Ultrasonic assisted green protocol for the synthesis of sulfamides

Article abstract of DOI:10.1080/10426507.2017.1287184

An improved environmentally benign method for synthesis of sulfamides under focused ultrasound irradiation and under solvent-free and catalyst-free conditions has been carried out by the reaction of amines or amino esters with sulfuryl chloride. This approach allows the synthesis of products in excellent yields and in short reaction time.

Full text of DOI:10.1080/10426507.2017.1287184

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Ultrasonic assisted green protocol for the synthesis of sulfamides
Ismahene Grib, Billel Belhani, Khaoula Bechlem, Radia Bouasla, Nour-Eddine Aouf,
Malika Berredjem*
Laboratory of Applied Organic Chemistry, Synthesis of Biomolecules and Molecular Modeling
Group, Badji-Mokhtar, Annaba University, Box 12, 23000 Annaba, Algeria.
Corresponding author E-mail: mberredjem@yahoo.fr
Abstract
An improved environmentally benign method for synthesis of sulfamides under focused
ultrasound irradiation and under solvent-free and catalyst-free conditions has been carried out by
the reaction of amines or amino esters with sulfuryl chloride. This approach allows the synthesis
of products in excellent yields and in short reaction time.
Keywords
Sulfamide, ultrasound irradiation, sulfuryl chloride, green chemistry.
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Introduction
The sulfamide (RNHSO2NHR) functional group has been extensively used in organic synthesis.
This moiety has been a prevalent pharmacophore found in many medicines and drug candidates
and has found utility in several applications such as; anticonvulsant, antihypertensive,
hyperglycemia, histamine H2-receptor antagonist, herbicide, HCMV inhibitors) [1, 7]. The
sulfamide can be considered to be a bioisosteric replacement for many functionalities; carboxylic
acid, urea, carbamate and even amide. The sulfuryl chloride (SO2Cl2), in particular, is a
precursor with extensive uses in organic synthesis [8-11], it is mostly used in the introduction of
a sulfamide moiety in biomolecules.
Various methodologies have been developed for the synthesis of sulfamides [12-17] most of the
methods involve the use of solvent, high cost, long reaction time, use of stoichiometric and even
excess amounts of reagents, drastic reaction conditions, tedious manipulations in the isolation of
the pure products, and side reactions. They can be prepared from commercial sulfamide H2N-
SO2-NH2, by heating with an amines [18-20] or by the reaction of a substituted sulfamoyl
chloride with amines in the presence of triethylamine or pyridine at low temperature (-78 °C to -
30 °C), [6]. Recently, new series of sulfamides is described by Chen et al. by stirring catechol
sulfate with an amine in CH2Cl2 in the presence of NEt3 as the base promoted the first
substitution reaction. Repeating such a process with the (S)-2-amino-1-N-Boc- pyrrolidine in
refluxing DCE gave rise to the disubstituted sulfamides [21], Cano and co-workers reported a
suitable preparation of sulfamides by condensation of sulfamoyl chloride with amines of the
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corresponding fatty acids in toluene [22], Fettes and co-workers proposed a general and
efficient synthesis of sulfamides by the reaction between 4-nitrophenyl 3- or 5’-sulfamates
(produced from 4-nitrophenyl chlorosulfate) with amine functionalities of other nucleosides [23].
One of the key areas of green chemistry is the reduction or elimination of expensive catalyst and
solvents in chemical processes and replaces them with environmentally friendly processes or
methodologies. One of the powerful tools used to connect economic features with the green
concerns is performing organic reactions under ultrasound irradiation and solvent-free conditions
[24-33].
Following our efforts to develop green chemistry methods and our interest in the use of
ultrasound in organic synthesis as well as on the introduction of sulfamide moiety to prepare of
useful biomolecules, we report here a novel, easy, and convenient method for the preparation of
sulfamides directly from easily available sulfuryl chloride, under catalyst and solvent free
conditions, improved by ultrasonic irradiation.
Results and discussion
In our study, we carried out the condensation of 2 mmol of primary amines with 1 mmol of
SO2Cl2 in the absence of any catalyst or solvent under ultrasound irradiation; the reaction was
completed in just 30-40 min (Scheme 1). The process was promoted by direct immersion of
reaction vessels into the ultrasonic cleaning bath which provides a fairly even distribution of
energy into the reaction medium.
Encouraged by this result, we extended the reaction to aminoester derivatives under ultrasonic
irradiation (Scheme 1). In all cases, we obtained the bis-amino ester sulfamides products (7-9)
with good yields (87-91%).
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Thus, we observed that ultrasound irradiation played an essential role from the result of the
reaction. The rapid kinetics under mild conditions, simple work-up and easy purification are
added advantages of this protocol.The results are summarized in Table 1.
Compared with traditional methods, ultrasonic irradiation is suitable and simply controlled and it
is considered a green powerful synthetic technique in chemical processes to accelerate reactions.
Conclusion
In conclusion, we have developed a facile and green protocol for the synthesis of sulfamides by
condensation of amines or aminoesters derivatives with sulfuryl chloride under ultrasonic
irradiation, solvent- and catalyst-free conditions in high yields. This protocol has also several
other advantages such as; simple experimental procedure, solvent-less conditions and the
absence of any competitive or side reactions.
Experimental
Materials
The chemicals used in this work were obtained from Fluka and Merck Chemical Company and
were used without purification.
Apparatus
Sonication was performed in a FUNGILAB ultrasonic bath with a frequency of 45 kHz and an
output power of 250 W. The reactions were carried out in an open glass tube (diameter: 25 mm;
thickness: 1 mm; volume: 20 mL). Melting points were uncorrected and measured in open
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capillary tubes on an Electro thermal apparatus. H-NMR and C-NMR spectra were recorded
on a Bruker spectrometer (250 or 400 MHz) using TMS as internal standard and CDCl3 as
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solvent. Mass spectra were recorded on a Shimadzu QP 1100 Ex mass spectrometer operating at
an ionization potential of 70 Ev. IR spectra were recorded as KBr pellets on a Perkin Elmer 600
spectrophotometer and an Impact 400 Nicolet FT-IR spectrophotometer. Elemental analysis was
recorded on a EURO E.A 3700.
General procedure for the synthesis of sulfamides
In a 10 mL round bottom flask was taken amine or aminoester (2 mmol) and sulfuryl chloride (1
mmol) was added. Then reaction mixture was subjected to ultrasonication by an ultrasonic bath
with a frequency of 45 kHz for appropriate time (30-40 min) at 40°C. After completion of the
reaction, the mixture was crystallized in diethyl ether overnight and the product was filtered and
dried.
The Supplemental Materials contains sample 1H, 13C NMR, IR and mass spectra for the new
products (Figures S 1 – S 9).
Spectral data
N,N’-bis benzylsulfamide (1, C14H16N2O2S)
Powder; 92 % yield; 1H NMR (400 MHz, CDCl3): δ = 7.25-7.50 (m, 10H, H-Ar), 4.40 (t, 2H,
13
2NH), 4.20 (d, 4H, 2CH2) ppm. C NMR (100 MHz, CDCl3): δ = 44.0, 126.9, 128.5, 141.6. IR
(KBr, ν cm-1): 3273 (NH), 1316 & 1145 (SO2). MS (m/z) = 277.1 [M+1]+.
Calc. for C14H16N2O2S: C, 60.85; H, 5.84; N, 10.14; S, 11.60 Found: C, 60.86; H, 5.87; N,
10.16; S, 11.62.
N,N’-bis phenylsulfamide (2, C12H12N2O2S)
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Powder; 89 % yield; 1H NMR (400 MHz, CDCl3): δ = 6.90-7.30 (m, 10H, H-Ar), 4.10 (s, 2H,
2NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 120.0, 124.1, 137.2, 147.2. IR (KBr, ν cm-1): 3294
(NH), 1317 & 1137 (SO2). MS (m/z) = 249 [M+1]+.
Calc. for C12H12N2O2S: C, 58.05; H, 4.87; N, 11.28; S, 12.91. Found: C, 58.09; H, 4.89; N,
11.30; S, 12.89.
N,N’-bis 3-fluorophenylsulfamide ( 3, C12H10F2N2O2S)
Powder; 82 % yield; 1H NMR (400 MHz, CDCl3): δ = 6.69-7.21 (m, 8H, H-Ar), 4.31 (s, 2H,
2NH) ppm.13C NMR (100 MHz, CDCl3): δ = 118.6, 120.1, 136.1, 143.5. IR (KBr, ν cm-1): 3298
(NH), 1311 & 1125 (SO2). MS (m/z) = 285 [M+1]+.
Calc. for C12H12N2O2S: C, 50.70; H, 3.55; N, 9.85; S, 11.28 Found: C, 50.75; H, 3.57; N, 9.89;
S, 11.31.
N,N’-bis 2-chloroethylsulfamide (4, C4H10Cl2N2O2S)
Powder; 91 % yield;1H NMR (400 MHz, CDCl3): δ = 4.81 (s, 2H, 2NH), 3.61 (t, J=5.8 Hz, 4H,
2CH2-Cl), 3.52 (q, J=5.91 Hz, 4H, 2CH2-NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 41.7, 43.1.
(KBr, ν cm-1): 3267 (NH), 1317 & 1133 (SO2). MS (m/z) = 221 and 223 [M+1]+.
Calc. for C4H10Cl2N2O2S: C, 21.73; H, 4.56; N, 12.67; S, 14.50. Found: C, 21.75; H, 4.52; N,
12.67; S, 14.52.
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N,N’-bis propylsulfamide (5, C6H16N2O2S)
Powder; 90 % yield; 1H NMR (400 MHz, CDCl3): δ = 4.25 (s, 2H, 2NH), 3.0 (t, J=7.1, 4H,
2CH2-N), 1.65 (m, 4H, 2CH2), 0.9 (t, J=7.3, 6H, 2CH3), ppm. 13C NMR (100 MHz, CDCl3): δ =
11.2, 21.9, 42.8. IR (KBr, ν cm-1): 3278 (NH), 1317 & 1148 (SO2). MS (m/z) = 181[M+1]+.
Calc. for C6H16N2O2S: C, 39.98; H, 8.95; N, 15.54; S, 17.78 Found: C, 39.90; H, 8.92; N,
15.51; S, 17.75.
N,N’-bis cyclohexylsulfamide (6, C12H24N2O2S)
Powder; 90 % yield; 1H NMR (400 MHz, CDCl3): δ = 4.30 (s, 2H, NH), 3.45 (s, 2H, 2CH-N),
2.22 (m, 4H, 2CH2-CH2-CH2), 1.67 (m, 8H, 4CH2-), 1.35 (m, 8H, CH2-cyc) ppm. 13C NMR (100
MHz, CDCl3): δ = 24.8, 25.0, 32.1, 43.0. IR (KBr, ν cm-1): 3284 (NH), 1317 & 1140 (SO2). MS
(m/z) = 261 [M+1]+.
Calc. for C12H24N2O2S: C, 55.35; H, 9.29; N, 10.76; S, 12.31. Found: C, 55.37; H, 9.31; N,
10.72; S, 12.34.
N,N’-sulfonyl Bis-L-phenylalanine methyl ester (7, C20H24N2O2S)
Powder; 91 % yield; 1H NMR (400 MHz, CDCl3): δ = 7.37-7.81 (m, 5H, H-Ar), 4.65 (s, 2H,
NH), 4.10 (t, 2H, *CH), 3.94 (s, 6H, 2CH3), 3.24-2.98 (2dd, 4H, CH2) ppm. IR (KBr, ν cm-1):
3291 (NH), 1327 & 1151 (SO2). MS (m/z) = 421 [M+1]+.
Calc. for C20H24N2O2S: C, 57.13; H, 5.75; N, 6.66; S, 7.63 Found: C, 57.15; H, 5.77; N, 6.67; S,
7.65.
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N,N’- sulfonyl Bis-L-leucine methyl ester (8, C14H28N2O6S)
Powder; 87% yield;1H NMR (400 MHz, CDCl3): δ = 4.23 (s, 2H, NH), 4.14 (t, 2H, *CH), 2.93
(t, 4H, 2CH2), 1.52 (m, 2H, 2CH), 1.02 (m, 12H, 2CH3) ppm. IR (KBr, ν cm-1): 3241 (NH), 1322
& 1141.24 (SO2). MS (m/z) = 353 [M+1]+.
Calc. for C14H28N2O6S: C, 47.71; H, 8.01; N, 7.95; S, 9.10. Found: 47.73; H, 8.03; N, 7.97; S,
9.12
N,N’- sulfonyl Bis-L-valine methyl ester (9, C12H24N2O6S)
Powder; 88% yield;1H NMR (400 MHz, CDCl3): δ = 4.34 (s, 2H, NH), 4.09 (d, 2H, *CH), 2.41
(m, 2H, 2CH), 1.10 (m, 12H, 2CH3) ppm. IR (KBr, ν cm-1): 3261 (NH), 1324 & 1151 (SO2). MS
(m/z) = 325 [M+1]+.
Calc. for C12H24N2O6S: C, 44.43; H, 7.46; N, 8.64; S, 9.88. Found: C, 44.45; H, 7.47; N, 8.65;
S, 9.86
Acknowledgments
This work was financially supported by The General Directorate for Scientific Research and
Technological Development (DG-RSDT), Algerian Ministry of Scientific Research, Applied
Organic Laboratory (FNR 2000). We also thank Pr. Jacques Lebreton from the University of
Nantes for their help in the identification for all products in NMR and MS.
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Table 1. Synthesis of bis-alkyl/aryl sulfamides under ultrasound irradiation
Entr
y
Amine
Products
Time Yield(%) m.p found
m.p Lit.
(°C)
(min)
(°C)
1
2
30
92
180-182
181-183**
35
35
30
89
82
91
175-177
121-123
81-83
-
-
-
3
4
40
32
90
90
113-115
143-145
110-112**
148-150**
5
6
37
35
91
87
115-117
116-118*
7
8
78-80
93-95
78-80*
94-96*
35
88
9
*[34], ** [14]
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Scheme 1. Synthesis of sulfamides under ultrasonic irradiation.
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