Multicomponent synthesis of sulfonamides from triarylbismuthines, nitro compounds and sodium metabisulfite in deep eutectic solvents

Article abstract of DOI:10.1039/c9gc01541h

A sustainable synthesis of sulfonamides using a copper-catalysed process starting from triarylbismuthines, Na₂S₂O₅ and nitro compounds in a Deep Eutectic Solvent (DES) as a reaction medium is described. Thus, triarylbismuthines are used as reagents for the incorporation of SO₂ into organic motifs. The bismuth salts formed as by-products can be easily removed from the crude reaction mixture by precipitation with water, while the use of volatile organic compounds (VOCs) as solvents can be avoided in the entire process. The eutectic mixture employed as the solvent is fully characterised, with the preliminary results proving its low toxicity. The designed DES also allows for a novel multicomponent reaction which saves time and reduces purification steps, energy and cost.

Full text of DOI:10.1039/c9gc01541h

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DOI: 10.1039/C9GC01541H
ARTICLE
Multicomponent Synthesis of Sulfonamides from
Triarylbismuthines, Nitro Compounds and Sodium Metabisulfite
in Deep Eutectic Solvents
Received 00th January 20xx,
Accepted 00th January 20xx
Xavier Marset,a Javier Torregrosa-Crespo,b Rosa M. Martínez-Espinosa,b Gabriela Guillena,*a Diego
DOI: 10.1039/x0xx00000x
J. Ramón*a
A sustainable synthesis of sulfonamides using a copper-catalysed process starting from triarylbismuthines, Na2S2O5 and
nitro compounds is described, in a Deep Eutectic Solvent (DES) as reaction medium. Thus, triarylbismuthines are used as
reagents for the incorporation of SO2 into organic motifs. The bismuth salts formed as by-product can be easily removed
from the crude reaction mixture by precipitation with water, while the use of volatile organic compounds (VOCs) as
solvents can be avoided in the entire process. The eutectic mixture employed as solvent is fully characterised, with the
preliminary results proving its low toxicity. The designed DES also allows for a novel multicomponent reaction which saves
time,
reduces
purification
steps,
energy
and
cost.
advantages, since it is an inexpensive reagent used in food
industry. It is known to yield SO2 under heating or in the
presence of water,10 generating only Na2SO3 as waste, thus
avoiding the generation of toxic organic by-products. In this
case, a DES was used as green reaction medium to carry out
the sulfone synthesis, benefitting from the enhanced SO2
solubility in this type of medium.11
DESs are solvents formed by combining a hydrogen-bond
donor and an acceptor, affording a mixture with strong
interactions. As a consequence, a depression of the melting
point of the mixture is observed.12 Since its discovery,
hundreds of mixtures have been found to form a eutectic
phase, with more than ten million low-transition-temperature
mixtures being available.13 Changing one of the DES
components can modify dramatically its properties. Thus, DESs
can be designed for each reaction by choosing carefully the
eutectic components. In addition, most of the components are
naturally-occurring, bio-renewable, biodegradable or can be
bio-assimilated, which makes these solvents an interesting
alternative to traditional hazardous organic solvents.14
Despite the obvious sustainable advantages of DESs as
reaction media, there is still controversy about their potential
toxicity; several reports support the theory that DESs are non-
toxic, eco-friendly, biodegradable and benign solvents, whilst
other similar studies demonstrate exactly the opposite.15 For
this reason, a rigorous analysis of the real toxicity of each new
mixture must be performed.
In this study, a new multicomponent reaction using tri-
arylbismuth reagents as starting materials to generate
sulfonamides was planned. Triarylbismuthines are non-toxic,16
and unlike other organometallic reagents (such as boron or tin
derivatives) can react with 3 equivalents of an electrophilic
reagent (in this case SO2), increasing the atom economy of the
Introduction
The manufacturing of active pharmaceutical ingredients
(APIs) generates more waste than any other process within the
existing chemical industries.1 The sulfonamide functional group
is widely present in pharmacologically active compounds,2
which include those related to new research3 on anticancer
active molecules.4 Despite its undeniable interest, traditional
methods for its synthesis are still prevailing.5 For more than a
century, sulfonamides have been mostly prepared from
amines and activated sulfonyl derivatives,6 usually sulfonyl
chlorides. This method is efficient but relies entirely on the use
of stoichiometric sulfonyl chlorides, which are not stable or
commercially affordable and generate stoichiometric amounts
of corrosive HCl. For this reason, new methodologies avoiding
the use of unstable and toxic reagents, harsh reaction
conditions or dry volatile organic compounds (VOCs) as
solvents are demanded.
Multicomponent methods7 have also been explored using
SO2 surrogates under transition metal catalysis.8 Recently, we
reported the efficient multicomponent synthesis of sulfones
from aryl boronic acids, sodium metabisulfite (a food additive)
and electrophiles as alkylating reagents catalysed by Pd
nanoparticles.9 The use of sodium metabisulfite possess some
a. Instituto de Síntesis Orgánica (ISO) and Departamento de Química Orgánica.
Facultad de Ciencias. Universidad de Alicante. Apdo. 99, E-03080-Alicante, Spain.
b. Departamento de Agroquímica y Bioquímica. División de Bioquímica y Biología
Molecular. Facultad de Ciencias. Universidad de Alicante. Apdo. 99, E-03080-
Alicante, Spain.
Emails: djramon@ua.es, gabriela.guillena@ua.es
†
Electronic supplementary information (ESI) available: DSC analyses,
characterisation data, and 1H-NMR and 13C-NMR data.
See DOI: 10.1039/x0xx00000x
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process. As the Bi-C bond energy is quite low, the reactivity
displayed by these reagents would be enhanced.17 The
reaction of triarylbismuth reagents with Na2S2O5 as SO2 source,
would provide aryl sulfinates that could react in situ with nitro
compounds.18 The Na2SO3 by-product formed during the first
sulfonylation step, reacts with hydrogen donor compounds
giving NaHSO3, a potential reductant.19 The corresponding
View Article Online
DOI: 10.1039/C9GC01541H
AcChCl:Acetamide (1:2)
AcChCl:Urea (1:2)
ChCl:Acetamide (1:2)
ClChCl:Urea (1:2)
ChCl:Urea (1:2)
MeOH
reaction intermediate would afford, after reduction,
a
Toluene
sulfonamide as product. This strategy reduces the by-product
formation, meeting the Green Chemistry criteria.20
0
20
40
60
80
100
Yield of 4a (%)
Results and discussion
Figure 2. Solvent optimisation.
The study was started by optimising the reaction conditions
to
yield
N-phenylbenzenesulfonamide
(4a),
using
With these optimised conditions in hand, the scope of nitro
compounds was evaluated (Chart 1). No effect on the
electronic properties of the substituents of the nitro arene was
observed.
Good to excellent yields were obtained for nitro arenes
bearing neutral, electron-donating or electron-withdrawing
groups. The reaction was chemoselective, as no Suzuki-type
by-product was observed.21 This transformation was also
compatible with nitro alkanes, although the product was
obtained in lower yield (4m). The reaction could also take
place twice in the same substrate by using 1,3-dinitrobenzene
as starting material (4i).
Then, the scope of Ar3Bi was evaluated (Table 1). The
reaction exhibited good to excellent yields for triarylbismuth
reagents bearing neutral or electron donating groups (5a-5e)
and lower yields were obtained with electron-withdrawing
groups (5f-5i). The use of more complex structures and
functional groups is also compatible, making the synthesis of
biologically active compounds in a single step possible
(Scheme 1).22
triphenylbismuthine (1a), Na2S2O5 (2), and nitrobenzene (3a)
as the model reaction (Table S1). Using choline chloride
(ChCl):acetamide (1:2) as solvent, different copper sources
were analysed. The use of just 1 mol% of CuCl yielded the
desired product in 43% yield without the need of any external
ligand or base. Next, different DESs and conventional organic
solvents were tested. However, none of them afforded better
results. The reaction did not take place in organic solvents or
water. Although the reaction did not proceed in ChCl:Urea
(1:2) or chlorocholine chloride (ClChCl):Urea (1:2), yields
around 50% were obtained both, in ChCl:Acetamide (1:2) and
acetyl choline chloride (AcChCl):Urea (1:2). Therefore a new
mixture, AcChCl:Acetamide (1:2), was deemed the most
suitable reaction medium. These components were found to
form a eutectic mixture in a 1:2 molar ratio (according to DSC
analysis, Fig. 1). To the best of our knowledge, this mixture has
not been described previously in the literature.
By using this novel DES as medium, 99% yield was obtained,
proving that both components of the DES mixture have an
important effect in the reaction course (Fig 2).
120
110
100
90
80
70
60
50
0
0.2
0.4
0.6
0.8
1
AcChCl
Acetamide
Acetamide molar fraction
Figure 1. Phase diagram of the mixture acetylcholine chloride:Acetamide.
Chart 1. Scope of nitro compounds. Reaction conditions: Ph3Bi (0.2 mmol), Na2S2O5
(1.32 mmol, 251 mg), CuCl (0.59 mg, 1 mol%) and ArNO2 (1.2 mmol) in 1.5 mL of DES
were stirred at 80 oC for 24 h. Isolated yields are based on the consumption of the
three phenyl groups attached to Bi.
2 | J. Name., 2012, 00, 1-3
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Table 1. Scope of triarylbismuthines.a
View Article Online
DOI: 10.1039/C9GC01541H
Scheme 2. Gram-scale reaction without using VOC solvents.
Entry
Ar
Product
5a
5b
5c
5d
5e
5f
5g
5h
Yieldb
82%
75%
71%
72%
78%
49%
62%
28%
48%
1
2
3
4
5
6
7
8
9
4-MeC6H4
1-naphtyl
4-MeOC6H4
3,4,5-MeOC6H2
4-Me2NC6H4
4-FC6H4
4-BrC6H4
2-CF3C6H4
3-CF3C6H2
In view of the obtained results, a possible mechanism has
been proposed. The first step involved the disaggregation of
Na2S2O5 through a homolytic cleavage of the S-S bond. This
step includes the formation of radical intermediates,24 in
accordance with our radical-trapping experiments. Running
the reaction in the presence of TEMPO (2,2,6,6-
etramethylpiperidine 1-oxyl) completely inhibits the product
formation. However, when TEMPO was added to the pre-
formed sodium sulfinate, CuCl, nitrobenzene and NaHSO3, the
reaction proceeded, although with lower yields. These radical
5i
a Reaction conditions: Ar3Bi (0.2 mmol), Na2S2O5 (1.32 mmol, 251 mg), CuCl (0.59
mg, 1 mol%) and PhNO2 (1.2 mmol, 123 L) in 1.5 mL of DES were stirred at 80 o
C
b
for 24 h. Isolated yields based on the consumption of the three aryl groups
attached to Bi.
intermediates suffer
a
disproportionation to afford
electrophilic SO2 and the by-product Na2SO3. Next, SO2
undergoes insertion between C-Bi bond.25 Given that a large
excess of chloride anions is present in the medium, BiCl3 may
be released, alongside the corresponding sulfinate. Finally, the
sulfinate reacts with the nitro arene, being reduced by
19d
NaHSO3
(generated from Na2SO3 and moisture) to yield
sulfonamide, in a process catalysed by copper (Scheme 3).
DES physicochemical characterisation.
Scheme 1. Synthesis of anti-leprosy compound 5j.
Since the eutectic mixture employed in this study has not
been described previously,
characterisation was performed. First, the density was
measured employing a 50 mL pycnometer (equation 1).
a complete physicochemical
The recycling of the DES and catalyst was attempted by the
extraction of the product using immiscible organic solvents,
and subsequent addition of fresh reagents to perform a new
reaction cycle.23 However, the use of 2-MeTHF as extraction
solvent for this purpose was unsuccessful, since the reaction
yield dropped from 98% to 27% in the second cycle. This was
probably due to the salts formed during the process affecting
the DES structure and therefore limiting its recyclability.
Alternatively, in order to avoid the use of VOC solvents in the
process, a gram-scale reaction was performed. At the end of
the reaction process, a solution of HCl (0.5 M) was added in
order to remove the bismuth-waste, obtaining product 4a as a
precipitate which was filtered and rinsed with water. In this
case, the use of VOC solvents was completely avoided during
the whole process, obtaining 1.19 g of compound 4a with high
퐦퐃퐄퐒
훒퐃퐄퐒
=
훒퐰퐚퐭퐞퐫 = ퟏ.ퟎퟗ 퐠/퐦퐋
°
(28 C)
퐦퐰퐚퐭퐞퐫
Equation 1. Density of DES.
The pH value is a very important parameter to be
measured for a new solvent. It can be crucial for the corrosion,
catalytic or dissolution properties of the solvent, limiting its
industrial applicability. In non-aqueous solutions, pH depends
on temperature and on the chemical potential of hydrogen.
1
purity (85% yield, see Fig S1 for H NMR). A similar result was
obtained through VOC extraction using EtOAc as solvent
(Scheme 2). When the reaction was quenched with only water
and the organic products were extracted with EtOAc, the
formation of a precipitate containing bismuth salts was
observed. After removal of the precipitate, an ICP-mass
analyses of both, the organic and aqueous layer, showed only
a presence of 0.02% and 2.3% of bismuth, respectively.
To have some insights in the reaction mechanism, several
control experiments were performed (see supporting
information).
Scheme 3. Plausible reaction mechanism.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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The chemical potential depends on the presence of ions
View Article Online
DOI: 10.1039/C9GC01541H
6.4
6.2
6
and hydrogen-bonding with other species.26 It was observed
that the pH value decreased linearly with the acetamide molar
fraction (Fig. 3); meaning that the more hydrogen bonds
available, the lower the chemical potential of hydrogen was
and the lower pH value was obtained. The phase diagram (Fig
1) was plotted using the individual differential scanning
calorimetry analyses of several mixtures containing different
proportions of the two DES components (Fig S4).
5.8
5.6
5.4
5.2
0.4
0.5
0.6
0.7
0.8
Finally, the potential toxicity of this novel eutectic mixture
was studied. Preliminary studies carried out with strains of
mesophilic bacteria showed that the DES is non-toxic for
concentrations below 300 mM. Nevertheless, further studies
will be carried out in order to completely assess the DES
toxicity.
χAcetamide
Figure 3. pH values depending on the acetamide molar fraction.
Synthesis of Ar3Bi.
For commercially available organomagnesium reagents: a
solution of the BiCl3 in dry THF (1M) was added dropwise over
a solution of ArMgBr in THF or Et2O (1M) under argon
atmosphere with magnetic stirring. Once the addition was
completed, the solution was heated to reflux for 12 h. Then,
the reaction was allowed to reach room temperature and
poured slowly over a cold saturated aqueous solution of
NH4Cl. Product was extracted 3 times with Et2O. The combined
organic phases were dried over MgSO4 and the solvent was
removed under reduced pressure.27
Experimental
General
Melting points were obtained with a Reichert Thermovar
apparatus. NMR spectra were recorded on a Bruker AC-300
1
(300 MHz for H and 75 MHz for 13C) using CDCl3 as a solvent
and TMS as internal standard for H and 13C; chemical shifts
1
are given in δ (parts per million) and coupling constants (J) in
Hertz. FT-IR spectra were obtained on a JASCO 4100LE (Pike
Miracle ATR) spectrophotometer. Mass spectra (EI) were
obtained at 70 eV on a Himazdu QP-5000 spectrometer, giving
fragment ions in m/z with relative intensities (%) in
parentheses. The mass spectrometry analyses of high
resolution (HRMS) were performed in the unit of Mass
Spectrometry of the Technical Services Research at the
University of Alicante with a spectrometer Finnigan MAT95-S.
DIP analyses were performed using an Agilent mass
spectrometer, model Network 5973 Mass Selective with direct
sample introduction to the ion source through the SIS
(Scientific Instrument Services) probe Direct Insertion Probe
(73DIP-1).The chromatographic analyses (GLC) were
determined with a Hewlett Packard HP-5890 instrument
equipped with a flame ionization detector and 12 m HP-1
capillary column (0.2 mm diam, 0.33 mm film thickness, OV-1
stationary phase), using nitrogen (2 mL/min) as a carrier gas,
Tinjector = 275 oC, Tdetector = 300 oC, Tcolumn = 60 oC (3 min) and 60-
270 oC (15 oC/min), P = 40 kPa. Thin layer chromatography
(TLC) was carried out on Schleicher&Schuell F1400/LS 254
plates coated with a 0.2 mm layer of silica gel; detection by
UV254 light. DSC analysis were carried out on a METTLER
TOLEDO equipment, model TGA/SDTA851e/LF/1600, and EM
For non-commercially available organomagnesium reagents:
the corresponding aryl iodide (6.2 mmol) was dissolved in dry
o
THF and cooled to -78 C in an acetone bath. A n-butyllithium
solution (2.5 M, 6.2 mmol) was added dropwise and the
mixture was stirred at that temperature for 1 h. Then, a
solution of BiCl3 (2 mmol) in dry THF was added dropwise and
the mixture was slowly allowed to reach room temperature.
The corresponding mixture was stirred overnight at rt and then
quenched with sat. aq. NaHCO3. The aqueous layer was
extracted with EtOAc (15 mL x 3) and the combined organic
layers washed with H2O and brine. The organic layer was dried
over MgSO4, filtered and reduced under reduced pressure.
Ar3Bi were usually purified by recrystallization from hot EtOH
or by flash chromatography using a mixture of EtOAc and
hexanes.30
Synthesis of sulfonamides.
A solution of Ar3Bi (0.2 mmol), sodium metabisulfite (1.32
mmol), CuCl (0.006 mmol) and the corresponding nitro
compound (1.2 mmol) in 1.5 mL of DES was stirred for 24 h at
80 °C in a reaction vessel opened to air. Once the reaction was
completed, water was added to dissolve the DES phase. A
precipitate containing the bismuth waste was formed. The
bismuth by-product was only soluble in acidic aqueous
solutions. The aqueous suspension was extracted three times
with EtOAc. The sulfonamide product and the excess of nitro
compound were dissolved in EtOAc. The combined organic
layers were dried over MgSO4 and concentrated under
reduced pressure. Products were usually purified by
analysis on
a PFEIFFER VACUUM, model THERMOSTAR
GSD301T. pH measurements were performed using a Mettler
Toledo SevenEasy S20 pH-meter. Reactions carried out under
microwave irradiation were performed on a MW CEM
Discovery 908010 apparatus. Column chromatography was
performed using silica gel 60 of 40-63 mesh. All reagents were
commercially available (Acros, Aldrich, Fluorochem) and were
used as received.
4 | J. Name., 2012, 00, 1-3
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Alternatively, product could be isolated by quenching the
reaction mixture with HCl (0.5 M) and filtering the suspension.
The filtrate was rinsed with distilled water to afford products
4/5 in high purity, although with lower yields than in the
previous method due to the slight solubility of sulfonamides in
water. Isolated yields are based on the consumption of the
three aryl groups attached to Bi.
7.
8.
Conclusions
In summary, an efficient one-pot, one-step synthesis of
sulfonamides is described in this study; starting from
unactivated reagents such as nitro compounds and
triarylbismuthines, with Na2S2O5 as SO2 source and reductant.
This process, catalysed by copper chloride in a ligand-free
fashion has been demonstrated to be chemoselective, simple,
and air and moisture insensitive. In addition, in this study non-
toxic reagents are used, and the excess of by-product
formation is reduced, following most of the Green Chemistry
principles. The resulting bismuth salts are easily removed from
the reaction crude mixture by precipitation with water. The
eutectic mixture here described has been characterised, with
preliminary analyses showing low toxicity.
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
This work was supported by the University of Alicante
(VIGROB-173 and VIGROB-309) and the Spanish Ministerio de
Economía, Industria y Competitividad (CTQ2015-66624-P and
PGC2018-096616-B-I00). X.M. and J.T.C. thank Generalitat
Valenciana (ACIF/2016/057 and ACIF/2016/077) for their
fellowships. We gratefully acknowledge the polishing of our
English by Mrs. Oriana C. Townley.
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