Efficient synthesis of organic thioacetates in water

Article abstract of DOI:10.1039/c8ob01896k

Thioacetates as precursors of thiols are interesting starting points for synthesizing other organosulfur compounds. Herein, we propose a simple, efficient and fast method to obtain organic thioacetates using water as a solvent. Taking into account the great attention that has been paid toward environmentally friendly synthetic procedures in the past decades, we prove the role and the strength of the thioacetate anion as a nucleophile for nucleophilic displacement reactions in an aqueous medium. The reactions were carried out under pH control, to prevent the decomposition of the mesylate starting materials, using potassium carbonate as a safe and mild base. A simple work up allows products to be obtained with excellent yield and acceptable purity.

Full text of DOI:10.1039/c8ob01896k

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Efficient Synthesis of Organic Thioacetates in Water
F. Olivito1,2*, P. Costanzo1, M. L. Di Gioia3, M. Nardi2,4, M. Oliverio1, A. Procopio1.
Received 00th January 20xx,
Accepted 00th January 20xx
Thioacetates as precursors of thiols, are interesting starting point to synthesize other organosulfur compounds. Herein, we
propose a simple, efficient and fast method to obtain organic thioacetates using water as a solvent. Taking into account
the great attention which has been put on environmentally friendly synthetic procedures in the last decades, we prove the
role and the strenght of thioacetate anion as nucleophile for nucleophilic displacement reactions in an aqueous medium.
The reactions were carried out under pH control, to prevent the decomposition of mesylate starting materials, using
potassium carbonate as a safe and mild base. A simple work up allows to obtain products with eccellent yield and
acceptable purity.
DOI: 10.1039/x0xx00000x
www.rsc.org/
conventional synthesis of thioacetates is carried out through a
nucleophilic substitution, starting from organic halides or activated
alcohols, using thioacetate anion as nucleophile. Moreover,
unsaturated thioacetates, such as alkenyl-thioacetates, are
Introduction
Organosulfur compounds are an important class of organic
important reagents to obtain the access to unsaturated
molecules, the importance of which is well recognized today for organosulfur compounds. One of the most important examples of
1-3
unsaturated organosulfur compounds with great benefits on human
health are represented by allium species plants, in which garlic
plays an important role.37 Divekar et al. proposed a palladium
catalysed synthesis of allylic thioacetates to obtain allylic thiols
using thioacetate anion.38
many synthetic purposes.
These molecules are also studied and
manipulated due to the great biological and pharmacological
potential, with many positive effects on human health.4-6
Organosulfur compounds are not only important for nutrition,7 but
they are also building blocks that play key roles in many biological
structures and functions and therefore essential for the whole
life.8,9 Organosulfur chemistry includes a bewildering number of
Nevertheless, the classical procedures are characterized by long
reaction times, toxic apolar aprotic solvents, and low purity that
requires chromatographic techniques with important solvent
waste.39-41 Thus, the development of
a simple, rapid and
molecules
and
sulphides,
disulphides,
sulphonamides,
thiosulfinates, isothiocyanates, are just some examples that occur
widely in nature.10-14
environmentally friendly procedure is very valuable. Potassium
thioacetate or thioacetic acid represent the sources of thioacetate
anion commonly used, but this nucleophile works well only in
conventional solvents, or by anionic activation using silica gel as
support.42-45 Traditional procedures are often improved or
One of the common synthetic route to obtain these molecules
starts from thiols,15-18 which have also, a wide range of application
in polymer chemistry, medicinal chemistry, biochemistry and
scaffolds chemistry.19-23 Due to the structural diversity of
organosulfur compounds in nature and in numerous biological
systems,24-27 the development of an alternative and cheap strategy
to access these molecules is still attractive.
overcome by green strategies, with the aim to avoid toxic reagents,
46-49
solvents or purification procedures.
There are no reported
literature methodologies that prove the action and the strength of
thioacetate anion in aqueous medium without any catalyst. The
role of water has been changing so fast during the past years and
applications in chemistry continue to grow incessantly and, as a
consequence, it is a perfect candidate to create a green reaction
medium.50-52
Organic thioacetates are the most used precursors to these
molecules and can be converted to thiols via many strategies.28-32 In
the last years many synthetic methods have been discovered.33-36
A
Here, we report a general synthetic procedure to afford organic
thioacetates in aqueous medium, starting from organic mesylates,
under pH control. The reaction performed in water, together with
the use of a mild base and low temperatures, the absence of any
catalyst and of by-products, is a good result to have a mild and
environmentally friendly methodology.
1Dipartimento di Scienze della Salute, Università Magna Græcia, Viale Europa,
Germaneto, CZ, Italy. E-mail: fabrizioolivito@gmail.com
2Dipartimento di Chimica, Università della Calabria, Cubo 12C, Arcavacata di
Rende, CS, Italy.
3Dipartimento di Farmacia e Scienze della Salute e della Nutrizione, Edificio
Polifunzionale, Università della Calabria, 87030 Arcavacata di Rende, Cosenza,
Italy.
4Dipartimento di Agraria, Università Telematica San Raffaele, Roma, Via di Val
Cannuta, 247, 00166, Italia.
†Electronic supplementary informaꢀon (ESI) available: Synthetic procedures, GC-
MS and NMR spectra. See DOI: xxxxxxxxxxxxxx
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The addition of K2CO3 as a mild base in the reaction mixture
enables the formation of the desired product in good yields
(Table 1, entries 4-6). The reaction is almost quantitative in
Results and discussion
In our search for a simple and green procedure, the use of organic two hours at 40 °C using 1.5 equivalents of thioacetate or
thioacetic acid and 3 equivalents of base (Table 1, entry 7). The
use of a slight excess of thioacetate source is essential for the
halides proved to be unfavourable due to the facile hydrolysis of
this species in the aqueous system, together with complications
related to their toxicity and high environmental impact.53,54
Mesylates are a very attractive alternative, especially because in a
slightly basic medium these molecules are quite stable in water.
quantitative outcome.
A further increasing amount of
thioacetate does not affect the yield of the reaction (Table 1,
entry 8).
The use of a mild base is necessary for the pH control of the
optimized reaction, to prevent a reversible equilibrium due to
the nucleophilic power of water in acidic media.
To demonstrate this statement, we performed a correlation
study between pH of the mixture and reaction yield (Table 2).
We proved that in a slight alkaline aqueous medium, (pH near
10), the displacement of the mesylate leaving group by
thioacetate anion proceeds completely (Table 2, entry 4).
Morita and collaborators developed
a strategy to convert
quantitatively alcohols to mesylates in water at pH near 10.55 We
used the same system to convert mesylates to thioacetates.
Our aim was to find a synthetic protocol to obtain thioacetates
in aqueous medium, with short times, no hazardous reagent,
and a simple work up without any further purification.
Potassium thioacetate or thioacetic acid can be used as
thioacetate source in water (Scheme 1).
Table 2. Correlation between pH of the mixture and reaction yield.a
Entry
K2CO3(M)b
pH
Yield(%)c
1
2
3
0.1
0.2
0.3
0.4
8.0
8.5
9.0
9.5
65
72
84
93
Scheme 1. Nucleophilic displacement of organic mesylates in water by
thioacetate anion.
4
a
This optimization was conducted starting from benzylmesylate
(1a). The pH of the mixture was measured by pH meter. bThe
concentration of potassium carbonate in water was expressed in
molarity. c Yield calculated by GC-MS.
We initiated our investigation starting from benzyl mesylate
(
1a), freshly synthetized almost quantitatively, from benzyl
alcohol by a procedure reported in literature.56
Our first attempt was to convert the reagent to thioacetates
without any use of bases (Table 1, entry 1). The reaction didn’t
succeed because yield was not satisfactory. Even when the
reaction was performed at higher temperatures with increased
reaction times and increased amount of potassium
thioacetate, the yield was quite low (Table 1, entries 2 and 3).
One of the reason for this failure was the instability of
methanesulfonates in aqueous acidic medium.
The use of potassium carbonate is consistent with our
purpose. It is a good alternative to regulate pH respect to
conventional stronger bases. It is a natural salt, with very low
toxicity and safe to handle, so it can play a role in a sustainable
procedure as reported by many examples during the past years.57,58
We also tried to replace K2CO3 with NaOH as a stronger base to
reduce the quantity used, but 2 equivalents in any case were
necessary to obtain a comparable result with the same pH.
With these optimized conditions in hand, we have evaluated
the scope of the present method for a variety of allylic
substrates, the results are summarized in Table 3.
Table 1. Reaction optimization for the synthesis of
benzylthioacetate from benzylmesylate. a
As expected, allyl mesylate afforded 2b in 92% yield, final
extraction in diethyl ether allows to obtain a quite pure
product in almost quantitative yield and without any further
purification (Table 3, entry 2).
b
Entry
KSAc b
1.5
2
K2CO3
Temp. (°C)
Time (hrs)
Yield(%)c
20
The starting mesylates are freshly prepared using the
conventional procedures and used immediately. A fast and
efficient procedure was developed. Benzylic, allylic and
propargylic mesylates are easily converted almost totally to
thioacetates (Table 3, entries 1, e and 6). Usually these
substrates have a borderline behaviour between SN1 and SN2
mechanism, but in our study we observed a behavior typical of
an SN2-type reaction. Allylic groups favours mostly this type of
reaction because of the combination with the negatively
charged transition state. Erden and coworkers proved by
synthetically and computationally studies how strong the SN2
reaction is accelerated by allylic groups.59
In our case, this reaction is also stereospecific with total
retention of configuration (Table 3, entries 3 and 4). We
proved that the propargylic group is also activating like the
allylic groups and the reaction gives the same outcome (Table
3, entry 6).
1
2
3
4
5
6
7
8
0
0
0
1
2
3
3
3
25
40
80
25
40
25
40
40
2
4
5
2
4
2
2
2
35
2.5
1.5
2
36
40
60
1.5
1.5
2
75
93
94
a The reaction was performed using a round bottom flask equipped
with a magnetic stirrer and a reflux condenser. 2 ml of H2O for 1
mmol of reagent. Either potassium thioacetate or acetic acid can be
used.b Quantities are expressed in equivalents. c Yield calculated by
GC-MS.
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Table 3. Synthesis of benzyl, allyl, and propargyl thioacetates. a
Table 4. Optimization strategy for the synthesis of 5-
hexenylthioacetate 1d a
Yield(%)b
.
Entry
Reagent
Product
1
94
b
Entry
KSAc b
K2CO3
Temp.(°C)
Time (hrs)
Yield(%)c
1a
2a
1b
2b
3b
4b
1
2
3
4
5
6
7
8
1.5
2
0
0
0
1
2
3
3
3
25
40
80
25
40
80
80
80
2
4
6
2
4
6
4
2
10
18
24
38
45
95
94
93
2
96
97
93
2.5
1.5
2
OMs
3c
4c
2
1.5
3a
4a
1.5
a The reaction was performed using a round bottom flask equipped
with a magnetic stirrer and a reflux condenser. 2 ml of H2O for 1
mmol of reagent. Either potassium thioacetate or acetic acid can
be used.b Quantities are expressed in equivalents. c Yield calculated
by GC-MS.
5
6
97
96
5a
6a
5b
6b
These optimized conditions were used for various saturated
and unsaturated mesylates (Table 5). The results
demonstrated that the reaction is accelerated by allyl groups,
nevertheless, the reaction with non-allyl unsaturated reagents
(Table 5, entries 1-3) and saturated reagents (Table 5, entries
4-6), was also suitable to generate the desired products in
excellent yields.
The reaction yields are almost the same for both saturated and
unsaturated molecules demonstrating that the unsaturation
doesn’t interfere with this reaction (Table 5).
a The reaction was conducted in a round bottom flask equipped with
magnetic stirrer and reflux condenser at 40°C. b Yield calculated by GC-
MS.c The stereospecificity was determined by 1H and 13C-NMR
spectroscopy.
Table 5. Synthesis of saturated and unsaturated thioacetates.a
The efficacy of this method was further tested using saturated
and unsaturated mesylates without allyl groups in their
structure (Scheme 2).
Entry
Reagent
Product
Yield(%)b
1
96
1c
2c
3c
1d
2
3
97
96
2d
Scheme 2. Nucleophilic displacement reaction of saturated and
unsaturated methanesulfonates in aqueous medium.
3d
4
95
In Table 4 are summarized the most important attempts to
optimize the reaction starting from 5-hexenyl-1-mesylate 1c. In
the absence of potassium carbonate the result was
unsatisfactory (Table 4, entries 1- 3).
The reaction yield becomes from good to excellent by raising
the temperature and increasing the amount of the base (Table
4, entries 4-8). The use of three equivalents of potassium
carbonate allows the reaction mixture to have a pH near 10.
The absence of an allyl group in the starting compound
allowed us to understand how much the allyl group influences
the reaction and to prove that a different unsaturation site
does not affect the result.
4c
5c
6c
4d
5d
6d
5
6
96
97
a
The reaction was conducted in a round bottom flask equipped
with magnetic stirrer and reflux condenser at 80°C.
calculated by GC-MS.
b
Yield
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comparison with others species and no nucleophilic
Further investigations were attempted to define if this displacement occurs in that direction.
reaction follows a nucleophilic displacement with first or
Table 7. Nucleophilic displacement of benzyl-mesylate in aqueous
media with acetate anion as the nucleophile.a
second kinetic order. Secondary and tertiary mesylates were
used to verify if there is a two-step mechanism involving a
carbocation formation (Table 6).
There is no nucleophilic displacement on the secondary
carbons using the optimized conditions (Table 6, entries 1 and
2). We tried to push the reaction toward the product
formation, using a secondary allyl mesylate, but we had no
success (Table 6, entry 2). In the case of tertiary carbons, the
reaction did not work neither (Table 6, entry 3).
This result is consistent with our hypothesis; in fact, we proved
that using secondary and tertiary mesylates as starting
compounds the reaction mechanism doesn’t proceed through
a carbocation formation, thus the reaction follows a SN2
mechanism instead of SN1. Finally, the failure of the reaction
observed in the case of phenyl mesylate shows that the only
reasonable mechanism is a nucleophilic substitution (Table 6,
entry 4). The same reactions performed without base in
neutral conditions have the same result, so we can confirm
that there are not competitive mechanistic pathways.
b
Entry
KAc b
K2CO3
Temp(°C) Time (hrs)
Yield(%)
1
2
3
4
5
6
7
8
1.5
2
2.5
1.5
2
1.5
1.5
2
0
0
0
1
2
3
3
3
25
40
80
25
40
25
40
40
2
4
5
2
4
2
2
4
0
0
0
0
0
0
0
0
a
The reaction was performed using a round bottom flask equipped
with a magnetic stirrer and a reflux condenser. 2 ml of H2O for 1 mmol
of reagent. Either potassium acetate or acetic acid can be used.b
Quantities are expressed in equivalents.
Lastly, we elucidate the role of the water as the solvent for the
successful performance of the developed reaction, despite,
water is generally excluded for an SN2 reaction.62 Here, we use
a slight basic aqueous medium, with different anions in
solution, generated from the reagent and the base used. One
of the reason why a polar protic solvent is not convenient for a
SN2 reaction is the solvation effect.63,64 We proved that water
does not affect negatively the reaction but it behaves like a
catalyst instead. We used potassium thioacetate or thioacetic
acid as a thioacetate sources, that are completely ionized in
this basic medium. At the start of the reaction we noticed a
particular situation inside the reaction flask. There were many
drops in the aqueous mixture that, after completion of the
reaction, disappeared and the solution became clear with a
distinctive separation of two phases. All the mesylates and the
thioacetate derivatives are immiscible in water. Our
hypothesis is that the reaction occurs at the aqueous interface
Table 6. Synthesis of secondary, tertiary and phenyl thioacetates.a
Entry
Reagent
Product
Yield(%)
1
0
1f
2f
1e
2e
2
3
0
0
3e
3f
with
a slight dependence from temperature. Probably
thioacetate anion continues to be a strong nucleophile in this
medium because the presence of others anions and cations
make the water molecules occupied and less available for
solvation. We tried to substitute thioacetate anion with other
sulfur nucleophiles like thiophenolate anion and other
aliphatic thiolate anions but the reaction didn’t succeed
probably due to a more steric hindrance and a different
nucleophilicity of these anions in this reaction medium.
Against the conventional procedure, we have an almost
quantitative, fast and at the same time green reaction that
avoid the use of the classical polar aprotic solvents like DMF or
DMSO.
4
0
4f
4e
aAll reactions was conducted in a round bottom flask equipped
with magnetic stirrer and reflux condenser at 40°C and 80°C for 2
and 4 hours. 2 ml of H2O for 1 mmol of reagent. 1.5 mmol of
potassium thioacetate or acetic acid have been used.
The correlation between SN2 reaction and nucleophilic
strength is well known and reported.60,61 Sulfur is more
nucleophilic than oxygen, for this reason we carried out the
same reaction on allylic mesylates using acetate anion as a
weaker nucleophile instead of thioacetate anion.
This comparison allowed us to define if this reaction is affected
or not by nucleophilic strenght. We performed the nucleophilic
displacement reaction using acetate anion under the
optimized conditions. No substitution of the mesylate leaving
group was observed even raising temperature, time and the
base (Table 7). These data confirm that the reaction is
dependent by the nucleophilic strength. Acetate anion doesn’t
have the same nucleophilic character in this medium in
Conclusions
We developed a simple, mild and efficient procedure to convert
organic mesylates to thioacetates. The reaction apparatus is simple
and all reagents are safe to handle. Potassium carbonate as a pH
controller is a green alternative to strong bases. We proved by
different experiments that this nucleophilic displacement reaction
follows a SN2 type mechanism. Despite the classical SN2 procedure,
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no toxic solvents were used. This procedure in water is a valid potassium carbonate solution were added. 1.5 eq of potassium
alternative to conventional methods and a suitable access to the thioacetate or acetic acid were added dropwise to the solution
synthesis of different types of thiols and of course an efficient under stirring. The mixture was stirred at 40 °C with a reflux
starting point for the synthesis of more complex organosulfur condenser for almost 2 hours. The organic phase was extracted
compounds.
with a small portion of diethyl ether and washed three times with
water. The organic phase was dried over Na2SO4 and the solvent
removed under vacuum. The product was recovered as a yellow
liquid in an almost quantitative yield (GC-MS).
Conflict of interest
There are no conflicts of interest to declare.
General procedure for the synthesis of primary thioacetates (1d-
6d)
Experimental section
2.8 mmol of freshly prepared mesylate were put in a one neck
round bottom flask. In the same flask 20 ml of 0.4 M aqueous
potassium carbonate solution were added. 1.5 eq of potassium
thioacetate or acetic acid were added to the solution under stirring.
The mixture was stirred at 80 °C under reflux for almost 2 hours.
The organic phase was extracted with a small portion of diethyl
ether and washed three times with water. The organic phase was
dried over Na2SO4 and the solvent removed under vacuum. The
product was recovered as a yellow liquid in an almost quantitative
yield (GC-MS).
General
Commercially available reagents were purchased from Sigma-
Aldrich Chemical Co. (Milano, Italy) and used as supplied unless
stated otherwise. All reactions were carried out in atmospheric
conditions. 1H NMR spectra were recorded at 300 MHz, while 13C
NMR spectra were measured at 75 MHz. Spectral analysis was
performed at 293 K on diluted solutions of each compound by using
CDCl3 as the solvent. Chemical shifts (δ) are reported in ppm and
referenced to CDCl3 (7.25 ppm for 1H and 77.0 ppm for 13C spectra).
Coupling costants (J) are reported in Hertz (Hz). Reaction mixtures
were monitored by thin layer chromatography (TLC) using Merck
Silica gel 60 F254 precoated aluminium sheets or Merck Aluminium
oxide 60 F254 neutral precoated alluminium sheets, UV light (254
nm), iodine or diluted solution of H2SO4 for the detection.
Evaporation of solvents was performed at reduced pressure using a
rotary vacuum evaporator. The GC-MS Shimadzu workstation is
constituted by a GC 2010 (provided of a 30 m-QUADREX 007–5MS
capillary column, operating in “split” mode, 1 ml min−1 flow of He as
carrier gas) and a 2010 quadrupole mass-detector.
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