On the development of a nucleophilic methylthiolation methodology

Article abstract of DOI:10.1039/d0ob01149e

Methylthiolation reactions are usually explored to access organosulfur compounds using methanethiol, an extremely flammable and toxic compound. Herein, methylthiomethyl esters were successfully applied as novel methylthiolation reagents in a low cost, transition-metal-free methodology. These reagents allowed the methylthiolation of a wide scope of chalcones, acyl ester derivatives and Morita-Baylis-Hillman acetates with good group tolerance, affording the methylthiolated products in moderate to excellent yields. The reaction mechanism was investigated through several control experiments, as well as by theoretical calculations employing Density Functional Theory. The results strongly support that a sulfurane and a sulfonium ylide appear as key intermediates and that a Pummerer type rearrangement is also crucial for the formation of this novel reagent. Furthermore, the methylthiolation mechanism is likely to proceed through the nucleophilic attack of the reagent, followed by an entropically favoured step involving the acetate attack to the positively charged species, then releasing the product. This journal is

Full text of DOI:10.1039/d0ob01149e

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21 December 2017
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DOI: 10.1039/D0OB01149E
ARTICLE
On the Development of a Nucleophilic Methylthiolation
Methodology
Bernardo Basbaum Portinho de Puga Carvalho,a Adriane Antonia Pereira Amaral,a Pedro Pôssa de
Castro,a Fernanda Cerqueira Moreira Ferreira,a Bruno Araújo Cautiero Hortab and Giovanni Wilson
Amarantea*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Methylthiolation reactions are usually explored to access organosulfur compounds using methanethiol, an extremely
flammable and toxic compound. Herein, methylthiomethyl esters were successfully applied as novel methylthiolation
reagents in a low cost, transition-metal-free methodology. These reagents allowed the methylthiolation of a wide scope of
chalcones, acyl ester derivatives and Morita-Baylis-Hillman acetates with good group tolerance, affording the
methylthiolated products in moderate to excellent yields. The reaction mechanism was investigated through several control
experiments, as well as by theoretical calculations employing the Density Functional Theory. The results strongly support
that a sulfurane and a sulfonium ylide appear as key intermediates and that a Pummerer type rearrangement is also crucial
for the formation of this novel reagent. Furthermore, the methylthiolation mechanism is likely to proceed through the
nucleophilic attack of the reagent, followed by an entropically favoured step involving the acetate attack to the positively
charged species, then releasing the product.
species. Although well-established, these reagents are
expensive, extremely flammable, difficult to handle and have
high toxicity profile.15
Introduction
Despite these drawbacks, several studies in literature still
Organosulfur compounds are found in all living organisms.
They are present in the fundamental building blocks of life, e.g.
cysteine and methionine, playing a significant role in the
physical-chemistry of proteins, ultimately modulating their
folding and biological function.1,2 The C-S bond is also found in
naturally occurring small molecules, as well as in synthetic
pharmaceutical compounds.3–6 Methylthiolation reactions are
commonly carried out in organic synthesis, mainly due to
important biological activities of compounds bearing the -SCH3
group.7,8 In organic synthesis, this group is also used for double
bond protection.9,10 In addition, sulfur containing groups can be
readily converted into other functional groups such as
sulfoxides, sulfones and disulfides.11–13
report its use. In the hope of avoiding or minimizing the use of
methanethiol, many research groups have recently tried to
develop novel alternative approaches. For instance, in 2012,
Gao et al. employed DMSO and a Lewis acid catalyzed approach
to generate methanethiol in situ,
allowing the direct
methylthiolation of heterocycles and thus affording cyclic
methyl thioethers (Scheme 1A).16 In 2015, Sun et al. synthesized
aryl methyl thioethers and methylene-bridged arylamines
through a highly regioselective p-methylthiolation in the
presence of in situ generated methanethiol radical (Scheme
1B).17 More recently, Skrydstrup et al. elegantly employed S-
methylisothiourea hemisulfate salt as a solid precursor for the
ex-situ generation of methanethiol, that in the presence of a
gold complex was able to promote the hydromethylthiolation
of olefins (Scheme 1C).18
Traditionally, the most used methylthiolation reagent is
methanethiol or its sodium salt. Alternatively, hydrogen sulfide
is used followed by methylation under basic reaction
conditions.14 Generally, these reagents act as nucleophilic
a. Chemistry Department, Federal University of Juiz de Fora, Campus Martelos, Juiz
de Fora, Minas Gerais, Zip Code 36036-900, Brazil.
Corresponding author: giovanni.amarante@ufjf.edu.br
b. Chemistry Institute, Federal University of Rio de Janeiro
Cidade Universitária, CT Centro de Tecnologia, Rio de Janeiro, Zip Code 21941-
909, Brazil.
Electronic Supplementary Information (ESI) available: Control experiments data,
copies of 1H NMR, 13C NMR, and IR spectra for all compounds, theoretical
calculations data including imaginary frequencies, intrinsic reaction coordinates,
electronic energies, enthalpies, and Gibbs free energies, and coordinates of
optimized stationary points. See DOI: 10.1039/x0xx00000x
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indicating that this sulfur intermediate could beVitehweArtpicrleimOnalirnye
DOI: 10.1039/D0OB01149E
source of the -SCH3 group.
Our investigation raised with an initial evaluation of the
viability of the methylthiolation reagent (Table 1). When
chalcone in the absence of the sulfur reagent was evaluated
(Entry 1), only traces of the product were detected. An increase
to 13% conversion was achieved by employing the
(methylthio)methyl 4-chlorobenzoate reagent (Entry 2),
suggesting that this compound can act as sulfur source. Further
optimization was carried out by adding sodium acetate salt,
resulting in a slight increase in the conversion (Entry 3). Finally,
the use of 5 mol % of the camphorsulfonic acid (CSA)
organocatalyst drastically enhanced product formation,
affording the best overall result (96% conversion – Entry 7).
Scheme 1. Methylthiolation methodologies using in situ and ex-
situ generated methanethiol as a key intermediate.
Table
1. Optimization of the methylthiolation reaction
employing benzoic acid derivatives.
Over the past decades, DMSO has been largely employed as
reaction solvent, due to its physical and chemical properties.
More recently, it has also emerged as a potential reagent in
organic synthesis.19–21 In this context, in 2017, our research
group developed an innovative methodology for
methylthiolation
of
electrophilic
carbons
using
dimethylsulfoxide as sulfur source.22 An intermediate was
trapped by the use of palmitic acid and it was proposed that it
could play a key role in the reaction mechanism (Scheme 2A).
Sulfur
reagent
Sodium
acetate
CSA
Time
(min)
Entrya
Conversionb
(mol%)
We then envisioned that the direct use of this thioether
derivative could have a potential applicability as a new
methylthiolating reagent rather than methanethiol. In the
present article, we present, a novel methylthiolating method
that, differently from previously reported reagents, is easy to
handle, not inflammable and not toxic. In this low cost,
transition-metal-free methodology, the sulfur reagent was
employed directly at the beginning of the reaction (Scheme 2B)
or formed in the reactive environment from DMSO.
(mmol)
(mmol)
1
2
3
4
5
6
7
-
-
-
-
-
-
5
5
5
5
20
30
30
30
30
30
30
Traces
13%
19%
71%
81%
88%
96%
2d (0.2)
2d (0.2)
2a (0.2)
2b (0.2)
2c (0.2)
2d (0.2)
0.2
0.2
0.2
0.2
0.2
a In all entries 0.2 mmol of chalcone was used. b Measured
from 1H NMR analysis of the crude reaction mixture.
Next, aiming to find the best general methylthiolating
reagent, the electronic effect of the substituent group on the
aromatic ring was evaluated. It was possible to observe that the
electron donor 4-OMe (Entry 4) group presented lower
conversion, while 3,4,5-OMe substituent (Entry 6) revealed an
improvement in conversion to 88%. The substituent that
presented the best conversion was 4-Cl (Entry 7). It is also
important to mention that no reaction occurs when oil bath
heating was employed instead of microwave irradiation.
Scheme 2. A) Isolation of a thioether derivative from palmitic
acid; B) Direct use of a thioether derivative as a methylthiolation
reagent.
Motivated by this promising initial result, we attempted to
realize the methylsulfenylation reaction employing different
substituted chalcones and acyl ester derivatives as substrates
(Scheme 3). The 1,4-addition products were successfully
Results and discussion
Due to the isolation of a neutral and stable sulfur
intermediate in our previous study,22 we envisioned that this
compound could act as a methylthiolating reagent. In addition,
the potassium trichloroacetate salt (KTCA) and acetic acid were
thought to be crucial for the in situ intermediate formation,
synthesized (3a-3l)and both electron donating and withdrawing
groups were well tolerated in meta- and para-positions of the
aryl group of the chalcone substrate, affording the desired
derivatives in moderate to excellent yields (up to 85%). An
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exception was ortho-Cl derivative that led to a low yield (35%), it was isolated only in 13% yield. The methylthiolated products
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DOI: 10.1039/D0OB01149E
nucleophilic substitution
possibly due to the greater steric hindrance. It is important to were obtained through
a
mention that catalytic amount of CSA is required for the demonstrating that the synthesized sulfur reagent can be
reaction with chalcone derivatives. When acyl ester derivatives successfully used in different reaction types and tolerate
were used, instead of 1,4-addition product only substitution different substrates.
reaction adducts were obtained (5a-5e) in good yield (ranging
from 63 to 72%) and with moderate Z/E ratio. It is important to
mention that in absence of CSA, acid-sensitive substrates can be
converted into the methylthiolated products.
Scheme 4. Substitution reaction employing the sulfur reagent
(Method A). a Z double bond configuration determined by NMR
nOe analysis (see ESI).
As an attempt to better comprehend the reaction
mechanism, control experiments were carried out. The
application of the deuterated sulfur reagent in the optimized
reaction conditions led to the methylthiolated product with
75% deuterium incorporation, indicating that the sulfur moiety
is mostly derived from the reagent (Scheme 5A). The in situ
generation of the reagent was also analyzed employing 4-
chlorobenzoic acid, affording the desired products in moderate
to good yields when that simple method was applied. Sub-
stoichiometric amount of 4-chlorobenzoic acid was also
investigated and led to
a minor formation of the
methylthiolated product. These results strongly suggest that
the sulfur reagent acts as a nucleophilic methylthiolating
reagent (for full details concerning these control experiments
see the ESI file).
Scheme 3. Reaction scope employing the sulfur reagent
(Method A). a CSA required only for chalcone derivatives.
Although its isolation is harsher due to the low boiling point of
this reagent, associated with the high temperatures reached
during microwave irradiation, the in situ formation of sulfur
intermediate from acetic acid is expected. Thus, we carried out
deuterium incorporation experiments aiming to generate this
reagent in situ. First, a control experiment using 3.2 equiv. of
deuterated sulfur reagent gave the corresponding product in
97% conversion and with 75% D-incorporation without acetic
acid (Scheme 5A). Competition between D-reagent and H-
reagent corroborates the reagent formed in situ, showing a
huge difference of D-incorporation depending on the reaction
condition (Scheme 5B and 5C). As a result, in both cases for
which an acyl ester substrate was considered, the in situ
The methylthiolation reaction of Morita-Baylis-Hillman
(MBH) acetates (compounds 4a-g) is known to undergo
isomerization during microwave irradiation and leads to the
desired methylthiolated products in low yields (only two
examples).22 Attempting to solve this problem, we prepared
MBH acetates bearing electron donating and withdrawing
groups (Scheme 4). Surprisingly, under the optimized reaction
conditions no isomerization was observed and a scope with a
variety of substituents was accessed (5a-5g) in moderate to
good yields. Moreover, groups such as p-Br, p-Cl and p-F as well
as the strong electron-donating group p-OMe, provided the
desired products in good yields (up to 82%). On the other hand,
the m-NO2 group led to a considerably lower yield (50%).
Although a derivative bearing a nitrile group could be prepared,
generated reagent led to
a higher incorporation ratio,
confirmed by 1H NMR of the crude reaction mixture.
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DOI: 10.1039/D0OB01149E
Scheme 5. Competition experiments between previously added
and in situ generated reagent.
We then turned our attention into in situ generation of the
acetic acid reagent, (methylthio)methyl acetate, into
a
methylthiolation scope. It was observed a good conversion for
both acyl ester derivatives and MBH acetates as substrates. On
the other hand, when chalcones were used low conversions
were detected. In order to attain better yields for chalcones
employing this methodology, the acetic acid must be
substituted by a more acidic reagent, such as 4-chlorobenzoic
acid, for an adequate activation of the substrate (products 3d
and 3e were successfully prepared through this protocol in,
respectively, 52% and 88% yield – full details are available in the
ESI file). A scope was then prepared employing this alternative
methodology, leading to the desired compound in moderate to
excellent yields (Scheme 6). This method allows the
methylthiolated product to be accessed with a good Z/E ratio
without the previous reagent preparation step, simplifying the
reaction conditions. When different aryl substituted groups
were evaluated, it was found that the methodology tolerated
well meta-, para- and even sterically bulky ortho-substituents
(with up to 97% yield). Noteworthy, both electron donating and
withdrawing groups, such as p-Me and m-OMe, led to high
yields.
Scheme 6. Reaction scope employing the in situ generated
reagent (Method B).
To illustrate the synthetic utility of the synthesized
products, we then performed two reactions aiming to transform
the sulfide into sulfoxide and sulfone groups (Scheme 7). To this
purpose the methylthiolated product (5b and 5c) were readily
oxidized using H2O2 to give the methylsulfoxide MBH derivative
(
6b) in 75% yield. The oxidation by using an excess of m-CPBA
generated the MBH methylsulfone derivative 6a in 89% yield.
Scheme 7. Oxidation of methylthiolated MBH derivative
products.
We then turned our attention towards the study of the
mechanism involved in the methylthiolation reagent formation.
To this purpose, theoretical calculations employing the Density
Functional Theory (DFT) were carried out for a sequence of
plausible reaction intermediates and transition states (full
details concerning the calculations are available in the ESI). This
proposed reaction mechanism is in line with control
experiments that revealed that both acetic acid or 4-
chlorobenzoic acid and sodium acetate are required for the
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formation of (methylthio)methyl acetate or (methylthio)methyl intermediates and transition states for the pathway employing
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DOI: 10.1039/D0OB01149E
4-chlorobenzoate, respectively.
acetic acidis presented in Figure 2.
The proposed mechanism is shown in Figure 1 and initiates
with the proton transfer between the acid and
dimethylsulfoxide, resulting in a positively charged sulfur
species that is highly susceptible to the nucleophilic attack of an
acetate or a 4-chlorobenzoate molecule (that can be either the
one formed as side product during the proton transfer step or
from the sodium acetate initially added), affording the
sulfurane intermediate 7. This proton transfer was found to
take place without a transition state (confirmed by a relaxed
scan analysis - data available in the ESI file) and is the rate-
limiting step with a reaction ΔG of 25.46 kcal mol-1 for acetic
acid or 19.63 kcal mol-1 when employing the more acidic 4-
chlorobenzoic acid. It is also worth mentioning that although a
considerable amount of energy is required for the acid-base
reaction between DMSO and the acid, the use of an excess of
acid and of microwave irradiation at 140 °C makes it more likely
to occur. Once the proton is transferred, the intermediate is
immediately trapped by an acetate or benzoate molecule,
avoiding the thermodynamically favored return into the acid
and DMSO. This suggests that the role of sodium acetate could
Figure 2. Optimized geometries of the reaction intermediates
and transition states for the reagent formation employing acetic
acid.
Next, the methylthiolation mechanism was also
investigated (Figure 3). A chalcone was chosen as substrate for
the calculations. The proposed mechanism initially involves an
acid-base reaction between the chalcone substrate and acetic
or 4-chlorobenzoic acid, resulting in a more electrophilic
Michael acceptor. This step is followed by the 1,4-addition of
the methylthiolation reagent, with the formation of a positively
charged sulfur intermediate (10). The formation of this
intermediate is endothermic, requiring 7.53 or 6.12 kcal mol-1,
and presents a reaction barrier (TS3) of 9.79 or 7.72 kcal mol-1.
Finally, an acetate or 4-chlorobenzoate molecule attacks the
reagent carbonyl moiety, with formation of formaldehyde, an
anhydride and the desired Michael-type adduct (11). Although
an appreciable energy barrier was found for the transition state
(TS4) involved in this step, it is accessible in the reaction
conditions (microwave irradiation at 140 °C). Most important,
the formation of two volatile side-products makes the reaction
entropically favored, especially after product tautomerization,
resulting in a reaction ΔG of -25.30 or -20.66 kcal mol-1.
be related to favoring the formation of the sulfurane
7. It is
worth mentioning that presents a bipyramidal trigonal
7
geometry, in which the hydroxyl and acetate groups are
positioned in the apical positions.
Figure
methylthiolation reagent
1. Reaction pathway for the formation of the
9
.
The reaction proceeds with intermediate
water, a process that is assisted by an acid molecule and
culminates with the formation of the sulfonium ylide . This
7 eliminating
8
step has an energy barrier of 15.66 or 19.52 kcal mol-1, perfectly
accessible at 140 °C, especially if water is removed by
evaporation, in which an increase in entropy would greatly
favor the reaction. Finally, a Pummerer reaction takes place,
affording the methylthiolation reagent 9. This step proceeds
almost barrierless and involves a five-membered ring transition
state (TS2), in accordance with previous studies involving this
transformation.23 It is also worth mentioning that this step is
greatly thermodynamically favored, with a ΔG of -47.47 or -
44.40 kcal mol-1. A general overview of the optimized
Figure 3. Reaction pathway for the methylthiolation reaction of
chalcones.
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Method B: In a dried 50 mL flask, 0.2 mmol of acyl VeieswteArrtioclre OMnBlinHe
acetate, 0.2 mmol of sodium acetate salt and additive of MS 4Å were
DOI: 10.1039/D0OB01149E
added with 1 mL of DMSO. The reaction mixture was heated in a
microwave reactor (50W, reflux mode) for 30 minutes. When the
temperature reached 100 °C (approximately 2 minutes after the
reaction start), 1.0 mmol of acetic acid was added.
Procedure for the preparation of sulfone: To a magnetically stirred
solution of the methylthiolated product (0.13 mmol) in 10 mL of
dichloromethane was added m-CPBA (0.58 mmol) at 0 °C for 30
minutes. The product was purified through extractions with an
aqueous solution of NaHCO3 (0.1 mol L-1) and dichloromethane
(DCM). The organic phase was treated with anhydrous Na2SO4 and
concentrated under reduced pressure.
Procedure for the preparation of sulfoxide: To a magnetically stirred
solution of the methylthiolated product (0.11 mmol) in 20 mL of
dichloromethane was added H2O2 (30 wt%) at 75 °C for 1 hour. The
reaction mixture was extracted with H2O/Dichloromethane (DCM)
and concentrated under reduced pressure.
Computational details: All calculations were performed using the
Gaussian09 package.30 The structures, molecular complexes (MCs)
and transition states (TSs) were optimized at the gas phase
employing the M06-2X functional31 and the 6-31G(d,p) basis set. The
vibrational analysis was then performed to ensure the identity of all
stationary points and to determine the thermal corrections to the
Gibbs free energy at 413.15 K (140 °C) and 1 atm. Transition states
were optimized employing the Berny algorithm or the QST2 method
and confirmed to have only one imaginary frequency. Intrinsic
Reaction Coordinates were also found for each transition state and
are available below.
Experimental
General Remarks: All purchased chemicals were employed without
further purification. Thin-layer chromatography (TLC) was performed
on TLC plates (silica gel 60 F254) and visualized by a UV lamp, column
chromatography was performed using 230−400 mesh silica gel.
Yields refer to chromatographically purified and spectroscopically
pure compounds. The 1H and 13C NMR spectra were recorded at 500
and 125 MHz, respectively. Chemical shifts for 1H and 13C NMR were
reported as δ (parts per million) relative to the signals of CHCl3 at
7.26 ppm (singlet) and 77 ppm (triplet), respectively. Chemical shifts
are reported employing the following peak abbreviation pattern: br,
broad, s, singlet, d, doublet, dd, double doublet, t, triplet, dt, double
triplet, q, quartet, pent, pentet, sext, sextet, and m, multiplet. High-
resolution mass spectra were acquired in the positive-ion mode using
a time-of-flight (TOF) mass spectrometer equipped with an MALDI
source.
General procedure for the preparation of Morita-Baylis-Hillman
adducts:
A
solution of aldehyde (0.5 mmol) and 1,4-
diazabicyclo[2.2.2]octane (0.5 mmol) in ethyl acrylate or acrylonitrile
(3.0 mmol) was stirred for 7 days. The crude reaction mixture was
extracted with chloroform (2x 10 mL); the organic phase was dried
with anhydrous Na2SO4 and concentrated under reduced pressure.
The residue was purified through column chromatography (elution:
hexanes to hexanes/acetate 10%).24,25
General procedure for the preparation of chalcones: A solution of
ketone (1 mmol) and sodium hydroxide (1.3 mmol) in a mixture of
water and ethanol (7.5:2.5 mL) was stirred at 0 °C for 10 minutes.
Then the aldehyde (1.0 mmol) was added dropwise to the solution.
The reactional mixture was extracted with H2O/Dichloromethane
(DCM); the organic phase was dried with anhydrous Na2SO4 and
concentrated under reduced pressure. The product was purified by
recrystallization at 70 °C with hexane/acetate.26-29
General procedure for the preparation of Morita-Baylis-Hillman
acetates: To a magnetically stirred solution of Morita-Baylis-Hillman
adduct (1.0 mmol) in 2 mL of dichloromethane were added
triethylamine (1.3 mmol), acyl chloride (1.2 mmol) and 4-
dimethylaminopyridine (10 mol%) at room temperature for 28 hours.
The reaction mixture was extracted with H2O/Dichloromethane
(DCM).
General procedure for the preparation of the methylthiolation
reagents: In a dried 50 mL flask, potassium trichloroacetate (1.2
mmol) and additive of MS 4Å were added with 3 mL of DMSO. The
reaction mixture was heated in a microwave reactor (50W, reflux
mode) for 20 minutes. When the temperature reached 100 °C,
benzoic acid derivative (0.8 mmol) and acetic acid (1.2 mmol) were
added.
General procedure for the preparation of compounds 3a-3l: In a
dried 50 mL flask, 0.2 mmol of chalcone, 0.2 mmol of
methylthiolation reagent, 5 mol% of CSA, 0.2 mmol of sodium
acetate salt and additive of MS 4Å were added with 1 mL of DMSO.
The reaction mixture was heated in a microwave reactor (50W, reflux
mode) for 30 minutes. The reaction mixture was extracted with
H2O/Dichloromethane (DCM).
General procedure for the preparation of compounds 5a-5o:
Method A: In a dried 50 mL flask, 0.2 mmol of acyl ester or MBH
acetate, 0.2 mmol of methylthiolation reagent, 5 mol% of CSA, 0.2
mmol of sodium acetate salt and additive of MS 4Å were added with
1 mL of DMSO. The reaction mixture was heated in a microwave
reactor (50W, reflux mode) for 30 minutes.
Next, for the determination of the electronic energy at the desired
level of theory, single-point energy calculations were subsequently
carried out using the previously optimized geometries at the M06-
2X-D3/6-31++G(d,p) level of theory and the Solvation Model Based
on Density (SMD) for dimethylsulfoxide32. The Gibbs Free Energy of
each structure was then calculated using equation 1,33,34 in which the
terms are, respectively, the Electronic Energy, the solvation Gibbs
Free Energy, and the thermal correction to enthalpy and entropy.
푮°풔풐풍 = 푬푮풂풔 + 푮푺풐풍풗 + 푮°푻
(ퟏ)
Conclusions
In conclusion, a new methylthiolation method which tolerates a
variety of substrates has been presented. In contrast with
methanethiol, the commonly employed methylthiolation
reagent, this methodology is safer. This method was
successfully applied to the methylthiolation of a wide scope of
chalcones, acyl ester derivatives and Morita-Baylis-Hillman
acetates with good group tolerance, allowing the access to the
desired products in moderate to excellent yields. Theoretical
studies were carried out for the better comprehension of the
formation of the sulfur reagent, with the data suggesting a
sulfurane and a sulfonium ylide as key intermediates. A
Pummerer rearrangement step is also crucial for the formation
of the reagent. The methylsulfenylation reaction was also
investigated and suggests the nucleophilic attack of the sulfur
reagent to the Michael acceptor, followed by an entropically
favored base-mediated step. The developed methodology is
transition metal-free, permits the methylthiolated products to
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23 M. Patil, C. Loerbroks, W. Thiel. Org. Lett., 2013, 15, 1682-
be accessed in a short reaction time and with tolerance to acid-
sensitive substrate.
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1685.
DOI: 10.1039/D0OB01149E
24 K. Morita, Z. Suzuki, H. Hirose. Bull. Chem. Soc. Jpn., 1968, 41
2815–2815.
,
25 K. H. Kim, S. H. Kim, H. J. Lee, J. N. Kim. Adv. Synth. Catal.,
2013, 355, 1977–1983.
Conflicts of interest
There are no conflicts to declare.
26 R. Bashary, G. L. Khatik. Bioorganic Chem., 2019, 82, 156–162.
27 N. Parveen, R. Saha, G. Sekar. Adv. Synth. Catal., 2017, 359
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Organic & Biomolecular Chemistry
Page 8 of 8
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DOI: 10.1039/D0OB01149E
A novel nucleophilic methylthiolation method is described. This process allows a diversity of either
conjugate additions or substitutions reactions in order to incorporate CH3S- group into activated carbons.