiadiazolidine-2-carboxamide
1,1-dioxide 3l
4.3.9 | N-(2-methoxyphenyl)-
1,2,5-thiadiazolidine-2-carboxamide
1,1-dioxide 3i
C10H12N4O6S, Rf = 0.54 (ethyl acetate/hexane: 5/5), yel-
low solid, yield 88%, Mp: 192ꢀC to 193ꢀC. 1H NMR
(400 MHz, DMSO-d6) δ:8.99 (d, J = 2.7 Hz, 1H, NHCO),
8.65 (s, 1H, H-Ar), 8.10 (t, J = 5.7 Hz, 1H, NHcyc), 7.98
(dd, J = 9.0, 2.7 Hz, 1H, H-Ar), 7.26 (d, J = 9.1 Hz, 1H,
H-Ar), 4.01 (s, 3H, OCH3), 3.66 (t, J = 6.2 Hz, 2H,
CH2cycN), 3.34 (d, J = 6.1 Hz, 2H, CH2cycNH). 13C NMR
(101 MHz, DMSO-d6) δ: 153.43, 150.34, 141.11, 128.40,
119.74, 113.30, 111.26, 57.43, 45.39, 43.41. Elemental
Anal. (%), calculated: C, 37.97; H, 3.82; N, 17.71;
found: C, 37.93; H, 3.82; N, 17.76.
C10H13N3O4S, Rf = 0.46 (ethyl acetate/hexane: 5/5), white
solid, yield 80%, Mp: 154ꢀC to 155ꢀC. 1H NMR (250 MHz,
DMSO-d6) δ: 10.50 (s, 1H, NHCO), 8.36 (s, 1H, NHcyc),
8.09 to 7.93 (m, 2H, H-Ar), 7.06 to 6.85 (m, 2H, H-Ar),
3.84 (s, 3H, CH3O), 3.65 (t, J = 6.3 Hz, 2H, CH2cycN),
3.30 (q, J = 6.2 Hz, 2H, CH2cycNH).13C NMR (63 MHz,
DMSO-d6) δ: 150.18, 148.50, 127.67, 123.69, 121.01,
119.15, 111.42, 56.31, 45.33, 43.39. MS (ESI+ 70 eV m/z):
LCMS: 270.4 ([M − H]−, 294 [M + Na]+, Elemental Anal.

HESSAINIA ET AL.
7
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4.3.13 | N-(2-methyl-4-nitrophenyl)-
1,2,5-thiadiazolidine-2-carboxamide
1,1-dioxide 3m
C10H12N4O5S, Rf = 0.53 (ethyl acetate/hexane: 5/5), white
solid, yield 80%, Mp: 199ꢀC to 200ꢀC. 1H NMR (400 MHz,
DMSO-d6) δ: 8.81 (d, J = 2.5 Hz, 1H, NHCO), 8.28 (s,
J = 9.8 Hz, 1H, H-Ar), 8.09 (t, J = 5.8 Hz, 1H, NHcyc), 7.87
(dd, J = 8.3, 2.5 Hz, 1H, H-Ar), 7.49 (m, 1H, H-Ar), 3.68 (t,
J = 6.3 Hz, 2H, CH2cycN), 3.38 to 3.32 (m, 2H, CH2cycNH),
2.33 (s, 3H, CH3).13C NMR (101 MHz, DMSO-d6) δ:
150.52, 146.52, 137.81, 135.96, 131.73, 118.37, 114.73,
45.35, 43.40, 18.26. Elemental Anal. (%), calculated: C,
40.00; H, 4.03; N, 18.66; found: C, 40.05; H, 4.07; N, 18.68.
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4.3.14 | Ethyl 4-(1,1-dioxide-
1,2,5-thiadiazolidine-2-carboxamido)
benzoate 3n
C12H15N3O5S, Rf = 0.44 (ethyl acetate/hexane: 5/5), white
solid, yield 90%, Mp: 150ꢀC to 151ꢀC. 1H NMR (400 MHz,
DMSO-d6) δ: 9.01 (s, 1H, NHCO,), 8.00 (t, J = 5.6 Hz, 1H,
NHcyc), 7.91 (d, J = 8.7 Hz, 2H, H-Ar), 7.56 (d,
J = 8.7 Hz, 2H, H-Ar), 4.29 (q, J = 7.1 Hz, 2H,CH2CH3),
3.66 (t, J = 6.4 Hz, 2H, CH2cycN), 3.33 (q, J = 11.7 Hz,
2H, CH2cycNH), 1.31 (t, J = 7.1 Hz, 3H, CH2CH3).13C
NMR (101 MHz, DMSO-d6) δ: 165.76, 150.39, 143.38,
130.79, 124.47, 118.54, 60.89, 45.31, 43.37, 14.67. Elemen-
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found: C, 46.00; H, 4.80; N, 13.43.
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ACKNOWLEDGMENTS
This work was generously supported by the General
Directorate for Scientific Research and Technological
Development (DG-RSDT) from Ministry of Higher Edu-
cation and Scientific Research.
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ORCID
Sihem Hessainia https://orcid.org/0000-0002-1105-2688
Abbes Boukhari https://orcid.org/0000-0002-3394-3908
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
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How to cite this article: Hessainia S,
Boukhari A, Cheraiet Z. An efficient one-pot
synthesis of N-(substituted phenyl)-1,2,5-
thiadiazolidine-2-carboxamide 1,1-dioxide
derivatives. J Heterocyclic Chem. 2019;1–7. https://
doi.org/10.1002/jhet.3767