Alternative synthetic strategies for new drug candidates. The thermolysis reaction of N-(benzyl)-N′-(tert-butoxycarbonyl)sulfamide to yield benzylsulfamide

Article abstract of DOI:10.1016/j.tca.2009.12.019

The hydrolysis of one sulfamide derivative under conventional conditions and under thermolysis reaction has been investigated. Comparison between these techniques revealed advantages in the use of thermal decomposition reaction to obtain sulfamides, due to the easy elimination of gaseous by-products produced in the reaction.

Full text of DOI:10.1016/j.tca.2009.12.019

Thermochimica Acta 501 (2010) 30–34
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Alternative synthetic strategies for new drug candidates. The thermolysis
reaction of N-(benzyl)-Nꢀ-(tert-butoxycarbonyl)sulfamide to yield
benzylsulfamide
I.D. Licka, L. Gavernetb,∗, L.E. Bruno-Blanchb, E.N. Ponzia
a CINDECA (CONICET-UNLP). Department of Chemistry, Faculty of Exact Sciences, National University of La Plata, 47 No. 257, La Plata, Buenos Aires, Argentina
b Medicinal Chemistry, Department of Biological Sciences, Faculty of Exact Sciences, National University of La Plata, 47 and 115, La Plata B1900BJW, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
The hydrolysis of one sulfamide derivative under conventional conditions and under thermolysis reaction
has been investigated. Comparison between these techniques revealed advantages in the use of ther-
mal decomposition reaction to obtain sulfamides, due to the easy elimination of gaseous by-products
produced in the reaction.
Received 13 October 2009
Received in revised form
21 December 2009
Accepted 22 December 2009
Available online 11 January 2010
© 2010 Elsevier B.V. All rights reserved.
Keywords:
Thermolysis reaction
Sulfamides
1. Introduction
corresponding amine in presence of triethylamine (TEA). The tert-
butoxycarbonyl group was then removed via trifluoroacetic acid
Sulfamides represent an interesting target in the field of medic-
inal chemistry. The sulfamide functional group comes out as one of
the most relevant structural motifs found in high affinity protein
ligands and pharmaceutically useful agents. Compounds bearing
this functionality have been tested as HIV protease inhibitors
[1,2], agonists of the 5-HTID receptor [3], active components
in epinephrine analogues [4], non-hydrolizable components of
peptide-mimetics [5] and carbonic anhydrase inhibitors [6–10].
Additionally, previous research from some of us and other
authors has considered alkyl/aryl sulfamides as new candidates for
antiepileptic drugs: Structures with the sulfamide function were
found active against one of the most widely used experimental
models for the preclinical stage in epilepsy research (MES test)
[11,12].
The selection of the synthetic routes to obtain sulfamides
is related to the position of the substituents. Symmetric N,Nꢀ-
disubtituted and tetrasubstituted sulfamides were prepared by
condensation of an excess of amine with sulfuryl chloride
[13–17]. In case of mono-substituted and N,N-disubstituted com-
pounds, the standard reaction involves the preparation of the
N-alkoxycarbonyl sulfamide derivative (compound named II,
Scheme 1) followed by acidic hydrolysis [18–22]. This intermediate
was prepared from chlorosulfonyl isocyanate, tert-butanol, and the
(TFA) [8,18–21].
Efficient synthetic procedures become relevant for rational drug
design methodologies. The promising results obtained in the bio-
logical stages for sulfamides and their derivatives, encourage us to
develop new synthetic strategies, in order to reduce the generation
of waste, and to avoid the use of toxic (and/or hazardous) reagents
and solvents.
Previous efforts to improve the synthetic method outlined
in Scheme 1 were performed by other investigators [23–24].
The first step in the reaction involves the synthesis of N-(tert-
butoxycarbonyl)aminosulfonyl chloride (compound I, Scheme 1), a
very instable intermediate against moisture. The generation of the
corresponding Burgess-type salt deactivates the intermediate I and
allows the subsequent reaction in mild conditions [23]. An alter-
native method was also proposed for the removal the carbamate
group of II, using a microwave-assisted method with silica-phenyl
sulfonic acid [24]. Following this line, we have focused this investi-
gation on the improvement of the last step of the reaction showed
in Scheme 1 by means of the substitution of the hydrolysis reac-
tion by the thermal decomposition of II, to obtain mono-substituted
and N,N-disubstituted sulfamides. This alternative method results
beneficial in several aspects, since the abolition of other reactants
and solvents reduce the impact on human health and the envi-
ronment. Furthermore, it is expected an improvement in the yield
of the thermolysis reaction, because the work up for the recovery
of the desired compound from the conventional reaction systems
always results in some losses.
∗
Corresponding author. Tel.: +54 2214235333.
E-mail address: lgavernet@biol.unlp.edu.ar (L. Gavernet).
0040-6031/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.tca.2009.12.019

I.D. Lick et al. / Thermochimica Acta 501 (2010) 30–34
31
Scheme 1. Synthetic route for mono-substituted and N,N-disubstituted sulfamides [18–22]. R = tert-butyl; R1, R2 = alkyl, aryl, H.
Scheme 2. Thermolysis reaction of N,N-dialkyl carbamates (reaction A) and mono-subsituted carbamates (reaction B).
We are not aware of any publication related to the study of
the mechanism of the thermolysis of N-alkoxycarbonyl sulfamides,
so we considered as reference the thermal decomposition of car-
bamates in the gas phase. The generally accepted mechanism of
decomposition of N,N-dialkyl carbamates implies an elimination
process, through a six-membered cyclic transition state to give the
corresponding amine, the alkene and CO2 (reaction A, Scheme 2)
[22,25–27]. In mono-substituted carbamates, the presence of a
hydrogen atom attached to the nitrogen atom is believed to be
responsible for the different mechanistic pathway, and the elim-
ination reaction proceeds via a four member cyclic transition state,
to give the corresponding isocyanate and the alcohol molecules
(reaction B, Scheme 2) [27].
disappearance of the sulfonyl carbamate II [12]. Then, the reaction
mixture is concentrated, and the excess of TFA is co-evaporated
with diethyl ether [12].
The products II and III were characterized and identified
using thin-layer chromatography, IR spectroscopy, 1H NMR spec-
troscopy, 13C NMR spectroscopy and elemental analysis [12].
2.3. Thermal stability of
N-(benzyl)-Nꢀ-(tert-butoxycarbonyl)sulfamide and
benzylsulfamide
In order to study the thermal stability of the structures, gravi-
metric thermal analysis (TGA) were performed for compounds II
and III, with a Shimadzu TGA 50 apparatus. 5 mg of compounds
were loaded in an aluminum crucible and heated from room tem-
perature (5 ◦C/min) in helium flow (20 mL/min) to 200 ◦C.
The investigation presented herein analyzes, as
a test
example, the thermolysis reaction of N-(benzyl)-Nꢀ-(tert-
butoxycarbonyl)sulfamide (structure II, Scheme 3). If the thermal
decomposition takes place in a similar pathway than carbamates
(pathway A, Scheme 2), the reaction would yield the expected
sulfamide (structure III, Scheme 3) and gaseous sub products
that can be easily eliminated of the reaction bulk. Accordingly,
we have compared and characterized the sulfamide obtained
from the standard hydrolysis of II with the product that results
from its thermal decomposition reaction. To the characterization
we have used Infrared spectroscopy, thin-layer chromatography
and nuclear magnetic resonance spectroscopy. Additionally, the
gaseous by-products of the thermolysis reaction were analyzed
via GC-TCD/MS.
2.4. Thermolysis test
The thermolysis tests were performed by gravimetric thermal
analysis (TGA) with a Shimadzu TGA 50 apparatus. 5 mg of com-
pound II were loaded in an aluminum crucible and heated from
room temperature (5 ◦C/min) in helium flow (20 mL/min) to 115 ◦C.
2.5. Characterization of the product obtained by thermolysis
2.5.1. Infrared spectroscopy (IR)
The FTIR spectra were carried out with an EQUINOX 55 spec-
trophotometer, from 4000 to 400 cm−1 and the samples were
prepared in form of pills with KBr. Only significant absorption bands
were reported here.
2. Experimental procedure
2.1. Synthesis of N-(benzyl)-Nꢀ-(tert-butoxycarbonyl)
sulfamide (II)
2.5.2. Thin-layer chromatography (TLC)
The chromatographic procedures were performed with alu-
minum backed sheets with silica gel 60 F254 (Merck, ref 1.05554),
and the mixture CH2Cl2:MeOH 30:1 was used as the elution sol-
vent. The spots were visualized with UV light (254 nm) and 5%
aqueous solution of ammonium molybdate (VI) tetrahydrate. The
results were expressed as retention factor values (Rf).
This compound was prepared according to the general pro-
cedure detailed in literature, using a solution of chlorosulfonyl
isocianate in CH2Cl2, tert-butanol, benzylamine and triethylamine
(firt step in Scheme 1, R = tert-butyl, R1 = benzyl, R2 = H) [12].
2.2. Synthesis of benzylsulfamide (III)
2.5.3. Nuclear magnetic resonance spectroscopy (NMR)
As explained before, the standard hydrolysis method involves
the acidic hydrolysis with a solution of TFA in dried CH2Cl2, until
Two hundred megahertz 1H NMR and 75.4 MHz 13C NMR spectra
were recorded on a Varian Gemini 200 spectrometer. The chemical
Scheme 3. Thermolysis reaction proposed for N-(benzyl)-Nꢀ-(tert-butoxycarbonyl)sulfamide.

32
I.D. Lick et al. / Thermochimica Acta 501 (2010) 30–34
shifts are reported in ppm (ı scale) relative to internal tetramethyl-
silane (TMS), and coupling constants are reported in Hertz (Hz).
We have used chloroform (CDCl3) solvent for compound II, and
dimethyl sulfoxide (DMSOd6) for the sulfamide obtained by tradi-
tional synthesis III and for the product of thermal decomposition.
2.6. GC–mass spectroscopy
The secondary gaseous products of the reaction were analyzed
using a gas chromatograph (Shimadzu 8-A) with a TCD detector on
line with a fixed bed reactor, which was fed with helium and heated
electrically from 30 ◦C up to 115 ◦C (and kept for 3 h at this temper-
ature). This technique allowed us the quantitative determination
of CO2 generated as by-product in the reaction.
Additionally, a mass spectrometer (Dycor System 2000) was
incorporated to the apparatus, on line with the reactor, in order
to detect all gaseous by-products.
Fig. 2. TGA diagrams that characterize the synthesis of benzylsulfamide by ther-
molysis. (a) Weight loss of II relative to the initial sample and (b) temperature.
3. Results and discussion
a higher degree of conversion and a shorter reaction time relative
to the traditional hydrolysis (yield: 62%, 14 h) [12] represents an
important optimization for this synthetic step.
3.1. Stability assays of compounds II and III
Heat stability assays were performed for 5 mg of compound II,
using a thermal gravimetric analyzer. The same experience was
carried out for 5 mg of compound III. The resulting TGA diagrams
are given in Fig. 1.
Fig. 1 indicates the thermal decomposition of the product and
the reactive. The benzylsulfamide decomposition starts at 140 ◦C,
and the N-(benzyl)-Nꢀ-(tert-butoxycarbonyl)sulfamide decompose
at 100 ◦C. If we assumed that the thermolisys of compound II gener-
ates benzylsulfamide III, carbon dioxide and gaseous hydrocarbon
sub products, the theoretical relative loss of mass would be 35.6%.
According to the TGA results, the loss in mass of compound II was
calculated as 34.0% relative to the initial sample, which corresponds
to a high degree of conversion, near to 95.5%.
3.2. Characterization of the products obtained by thermolysis
Table 1 shows the retention factors (Rf) found in TLC for com-
pounds II, III and for the product obtained by thermolysis. In the
last case, TLC showed two spots with Rf values that match with
the corresponding ones for compounds II and III. This fact probably
indicates that the desired product was obtained by heating, but the
reaction was incomplete. This observation is consistent with the
results found in TGA, where we assumed an incomplete reaction
due to the weight loss observed.
Another qualitative analysis of the samples was performed by
vibrational spectroscopy. Fig. 3 shows the FTIR spectra recorded for
compound III and for the product obtained by thermolisys. Both
spectra are similar, and they present absorption bands that are
characteristic for the expected functional groups SO2, NH and NH2.
In case of the sample obtained from thermolysis, there is a small
band associated with the presence of carbonyl group (1680 cm−1),
showing again an incomplete transformation of the reactant II. The
most significant absorption bands are summarized in Table 1.
To facilitate a more reliable detection of the product obtained
from thermolysis, the sample was purified following crystallization
standard procedures [12]. The pure solid obtained (white crystals,
Consistent with the TGA experiences, an intermediate tempera-
ture between 100 and 140 ◦C was selected to obtain the compound
III in isothermal conditions. Fig. 2 shows the weight loss of II to
obtain III at 115 ◦C.
The weight loss curve observed for compound II at 115 ◦C (Fig. 2)
pointed out a decrement in the mass that starts at the beginning of
the reaction and ends with a constant mass value after 110 minutes
of heating. In this isothermal experience the relative loss of mass
was 31%, with a yield of 87.1%. The achievement of the product with
Fig. 1. TGA diagrams that illustrate the weight loss of: (a) benzylsulfamide III and
(b) N-(benzyl)-Nꢀ-(tert-butoxycarbonyl)sulfamide II. Mass: 5 mg, QHe = 20 mL/min,
heat rate: 5 ◦C/min.
Fig. 3. FTIR spectra of: (a and aꢀ) benzylsulfamide; (b and bꢀ) N-(benzyl)-Nꢀ-(tert-
butoxycarbonyl)sulfamide treated at 115 ◦C in helium flow.

I.D. Lick et al. / Thermochimica Acta 501 (2010) 30–34
33
Fig. 4. Production of gaseous CO2 in the reactor, identified with a TCD detector.
Rf = 0.30) was analyzed using nuclear magnetic resonance spec-
troscopy (NMR). The chemical shift found for the purified product
match completely with the corresponding signals obtained from
compound III (Table 1). Additionally, there are no extra signals asso-
ciated with the carbamate group, which is present in the structure
of the reactant II.
The secondary products of the reaction were analyzed using a
fixed bed reactor, which was fed with helium and set on line to a gas
chromatograph with a TCD detector. Additionally, a mass detector
was incorporated to the apparatus, in order to get more information
about the gaseous by-products. According to the GC-TCD analysis,
gaseous CO2 was produced after heating compound II in the reactor
at 115 ◦C (Fig. 4). The calculated yield relative to the CO2 production
is 78.3%.
The mass detector corroborated the presence of CO2 (m/z = 44),
and detected another characteristic peaks for 2-methylpropene
(m/z = 56 and 41). This alkene was expected to be obtained if the
thermal decomposition of III proceeds in a similar pathway than the
carbamates previously studied (Scheme 3) [25–27]. It is worth men-
tioning that no charged fragments from isopropanol or isocianate
group were detected from mass spectroscopy.
4. Conclusions
The experimental data presented herein allowed us to char-
acterize and identify the products obtained by thermolysis of
N-(benzyl)-Nꢀ-(tert-butoxycarbonyl)sulfamide. By comparison of
the result obtained from TLC, IR and RMN spectroscopy, we
can conclude that the controlled heating of N-(benzyl)-Nꢀ-(tert-
butoxycarbonyl)sulfamide yields benzylsulfamide in a clean and
efficient manner.
The analysis of gaseous by-products encourage us to sug-
gest that the decomposition proceeds in a similar route than
N,N-dialkyl carbamates (reaction A, Scheme 2), giving CO2 and
2-methylpropene as secondary products. These molecules can be
easily eliminated from the reaction bulk, making easier the workup
procedure to obtain the pure benzylsulfamide. Additionally, the
thermolysis reaction proceeds faster than traditional hydrolysis
and it is not assisted by other reactants and solvents. The consid-
eration of these experimental advantages allowed us to determine
that the thermolysis reaction is a suitable synthetic alternative for
the preparation of this kind of compounds.
Acknowledgements
L.E. Bruno-Blanch is a member of the Facultad de Ciencias Exac-
tas, Universidad Nacional de La Plata; E.N. Ponzi, I.D. Lick and

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I.D. Lick et al. / Thermochimica Acta 501 (2010) 30–34
L. Gavernet are researchers from Consejo Nacional de Investiga-
ciones Cientıíficas y Tecnicas de la Republica Argentina (CONICET).
This research was supported in part through grants from Agencia
de Promoción Científica y Tecnológica, CONICET, and Universidad
Nacional de La Plata, Argentina.
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