Direct Monofluoromethylthiolation with S-(Fluoromethyl) Benzenesulfonothioate

Article abstract of DOI:10.1002/anie.201705633

An electrophilic shelf-stable monofluoromethylthiolating reagent S-(fluoromethyl) benezenesulfonothioate (1) was developed. In the presence of a copper catalyst, reagent 1 coupled with a variety of aryl boronic acids to give the corresponding monofluoromethylthiolated arenes in high yields. In addition, addition of reagent 1 to alkyl alkenes in the presence of a silver catalyst gave alkyl monofluoromethylthioethers in high yields.

Full text of DOI:10.1002/anie.201705633

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Direct Monofluoromethylthiolation with S-(fluoromethyl)
benzenesulfonothioate
Authors: Qunchao Zhao, Long Lu, and Qilong Shen
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201705633
Angew. Chem. 10.1002/ange.201705633
Link to VoR: http://dx.doi.org/10.1002/anie.201705633
http://dx.doi.org/10.1002/ange.201705633

10.1002/anie.201705633
Angewandte Chemie International Edition
COMMUNICATION
Direct
Monofluoromethylthiolation
with
S-(fluoromethyl)
benzenesulfonothioate
Qunchao Zhao,[a] Long Lu*[a] and Qilong Shen*[a]
Abstract: An electrophilic shelf-stable monofluoromethylthiolating
reagent S-(fluoromethyl)benezene sulfonothioate 1 was developed.
In the presence of a copper catalyst, reagent 1 coupled with a
variety of aryl boronic acids to give the corresponding
monofluoromethylthiolated arenes in high yields. In addition, addition
of reagent 1 to alkyl alkenes in the presence of a silver catalyst gave
alkyl monofluoromethylthioethers in high yields.
Figure 2. Approaches for the preparation of monofluoromethylthioethers.
Recently, the fluoroalkylthio groups including trifluoromethylthio
(-SCF3),[1] difluoromethylthio (-SCF2H),[2-3] and functionalized
difluoromethylthio group (-SCF2FG)[2,4] have attracted great
interests from both academics and pharmaceutical industry,
mainly due to their high yet tunable lipophilicity that may
dramatically improve the drug molecule’s pharmacokinetic
properties.[5] Consequently, in the past 5 years, new reagents
and methods that are capable of efficiently direct incorporation
of the fluoroalkylthio groups into small molecules have been
explosively developed.[1] Nevertheless, the missing essential
piece of this powerful fluoroalkylthiolating portfolio is the tools for
direct introduction of the monofluoromethylthio group (-SCH2F),
which is the key component in the anti-inflammatory drug
Fluticasone and its derivative Fluticasone propionate (Fig. 1).[7]
(Fig. 2, Eqs. 2-3).[12] However, these approaches generally
require the preformation of thiols or methyl thioether, which is an
easy task for simple substrates but might be problematic for
more complicated molecules. Thus, new approaches that could
easily and directly incorporate the monofluoromethylthio group
are urgently needed and remain a significant challenge.
Our group has recently reported several shelf-stable yet high
reactive electrophilic trifluoromethylthiolating,[13] difluoromethyl-
thiolating[3b-c,h]
or
ethoxycarbonyldifluoromethylthiolating[4c]
reagents that were able to react with a broad substrate scope
under mild conditions. As an extension of our interests in the
development of electrophilic fluoroalkylthiolating reagents, herein,
we
disclose
the
preparation
of
S-
(fluoromethyl)benezenesulfonothioate 1, a powerful monofluoro-
methylthiolating reagent that reacted with various aryl boronic
acids and olefins under mild conditions to give the
corresponding monofluoromethylthiolated compounds in high
yields.
To
the
best
of
our
knowledge,
S-
(fluoromethyl)benezenesulfonothioate represents the first
monofluoromethylthiolating reagent that could directly deliver the
monofluoromethylthio group into small molecules.
Figure 1. Drug molecules with monofluoromethylthio group.
S-(Fluoromethyl)benezenesulfonothioate 1 could be easily
synthesized in 87% yield on a 9.1 g scale by treatment of easily
available PhSO2SNa[14] with CH2FI[15] in DMF after 2.0 h at room
temperature. Alternatively, reagent 1 can also be prepared in
59% yield on a 6.1 g scale by direct nucleophilic substitution of
PhSO2SNa with CH2FCl after 12 h at 80 oC (Eq. 1). S-
(Fluoromethyl)benezenesulfonothioate 1, which is a colorless
liquid with a boiling point at 195 oC, was fully characterized by 1H,
Previously, preparation of monofluoromethyl thioethers was
reported to be mainly via an indirect approach that used the
thiolate or methylthioether as the starting materials. For example,
nucleophilic substitution of an appropriate thiolate with
chlorofluoromethane generated monofluoromethyl thioethers in
good yields (Fig. 2, Eq. 1).[8] Alternatively, monofluoromethyl
thioether can also be accessed by fluorination of methyl
thioether with an electrophilic fluorinating reagents such as N-
fluoro-2,4,6-trimethylpyridinium triflates,[9] DeoxoFluor[10] or F-
TEDA-BF4,[11] or by first electrophilic chlorination of the
corresponding methyl thioether, followed by halogen exchange
13C,
and
19F
NMR
spectroscopies.
S-
(fluoromethyl)benezenesulfonothioate
1
is not sensitive to
moisture, air or light. No detectable decomposition was
observed after six-month storage on shelf at ambient
temperature.
[a]
Q. Zhao, Prof. Dr. L. Lu, Prof. Dr. Q. Shen
Key Laboratory of Organofluorine Chemistry
Shanghai Institute of Organic Chemistry
University of Chinese Academy of Sciences
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032
lulong@sioc.ac.cn; shenql@sioc.ac.cn
With the reagent in hand, we first chose the reaction of
reagent 1 with 4-biphenyl boronic acid as a model reaction to
optimize the reaction conditions. Our initial efforts using a
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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10.1002/anie.201705633
Angewandte Chemie International Edition
COMMUNICATION
Scheme 1. Optimization of the conditions for Cu-catalyzed
Scheme 2. Scope for the Cu-catalyzed monofluoromethyl-
thiolation of aryl boronic acids.a,b
monofluoromethylthiolation of aryl boronic acid.a,b
[a] Reaction conditions: 4-biphenyl boronic acid (0.2 mmol), reagent 1 (0.3
mmol), copper catalyst (10 mol %), base (2.0 mmol) in solvent (2.0 mL) at
room temperature for 12 h; [b] Yields were determined by 19F NMR analysis of
the crude reaction mixture with PhCF3 as internal standard; [c] 5.0 mol % of
CuSO4 was used; [d] 1.5 equiv of NaHCO3 was used; [e] 1.2 equiv of NaHCO3
was used; [f] 1.0 equiv of NaHCO3 was used.
[a] Reaction conditions: aryl boronic acid (0.5 mmol), reagent 1 (0.75 mmol),
CuSO4 (5.0 mol%), NaHCO3 (0.75 mmol, 1.5 equiv.) in MeOH (5.0 mL) at
room
temperature
for
12
h;
[b]
Isolated
yields;
[c]
The
monofluoromethylthioether was further oxidized using mCPBA (2.0 mmol, 4.0
equiv.) in CH2Cl2 at 0 oC for 1.0 h and the yields of the thioethers were
determined by 19F NMR spectroscopy using PhCF3 as an internal standard..
combination of copper salt with 2,2-bipyridine in the presence of
a variety of bases at different temperatures, conditions that have
previously been successfully applied for the coupling of aryl
boronic acids with electrophilic trifluoromethylthiolation[13a] or
difluoromethylthiolation,[13d] resulted in less than 10% yields.
of aryl boronic acids, and the results were summarized in
Scheme 2. In general, reactions of aryl boronic acids with both
electron-withdrawing and electron-donating substituted groups
occurred in high yields. However, it was found that some
(monofluoromethyl)arylthioethers, especially those with electron-
donating groups, easily underwent defluorination at room
temperature.[18] These compounds were then further oxidized by
mCPMA to the corresponding monofluoromethyl-substituted
sulfoxides (Scheme 2, 2d-f, 2q). Hindered aryl boronic acids
with an ortho-substituted group also reacted to give the
corresponding (monofluoromethyl)arylthioethers in high yields
(Scheme 2, 2h-o). Because of the weak basicity of NaHCO3,
challenging functionalized aryl boronic acids were compatible
with the reaction conditions. Reactions of aryl boronic acids with
functional groups such as aldehyde, enolizable ketone, ester,
amide, fluoride, chloride, bromide or iodide, sulfonyl, nitro and
cyano group occurred in good yields (Scheme 2, 2a-d and 2g-p).
Notably, the reaction is scalable. Reaction of 2-4-dichlorophenyl
boronic acid with reagent 1 on a 6.0 mmol scale under the
[16]
Interestingly, reaction using 10 mol% CuSO4 as the catalyst,
2.0 equivalents of NaHCO3 as the base and methanol as the
solvent occurred in full conversion after 12
h at room
temperature to give the corresponding (4-monofluoromethyl)-
1,1’-biphenyl thioether in 81% yield, as determined by 19F NMR
spectroscopy (Scheme 1, entry 1). Reactions using other
copper(II) salts such as Cu(OAc)2, CuBr2 or CuF2 occurred in
slightly lower yields, while the same reaction using copper(I) salt
such as CuI was completely ineffective at all (Scheme 1, entries
2-5). The choice of bases is important for the reaction. When
Na2CO3 was used as base, the yield of the product decreased to
50% (Scheme 1, entry 6). However, reactions using stronger
bases such as K2CO3 or Cs2CO3 were completely shut down
(Scheme 1, entries 7-8). Likewise, other bases that were
generally used to activate aryl boronic acids in cross-coupling
reactions such as CsF or KF were ineffective (Scheme 1, entries
9-10). It was also determined that the solvent was crucial for the
reaction. The formation of the desired monofluoromethylthiolated
arene was not observed when the reactions were conducted in
other alcohol solvents such as EtOH[17] or CF3CH2OH, or other
common solvents such as DMF, DMSO, THF, CH2Cl2 or toluene.
Finally, after further investigation of the amount of the catalyst
and the base, it was found that reaction conducted with 5.0
mol% CuSO4 and 1.5 equivalents of NaHCO3 were equally
effective (Scheme 1, entries 18-21).
standard
conditions
gave
the
corresponding
2,4-
dichlorophenylmofluoromethylthioether 2j in 81% isolated yield
(Scheme 2, 2j).
Having successfully developed a method for the introduction
of the monofluoromethylthio group onto sp2-hybridized aromatic
compounds, we turned our attention to investigate the method
that could introduce the monofluoromethylthio group onto sp3-
hybridized carbons. It was found that reactions of unactivated
alkenes with reagent 1 occurred smoothly under the slightly
modified conditions that were developed previously for the
addition of PhSO2SCF2H to alkenes.[3h] A variety of unactivated
alkenes reacted with reagent 1 to give the corresponding alkyl
On the basis of the results summarized in Scheme 1, the
reaction conditions of entry 19 in Scheme 1 were chosen to
study the scope of CuSO4 catalyzed monofluoromethylthiolation
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10.1002/anie.201705633
Angewandte Chemie International Edition
COMMUNICATION
Scheme 3. Scope for the Ag-catalyzed addition of reagent 1
corresponding product 3h in almost quantitative yield (Scheme 3,
3h).
with alkenes.a,b
To probe whether the reaction proceeds via a radical pathway,
we conducted some sets of experiment. It was found that the
reaction was completely inhibited by the addition of TEMPO and
partially inhibited by the addition of dibutylhydroxytoluene (BHT)
and 1,4-dinitrobenzene. Furthermore, the ring-opening product
was formed for the classic clock experiments (please see the
supporting information for details). These experiments suggest
that the addition of S-(fluoromethyl)benezene sulfonothioate 1 to
alkene proceeds via a radical-chain pathway.
Finally, the conditions for monofluoromethylthiolation of aryl
boronic acids or alkenes were applicable to structurally more
complicated compounds or drug molecules to make
monofluoromethylthio-substituted derivatives. For example,
monofluoromethylthiolated derivative of diacetone-D-glucose 4
was prepared in 74% yield from the corresponding boronic acid
4a, under the standard conditions (Fig. 3, Eq. 1). Likewise, the
aryl chloride bond of the cholesterol and triglycerides-lowering
drug Fenofibrate 5a[19] was easily converted to aryl boronic acid
5b by palladium-catalyzed coupling with (HO)2B-B(OH)2,
followed by in situ esterification with pinacol and hydrolysis at
room temperature. Treatment of the resulting boronic acid
derivative of Fenofibrate 5b with PhSO2SCH2F under the
optimized conditions afforded the monofluoromethylthiolated
compound 5 in 61% yield (Fig. 3, Eq. 2). Similarly, addition of
reagent 1 to Equipoise 6a,[20] a veterinarian steroid, in the
presence of
a
silver-catalyst and K2S2O8 formed the
[a] Reaction conditions: alkene (0.5 mmol), reagent 1 (0.6 mmol), AgNO3 (10.0
mol%), K2S2O8 (0. 5 mmol, 1.0 equiv.) in NMP/H2O (v/v =1:1, 2.0 mL) at 25 oC
for 12 h; [b] Isolated yields.
corresponding monofluoromethylthiolated product 6 in 84% yield.
In summary, we have successfully developed the first
electrophilic
monofluoromethylthiolating
reagent
S-
(fluoromethyl)benezenesulfonothioate 1 which can be easily
synthesized in high yields from easily available starting materials.
In the presence of a copper catalyst, reagent 1 was able to
couple with a variety of aryl boronic acids to construct the
C(sp2)-SCH2F bond in high yields under mild conditions. In the
presence of a combination of silver salt and an oxidant, reagent
1 added to non activated alkenes efficiently to form the
corresponding C(sp3)-SCH2F bonds in high yields. Studies on
further expanding the scope of the reagent 1 are undergoing
currently in our laboratory.
Acknowledgements
The authors gratefully acknowledge the financial support
from National Natural Science Foundation of China
(21625206, 21632009, 21372247, 21572258, 21572259,
21421002) and the Strategic Priority Research Program of the
Figure 3. Monofluoromethylthiolation of complicated drug-like molecules.
Chinese Academy of Sciences (XDB20000000)
.
monofluoromethylthioethers in high yields. Common functional
groups such as fluoride (3i), chloride (3n), bromide (3o and 3q),
iodide (3a), aldehyde (3p), enolizable ketone (3c), ester (3b, 3h-
o), amide (3r), or sulfonyl group (3d) were all compatible,
indicating the generality of the reaction conditions. Likewise,
substrates with heteroaryl moieties such as indolyl, furyl or
thienyl group also reacted to give the corresponding products in
high yields (Scheme 3, 3j-l). Furthermore, reaction of pent-4-en-
1-yl 4-methoxybenzoate with reagent 1 conducted on a 5.0
mmol scale under the optimized conditions afforded the
Keywords: fluorine • monofluoromethylthio • electrophilic •
boronic acid • alkene
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10.1002/anie.201705633
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COMMUNICATION
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[17] The mechanism of the Cu-catalyzed monofluoromethylthiolation of aryl
boronic acids remains elusive at this stage. Initial mechanistic studies
disclose that mixing 4-fluorophenyl boronic acid and NaHCO3 in MeOH
resulted in the formation of anionic [4-F-C6H5-B(OMe)2(OH)]﹣ species,
which was assigned by 19F and 5B NMR spectroscopy and mass
spectroscopy. However, no such species was observed when the same
reaction was conducted in EtOH (please see the supporting information
for details).
[18] (Monofluoromethyl)arylthioethers
with
electron-donating
groups
underwent defluorination at room temperature. For example, p-tert-
butylphenyl(monofluoromethyl)thioether was transformed into bis((4-
(tert-butyl)phenyl)thio)methane in 47% yield when it was left on bench
at room temperature for 2 h after normal workup (please see supporting
information for details about the mechanism of this transformation).
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[20] https://www.evolutionary.org/equipoise-boldenone-undecylenate
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10.1002/anie.201705633
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
An
electrophilic
shelf-stable
Qunchao Zhao, Long Lu* and Qilong
Shen*
monofluoromethylthiolating
reagent S-(fluoromethyl)benezene
sulfonothioate 1 was developed.
Reagent 1 coupled with a variety
Page No. – Page No.
Direct Monofluoromethylthiolation
with S-(fluoromethyl) benzene
sulfonothioate
of
aryl
boronic
acids
or
unactivated alkenes to give the
corresponding
monofluoromethylthiolated arenes
and alkanes in high yields.
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