Multicomponent Synthesis of Sulfones and Sulfides from Triarylbismuthines and Sodium Metabisulfite in Deep Eutectic Solvents

Article abstract of DOI:10.1002/ejoc.202000425

This study describes a novel and catalyst-free methodology for the multicomponent synthesis of a broad range of sulfones, disulfides, and sulfides from non-toxic triarylbismuthines (Ar₃Bi) and sodium metabisulfite (Na₂S₂O₅) in deep eutectic solvents (DESs). The fine tuning of the DESs properties allowed the solubility of all reagents, enhancing their reactivity, as well as, the recyclability of the reaction medium for at least 5 consecutive cycles. Thus, this versatile strategy uses non-toxic reagents without the need of metal catalysts in a sustainable solvent, being an interesting alternative to traditional hazardous protocols.

Full text of DOI:10.1002/ejoc.202000425

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Multicomponent Synthesis of Sulfones and Sulfides from
Triarylbismuthines and Sodium Metabisulfite in Deep Eutectic
Solvents
Authors: Beatriz Saavedra, Xavier Marset, Gabriela Guillena, and
Diego J. Ramón
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000425
Link to VoR: https://doi.org/10.1002/ejoc.202000425
01/2020

10.1002/ejoc.202000425
European Journal of Organic Chemistry
FULL PAPER
Multicomponent Synthesis of Sulfones and Sulfides from
Triarylbismuthines and Sodium Metabisulfite in Deep Eutectic
Solvents
Beatriz Saavedra, [a] Xavier Marset, [a] Gabriela Guillena, *[a] Diego J. Ramón*[a]
[a]
Beatriz Saavedra, Xavier Marset, Prof. Dr. Gabriela Guillena and Prof. Dr. Diego J. Ramón
Departamento de Química Orgánica and Instituto de Síntesis Orgánica (ISO), Facultad de Ciencias Universidad de Alicante, Apdo. 99, 03080 Alicante,
Spain.
Email: gabriela.guillena@ua.es; https://personal.ua.es/es/gabriela-guillena/
djramon@ua.es; https://personal.ua.es/en/djramon/research-group-of-diego-j-ramon.html
Supporting information for this article is given via a link at the end of the document.
Abstract: This study describes
a
novel and catalyst-free
requires thiol substrates and oxidative conditions.[5] The use of
this methodology has some restrictions due to the unpleasant
odor of thiols, their relatively limited commercial availability, as
well as, the incompatibility with the presence of oxidation-
sensitive functional groups in the starting materials. Another
widely used strategy to synthesize sulfones is the transition-
metal catalyzed sulfonylation with sulfonyl halides or sodium
sulfinates,[6] including sulfonyl-type radical additions.[7] All these
protocols are based on organic sulfur-containing reagents, which
are often difficult to prepare and therefore of limited availability.
A more versatile approach is the direct introduction of SO2
(g) in a three-component process.[8] However, this methodology
has important limitations, such as toxicity and the issues
associated with handling gaseous sulfur dioxide. An alternative,
that avoids these drawbacks, is the use of SO2-surrogates such
as DABSO[9] or inorganic sulfites.[10] Notwithstanding, there are
several aspects to improve these methodologies, such as the
use of specialized and expensive ligands and catalysts,
generally in high loadings. Also, other limitations are the
requirement for stoichiometric phase-transfer additives, air-
sensitive reagents, poor solubility of the inorganic sulfites in
organic media and the use of volatile and harmful solvents. As a
consequence, the development of new methodologies to access
diversely functionalized sulfur-containing molecules remains in
demand.
methodology for the multicomponent synthesis of a broad range of
sulfones, disulfides and sulfides from non-toxic triarylbismuthines
(Ar3Bi) and sodium metabisulfite (Na2S2O5) in deep eutectic solvents
(DESs). The fine tuning of the DESs properties allowed the solubility
of all reagents, enhancing their reactivity, as well as, the recyclability
of the reaction medium for at least 5 consecutive cycles. Thus, this
versatile strategy uses non-toxic reagents without the need of metal
catalysts in a sustainable solvent, being an interesting alternative to
traditional hazardous protocols.
Introduction
Organosulfur compounds play an essential role in organic
chemistry for the development of novel chemical structures.
Sulfones are important structural motifs that serve as versatile
intermediates in organic synthesis[1] and are used in classic
organic transformations such as the Ramberg-Bäcklund
rearrangement[2] and the Julia olefination.[3] In addition, sulfonyl-
containing compounds feature in a broad range of bioactive
molecules, and are common motifs in pharmaceuticals and
agrochemicals (Figure 1).[4]
The use of neoteric solvents could introduce new
opportunities in order to develop new reactions and approaches.
Deep eutectic solvents (DESs) are a new class of solvents,
which are generally composed by two or three cheap and safe
components, capable of associating with each other, through
mainly hydrogen bond interactions, to form a eutectic mixture.
DESs are important alternatives to volatile organic solvents due
to their unique properties, such as easy synthesis, low cost, low
volatility, high dissolution power, high biodegradability and
feasibility of structural design.[11] A glaring example of this, is the
eco-friendly formation of sulfides and sulfones in choline
chloride-based low transition temperature mixtures by a direct
nucleophilic addition of thiolate and sulfinate ions to in situ-
derived nitrosoalkenes from α-clorooximes, under air and mild
conditions.[12]
Figure 1. Representative biologically active sulfone motifs.
In this study and for the first time, the development of a
novel multicomponent methodology of synthesis of sulfur-
containing compounds (sulfones, disulfides and sulfides) is
described, taking into account all current environmental
requirements.[13] Achieved results are even superior to those
As a result of their widespread use, efficient and robust
approaches toward the synthesis of sulfones are highly
demanded. The common approaches to prepare sulfones
include oxidation of the corresponding sulfides, that usually
1
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10.1002/ejoc.202000425
European Journal of Organic Chemistry
FULL PAPER
reported using non-environmentally friendly protocols. The
protocol is based on the generation of aryl sulfinates[14] from
triarylbismuthines reagents (Ar3Bi) and Na2S2O5 as a non-toxic
sulfonyl source. DESs were used as a novel medium for sulfone
synthesis, taking the advantage of the high solubility of SO2 (g)
in this type of solvents.[15] The use of DESs enhanced the
reactivity, highlighting the great importance of the medium, and
leading to new reactivities in this type of sustainable solvents.
Also, triarylbismuthines are particularly attractive since they are
non-toxic, air and moisture stable and they can also transfer
their three aryl moieties, increasing the atom economy of the
process.[16]
Additionally, it is worth mentioning that the choice of an
appropriate DES was proven to be crucial for the reaction, thus
leading to opportunities to find new reactivities and
methodologies with less ecological footprint.
Once the optimal conditions were determined (entry 11 in
Table 1), the scope of this sustainable multicomponent
transformation was evaluated. First, different electrophiles were
used (Table 2). The reaction proceeded with different alkyl
halides, as electrophiles, (entries 1-3). 2-Chlorobenzo[d]thiazole
afforded product 4d in a good yield (entry 4). Less conventional
electrophiles such as diaryliodonium salts could be employed
(entry 5). Also, electron poor alkenes could react as
electrophiles in the sulfonylation reaction (entries 6-7). It is
worthy to note that the reaction conditions tolerated a wide
number of functionalities, including carboxylic acids.
Results and Discussion
Table 2. Scope of the electrophiles in the sulfonylation reaction.[a]
The study started by optimizing the reaction conditions using
triphenylbismuthine (1a), Na2S2O5 (2) and benzyl bromide (3a)
as the model reaction (Table 1). The reaction in typical organic
solvents failed or gave a modest result (entries 1-5). When protic
solvents were used, only in the case of methanol, the result was
promising (entries 6-8). Then, different eutectic mixtures were
tested (entries 9-11), obtaining a quantitative yield without
catalyst and using the non-toxic mixture acetylcholine
chloride:acetamide[17] (1:2; entry 11). These results highlighted
the ability of DESs to modulate reactivity properties fitting to
requirements of the reaction, such as activation role or solubility
of inorganic salts (Na2S2O5) and solubility of in situ generated
SO2. Also, the rest of the organic and intermediates formed by
the reaction, between triphenylbismuthine and the SO2-
surrogate are entirely dissolved in the DES mixture.
Entry
1
Electrophile (E+)
Product
Yield (%)[b]
90
4a
2
3
4b
4c
83
75
4
4d
85
Table 1. Solvent optimization of the sulfonylation reaction.[a]
5
6
4e
4f
40
80
Ph2IBF4
Entry
1
Solvent
Yield (%)[b]
7
4g
41
Toluene
0
2
CHCl3
0
[a] Reaction conditions: Ph3Bi (0.2 mmol), Na2S2O5 (1.32 mmol) and E+ (1.2
mmol) in 1.5 mL of solvent were stirred at 80 °C for 5 h. [b] Yield of compounds
isolated by column chromatography and calculated assuming that all three aryl
moieties are transferred.
3
Acetonitrile
7
4
DMSO
27
56
70
55
9
Next, different triarylbismuthines were evaluated (Table 3).
5
DMF
Slightly
better
yields
were
obtained
with
neutral
triarylbismuthines (entries 1-2), but, in general, the electronic
nature of the aromatic ring of triarylbismuthines does not seem
to have any effects on the scope of electrophiles (entries 3-8).
In the possible mechanism pathway, an aryl sulfinate salt is
postulated to be formed after the first reaction step. To
investigate the versatility of this process, including the tolerance
of organometallic reagent and solvent, we tested the addition of
iodine to the reaction mixture.[18] In this way, a radical process
could also take place in this new reaction medium, affording the
corresponding disulfide in the absence of any other reagent
(Table 4).
6
MeOH
7
EtOH
8
H2O
9
ChCl:glycerol (1:2)
ChCl:acetamide (1:2)
AcChCl:acetamide (1:2)[c]
57
30
99
10
11
[a] Reaction conditions: Ph3Bi (0.1 mmol), Na2S2O5 (0.66 mmol) and BnBr (0.60
mmol) in 0.75 mL of solvent were stirred at 80 °C for 5 h. Yield determined
by GC using tridecane as an internal standard.
chloride).
[b]
[c]
AcChCl (acetylcholine
2
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10.1002/ejoc.202000425
European Journal of Organic Chemistry
FULL PAPER
transformation to thiol derivative and reaction with
nucleophile/radical scavenger). The obtained results are
depicted in Table 5, showing moderate to good yields using
phenol/anisole derivatives (entries 1-2), N,N-dimethylaniline
(entry 3) or even indole as a nucleophile/radical scavenger
(entry 4). If a nucleophilic functionalized alkene is added, the
double bond reacts initially with the in situ formed radical thiol,
being then the radical trapped by the hydroxyl functionality
affording cyclic products 6e-g (entries 5-7).
Table 3. Scope of the triarylbismuthines in the sulfonylation reaction [a]
Entry
Ar
Product
4a
Yield (%)[b]
1
2
3
4
5
6
7
8
[a]
Ph
90
76
62
70
63
83
82
67
Table 5. Scope of the aryl sulfides [a]
1-naphthyl
4-MeC6H4
4-MeOC6H4
3,4,5-MeOC6H2
4-Me2NC6H4
4-FC6H4
4h
4i
4j
4k
4l
Entry
1
Nu-H or radical scavenger
Product
Yield
(%)[b]
4m
4n
4-BrC6H4
6a
6b
72
Reaction conditions: Ar3Bi (0.2 mmol), Na2S2O5 (1.32 mmol) and BnBr (1.2
mmol) in 1.5 mL of solvent were stirred at 80 °C for 5 h. [b] Yield of compounds
isolated by column chromatography and calculated assuming that all three aryl
moieties are transferred.
2
79
In this case, the electronic nature of the aromatic ring had a
notable impact in the reaction. In general, good results were
obtained with triarylbismuthines bearing neutral or electron
withdrawing groups (entries 1-2 and 5-6). Nevertheless, a
significant drop in the reaction yield was observed with electron-
donor substituents, such as methyl or methoxy groups (entries
3-4).
3
4
6c
6d
67
81
Table 4. Scope of the aryl disulfides [a]
5
6e
52
6
7
6f
77
73
Entry
Ar
Product
5a
Yield (%)[b]
6g
1
2
3
4
5
6
[a]
Ph
65
51
27
36
80
70
[a]
Reaction conditions: Ph3Bi (0.2 mmol), Na2S2O5 (1.32 mmol) in 1.5 mL of
solvent were stirred at 80 °C for 5 h, then I2 was added and the mixture was
1-naphtyl
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-BrC6H4
5b
stirred for 20 min. Finally, Nu-H or radical scavenger (1.2 mmol) was added
and the mixture was stirred for another 8h at 80 °C.
isolated by column chromatography and calculated assuming that all three aryl
moieties are transferred.
5c
[b]
Yield of compounds
5d
5e
Then, we decided to study the recyclability of the system,
which is a crucial point for the sustainability of the process. Once
the reaction was finished, the mixture was extracted with 2-
MeTHF[20] (a renewable volatile organic compound) to remove
all organic compounds from DES, and the mixture of DES could
be reused up to 5 consecutive cycles under the same reaction
conditions, with only a slightly decrease in the yields (Figure 2).
Another important aspect to be controlled in a sustainable
process is the waste materials. Thus, the amount of wasted
bismuth compounds could be also controlled just by adjusting
the pH of the aqueous work-up. When the model reaction (see
Table 1, entry 11) was quenched with only water and the organic
products were extracted with 2-MeTHF, the aqueous phase
contained 0.1% of the initial bismuth (ICP-OES analysis).
5f
Reaction conditions: Ph3Bi (0.2 mmol), Na2S2O5 (1.32 mmol) in 1.5 mL of
solvent were stirred at 80 °C for 5 h, then I2 was added and the mixture was
[b]
stirred for 20 min. Yield of compounds isolated by column chromatography.
Yield calculated assuming that all three aryl moieties are transferred and two
of them are in the final product.
Sulfinate salts have been employed as starting materials in
the synthesis of different sulfides. In these cases, iodine was
also added to the sulfinate allowing the synthesis of various
sulfides via C-H functionalization.[19] In view of those precedents,
a three step process in a one-pot manner was proposed for the
synthesis of various sulfides (formation of sulfinate salt,
3
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10.1002/ejoc.202000425
European Journal of Organic Chemistry
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However, if the presence of bismuth impurities in the desired
product are not allowed for some purposes, for instance in
medicinal chemistry, HCl 2.0 M can be added instead of water,
with 99% of the initial bismuth (ICP-OES analysis) remaining in
the aqueous layer, highlighting the possibility of controlling the
waste bismuth salts.
Scheme 2. Proposed mechanism for the synthesis of sulfones.
A plausible mechanism for the sulfides and disulfides
synthesis is also proposed in Scheme 3. Acetamide, one of the
DES components, or also other proton source from the media,
such as moisture, reacts with I2 to get hydrogen iodide. Then,
the in situ generated sulfinate (see Scheme 2), reacts repeatedly
with HI to give the corresponding hypoiodothioite, which could
react with a nucleophile to afford different sulfides or suffer
recombination to give symmetrical disulfides.[18]
Figure 2. Recyclability of the system.
A possible mechanism for the synthesis of sulfones is
depicted in Scheme 2. Firstly, Na2S2O5 disaggregation occurs
throw homolytic cleavage of the S-S bond. This step includes
radical intermediates,[21] which is in consonance with radical-
trapping experiments (Scheme 1). In this experiment, any
TEMPO-derived trapping product were detected. Only the
hydroxylamine or amine TEMPO derived products were
detected by MS-GC while triarylbismuthine remained
Scheme 3. Proposed mechanism for the sulfides and disulfides synthesis.
unchanged.
These
radical
intermediates,
suffer
a
disproportionation to afford solvated SO2. Then, SO2 undergoes
insertion between C-Bi bond.[22]
Conclusion
The excess of chlorides in deep eutectic medium, may favour
the BiCl3 released, affording the corresponding sulfinate. The
generation of the sulfinate intermediate could be detected
monitoring the reaction by phase-reversed HPLC, as has been
evidenced in a related proccess.[10b] Finally, sulfinate reacts with
an electrophile to give the desired sulfone product.
In summary,
a multicomponent synthesis of sulfones,
disulfides or sulfides from triarylbismuthines and Na2S2O5 in
AcChCl:acetamide (1:2), as reaction medium, has been
described for the first time. The results highlighted the
importance of the choice of the adequate solvent, which
enhanced the reactivity of the system and also, provides plenty
of opportunities for developing new and unexplored synthetic
routes. In terms of sustainability of this methodology, it is
interesting to mention that i) arylboronic acids have been
replaced by non-toxic aryl sources as Ar3Bi, increasing the atom
economy of the process (Ar3Bi can react with 3 equivalents of an
electrophile); ii) non-harmful reagent (Na2S2O5) has been used
as SO2 source; iii) the careful choice of DES allowed a good
solubility and reactivity of all reagents, allowing the recyclability
of the reaction 5 consecutive cycles in a non-toxic solvent
media; iv) the waste bismuth salt could be controlled adjusting
the pH of the aqueous solution used in the work-up v) and finally,
the process avoided the use of catalysts under aerobic
conditions.
Scheme 1. Radical trapping experiment.
Experimental Section
General. Solvents and reagents were used as obtained from commercial
sources and without purification. 1H NMR spectra were recorded on
Bruker AC-300 or AC-400 NMR spectrometers in proton coupled mode.
4
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10.1002/ejoc.202000425
European Journal of Organic Chemistry
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13C NMR spectra were recorded on Bruker AC-300 or AC-400 NMR
spectrometers, in proton decoupled mode at 20 °C; chemical shifts were
given in δ (parts per million) and coupling constants (J) in Hertz. Low-
resolution mass spectra (EI) were obtained at 70 eV on an Agilent
Technologies GC/MS-5973N spectrometer and low-resolution HPLC with
electrospray ionization (HPLC-ESI) mass spectra were recorded
employing an Agilent model 1100 Series, giving fragment ions in m/z with
relative intensities (%) in parentheses. High-resolution mass spectra
were obtained on an Agilent 7200 flight (Q-TOF) spectrometer. Infrared
spectra were measured on a Jasco FT/IR-4100 Fourier Transform
Infrared Spectometer. Melting points were obtained with a Reichert
Thermovar apparatus. The chromatographic analyses (GC) were
determined with a Younglin 6100 instrument equipped with a flame
ionization detector and 30 m HP-5 capillary column (0.25 mm diam, 0.33
was stirred for 20 min. Once the reaction was completed, water was
added to dissolve the DES phase. The aqueous suspension was
extracted with EtOAc (5 mL x 3). The combined organic layers were dried
over MgSO4 and concentrated under reduced pressure. Products were
usually purified by chromatography on silica gel (hexane/ethyl acetate).
General procedure for the synthesis of sulfides. A solution of Ar3Bi
(0.2 mmol), sodium metabisulfite (1.32 mmol) in 1.5 mL of DES was
o
stirred for 5 h at 80 C. Then, I2 (1.2 mmol) was added and the reaction
was stirred for 20 min, before the corresponding pro-nuclephile was
added (1.2 mmol). Once the reaction was completed, water was added to
dissolve the DES phase. The aqueous suspension was extracted with
EtOAc (5 mL x 3). The combined organic layers were dried over MgSO4
and concentrated under reduced pressure. Products were usually
purified by chromatography on silica gel (hexane/ethyl acetate).
mm film thickness), using nitrogen (2 mL/min) as a carrier gas, Tinjector
=
270 ºC, Tcolumn = 60 ºC (3 min) and 60-270 ºC (15 ºC/min), P = 12 psi.
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. Column chromatography was performed using
silica gel 60 of 40-63 mesh. UV-Vis spectra were recorded in a
SHIMAZDU UV-1603 apparatus. The Inductively Coupled Plasma Optical
Emission Spectroscopy (ICP-OES) analysis were performed in the units
Technical Services Research at the University of Alicante with an
inductively coupled plasma optical emission spectroscopy: Perkin Elmer.
Optima 4300DV (Dual vision).
General Procedure for Recycling Experiments. The reaction was
performed according to the general procedure. Once the reaction was
completed, the reaction mixture was cooled to room temperature, and 2-
MeTHF (3 mL x 3) was added to the reaction vessel. The biphasic
mixture was stirred for 5 min, and the upper phase (VOC-phase, mainly
unreacted organic reagents and products) was separated by decantation
and analyzed by GC using tridecane as the internal standard. The
eutectic mixture was dried under vacuum and was charged again with
fresh reagents, repeating the process.
General
synthesis
of
Ar3Bi.
For commercially available
organomagnesium reagents, a solution of BiCl3 in dry THF (2 mmol, 1 M)
was added dropwise over a solution of ArMgBr in THF or Et2O (1 M)
under an argon atmosphere with magnetic stirring. Once the addition was
complete, the solution was heated at reflux for 12 h. Then, the reaction
was allowed to reach room temperature and poured slowly over a cold
saturated aqueous solution of NH4Cl. The product was extracted 3 times
with Et2O. The combined organic phases were dried over MgSO4 and the
solvent was removed under reduced pressure.[23]
Acknowledgements
This work was supported by the University of Alicante (VIGROB-
316FI) and the Spanish Ministerio de Economia, Industria y
Competitividad (PGC2018-096616-B-100). BS and XM thanks
Generalitat Valenciana (ACIF/2017/211 and ACIF/2016/057,
respectively) for their fellowships.
For non-commercially available organomagnesium reagents, the
corresponding aryl iodide/bromide (6.2 mmol) was dissolved in dry THF
and cooled to −78 °C in an acetone bath. A n-BuLi solution (2.5 M, 6.2
mmol) was added dropwise and the mixture was stirred at that
temperature for 1 h. Then, a suspension 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 × 3) and the combined organic layers were washed
with H2O and brine. The organic layer was dried over MgSO4, filtered and
concentrated under reduced pressure. Ar3Bi was usually purified by
recrystallization from hot EtOH or by flash chromatography using a
mixture of EtOAc and hexanes.[24]
Keywords: Bismuth • Multicomponent reactions • Solvent
effects • Sulfur • Sustainable chemistry
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General procedure for the synthesis of sulfones. A solution of Ar3Bi
(0.2 mmol), sodium metabisulfite (1.32 mmol) and the corresponding
electrophile (1.2 mmol) in 1.5 mL of DES was stirred for 5 h at 80 oC.
Once the reaction was completed, water was added to dissolve the DES
phase. The aqueous suspension was extracted with EtOAc (5 mL x 3).
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o
stirred for 5 h at 80 C. Then, I2 (1.2 mmol) was added and the reaction
5
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10.1002/ejoc.202000425
European Journal of Organic Chemistry
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Key Topic: Deep Eutectic Solvents. Efficient multicomponent synthesis of sulfones, disulfides and sulfides from triarylbismuthines
and Na2S2O5 in Deep Eutectic Solvents (DESs), has been described for the first time.
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This article is protected by copyright. All rights reserved.