Acid-Mediated Sulfonylthiolation of Arenes via Selective Activation of SS-Morpholino Dithiosulfonate

Article abstract of DOI:10.1021/acs.orglett.0c04289

A trifluoroacetic-acid-mediated desulfurilative sulfonylthiolation of arenes using SS-morpholino dithiosulfonate is described. This system is based on selective activation of the morpholino group over the tosyl group of the doubly transformable sulfur surrogate. Mechanistic studies suggested that the reaction proceeds through electrophilic aromatic substitution followed by sulfur extrusion. The wide substrate scope of this reaction and the transformability of the resulting thiosulfonates enable expeditious access to divergent multifunctionalized sulfides.

Full text of DOI:10.1021/acs.orglett.0c04289

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Letter
Acid-Mediated Sulfonylthiolation of Arenes via Selective Activation
of SS-Morpholino Dithiosulfonate
Kazuya Kanemoto,* Koudai Furuhashi, Yoshitsugu Morita, Teruyuki Komatsu, and Shin-ichi Fukuzawa*
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ABSTRACT: A trifluoroacetic-acid-mediated desulfurilative sulfo-
nylthiolation of arenes using SS-morpholino dithiosulfonate is
described. This system is based on selective activation of the
morpholino group over the tosyl group of the doubly transformable
sulfur surrogate. Mechanistic studies suggested that the reaction
proceeds through electrophilic aromatic substitution followed by
sulfur extrusion. The wide substrate scope of this reaction and the
transformability of the resulting thiosulfonates enable expeditious
access to divergent multifunctionalized sulfides.
romatic sulfides have a broad range of applications in
forming reactions that do not release toxic waste and
unpleasant odor, thiosulfonate synthesis via C−S bond
formation is rarely reported (Figure 1C),9,10 except via the
SN2 reaction.4d Herein we report the trifluoroacetic acid
(TFA)-mediated sulfonylthiolation of arenes using SS-
morpholino 4-toluene(dithioperoxo)sulfonate (7) entailing
the selective activation of the morpholino group over the
sulfonyl group and an unexpected desulfurization.
To examine the feasibility of selectively transforming the
leaving groups, we compared the reactivity of the sulfur-
bonded amino and sulfonyl groups. We performed a
competitive experiment for the C−S bond-forming reaction
using an equimolar mixture of sulfaniylamine 4 and
thiosulfonate 3c with anisole (1b) in the presence of TFA
(Figure 2A).8 As a result, sulfanyl amine 4 was completely
consumed to afford 4-methoxyphenyl 4-tolyl sulfide (5a) in
81% yield, and thiosulfonate 3c was recovered in 90% yield.
This result suggests that the amino group is selectively
activated over the sulfonyl group in the presence of a proton
source.
A
fields such as medicinal chemistry1 and materials science.2
The double C−S bond formation of doubly transformable
sulfur surrogates is a notable approach for efficient access to
aromatic sulfides bearing various combinations of substituents
(Figure 1A). This approach offers significant advances in the
conjugation of functional molecules for the assembly of hybrid
molecules3 or the facile preparation of sulfide libraries from
nonsulfur substrates.
Recently, electrophilic sulfur surrogates have attracted
increasing attention4,5 because they are transformable into
various organosulfur compounds without giving rise to catalyst
poisoning, nucleophilic side reactions, and unpleasant odors
due to the electron-withdrawing and masking effect of the
leaving group. Therefore, an electrophilic sulfide platform
bearing two leaving groups that are selectively transformable in
a sequential manner is highly sought-after (Figure 1B).
However, despite these potential advantages, only a few
examples of studies comparing the relative reactivity of leaving
groups with carbon nucleophiles are known.6,7 For example, N-
(chlorothio)imide,6a−c chlorothiocyanide,6d,e and N-
(thiocyanato)imide6f−j are known as doubly transformable
thiolating reagents. The applicability of these reagents is
limited because of the instability of chloro-containing reagents,
the limited transformation of organothiocyanide, and the
toxicity of the liberated cyanide.
On the basis of the results of this competition study, we
designed platform molecules 6 and 7 bearing morpholino and
tosyl groups on the sulfur and examined the reactivity thereof
in an electrophilic substitution reaction (Figure 2B).11 We
found that the treatment of S-morpholino 4-toluenethiosulfo-
nate (6) with anisole (1b) in the presence of TFA provided
the desired S-(4-methoxyphenyl) 4-toluenethiosulfonate (3b)
On the basis of the background and considering the high
stability of the S−SO2R bond, we envisaged that the selective
transformation of the S−NR2 bond over the S−SO2R bond is
possible via protonation (Figure 1D) due to (1) the hard and
basic character of the nitrogen atom, (2) the high reactivity of
the S−N+HR2 bond once activated,8 and (3) the stability of
the liberated ammonium salt.
Received: December 29, 2020
Published: January 29, 2021
In addition, despite the excellent transformability of the
resulting thiosulfonates4d,5 through a variety of C−S bond-
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On the basis of the initial experiment, we selected
dithioperoxosulfonate 7 as a sulfonylthiolating reagent because
of its favorable reactivity and availability13 compared with that
of 6 and then extensively screened the conditions for the
efficient synthesis of S-(4-methoxyphenyl) 4-toluenethiosulfo-
nate (3b) from anisole (1b) (Table 1). As a result, the desired
Table 1. Optimization of Reaction Conditions
a
entry
acid
solvent
yield (%)
b
1
2
3
4
5
6
7
8
TFA
TFA
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
toluene
benzene
THF
82
96
c
AcOH
TsOH
TfOH
AgOTf
FeCl3
N.D.
N.D.
N.D.
N.D.
N.D.
64
d
TFA
9
TFA
TFA
TFA
TFA
TFA
TFA
79
94
72
10
11
12
13
14
N.D.
N.D.
N.D.
Et2O
DMF
a
b
Yields were determined by NMR analysis, unless otherwise noted. 7
c
d
(1.0 equiv) was used. Isolated yield is shown. TFA (5.0 equiv) was
used.
Figure 1. Background and basic concept of this work.
thiosulfonate 3b was obtained in 96% yield when the reaction
was conducted with 1.1 equiv of 7 (entry 2). Interestingly, the
use of other acids instead of TFA proved ineffective (entries
3−7). This result indicated that the role of TFA was not only
as a proton source but also as a participant in the active
species.14 The desired product was obtained in lower yield
when the amount of TFA was reduced to 5 equiv (entry 8).
Using other solvents, including CHCl3, toluene, and benzene,
instead of CH2Cl2 lowered the yield (entries 9−14). Notably,
the entire experimental process was free from unpleasant
organosulfurous odors.
The optimized conditions (Table 1, entry 2) were
successfully applied to the p-toluenesulfonylthiolation of a
wide range of arenes with 7 (Figure 3) with complete
regioselectivity. Various arenes 1 bearing electron-donating
groups, including methoxy, methylthio, phenyloxy, phenylthio,
hydroxyl, and methyl, underwent p-toluenesulfonylthiolation
to afford S-aryl thiosulfonates 3d−j, leaving the said groups
intact. The p-toluenesulfonylthiolation of dopamine derivative
1k proceeded smoothly to afford the multisubstituted
thiosulfonate 3k in quantitative yield. Moreover, the reaction
of substituted naphthalenes also proceeded in good to
excellent yields, affording the corresponding thiosulfonates
3l−p. Notably, substrates containing an electron-withdrawing
ester moiety tolerated the reaction. In addition, the
sulfonylthiolation of heteroaromatic substrates, such as
thiophene, benzothiophene, and dibenzofuran, proceeded
smoothly to afford thiosulfonate 3q, 3r, and 3s in good yields.
Furthermore, the late-stage sulfonylthiolation of functional
molecules such as DTT (1t, conductive material), gemfibrozil
(hypolipidemic drug) methyl ester 1u, and metaxalone (1v,
Figure 2. Design of doubly transformable sulfur surrogate. (A)
Crossover experiment. (B) Comparison of sulfur reagents. Yields were
determined by NMR analysis.
in 67% yield. Surprisingly, the reaction of SS-morpholino 4-
toluene(dithioperoxo)sulfonate (7) under the same conditions
afforded the same product, whereas SS-(4-methoxyphenyl) 4-
toluene(dithioperoxo)sulfonate (8a) was not detected.12 The
reaction using di(4-toluenesulfonyl)sulfide (2) did not proceed
due to the low reactivity of the S−SO2R bond.
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Figure 4. Synthesis of diverse sulfides via the double C−S bond
formations of 7. (A) Conjugation of papaverine (1w) and glycine
imino ester 9. (B) Preparation of phenoxathiin derivative 5d via the
aryne reaction. (C) Sequential multisulfanylation of 1y. See the
Supporting Information for details.
(Figure 5). The reaction of anisole (1b) with 7 in the presence
of 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (TEMPO)
a
Figure 3. Substrate scope. Isolated yields are shown. Toluene was
b
used instead of CH2Cl2. TFA (5.0 equiv) was used.
muscle relaxant) afforded the corresponding thiosulfonates
3t−3v in good yield. It should be noted that all of the
transformations exclusively gave monothiolated products due
to the strong electron-withdrawing effect of the sulfonyl group.
This result is in contrast with some previously reported C−S
bond formations.15
As shown in Figure 1A, the wide substrate scope of the
sulfonylthiolation and the remarkable transformability of the
resulting thiosulfonate enable rapid access to divergent
combinations of aryl sulfides via double C−S bond formation
(Figure 4). For example, papaverine (1w, an antispasmodic
drug) and a glycine fragment were sequentially assembled into
platform molecule 7 to afford the hybrid molecule 5c in good
yield (Figure 4A).16 The rapid expansion of the ring system of
6-bromo-2-naphthol (1x) was also accomplished via TFA-
mediated sulfonylthiolation and subsequent C−S/C−O bond
formation with benzyne (Figure 4B).17,5e Furthermore, an
advantage of this direct mono C−S bond formation was
showcased by the sequential introduction of multiple different
sulfanyl groups on one molecule (Figure 4C).15 These results
clearly demonstrated the utility of platform molecule 7 for
combining nonsulfur carbon nucleophiles to afford function-
alized sulfides.
Figure 5. Mechanistic studies. (A) Sulfonylthiolation of anisole (1b)
in the presence of TEMPO. (B) Isolation of intermediate 8b before
desulfurization. (C) Desulfurization of 8b to 3y. aYields were
b
determined by NMR analysis. Isolated yield is shown.
did not significantly affect the formation of thiosulfonate 3b,
suggesting that radical intermediates are not involved (Figure
5A). Furthermore, treatment of 1,3,5-trimethoxybenzene (1y)
with 7 under standard conditions for 1 h afforded SS-aryl 4-
toluene(dithioperoxo)sulfonate 8b, the expected desulfuriza-
To gain insights into the mechanism of the TFA-mediated
sulfonylthiolation, we conducted several control experiments
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Figure 6. Calculated potential energy diagram (in kcal mol−1) obtained by the B3LYP/6-31+G(d,p) level of theory for the reaction of anisole (1b)
with SS-morpholino 4-toluene(dithioperoxo)sulfonate (7) to afford thiosulfonate 3b. Color code of atoms: hydrogen, white; carbon, gray; nitrogen,
blue; oxygen, red; fluorine, green; sulfur, yellow.
tion precursor intermediate, in 83% yield (Figure 5B). In
addition, the desulfurization of 8b to thiosulfonate 3y was
confirmed after the conversion of 8b in the presence of TFA
for 16 h (Figure 5C). The results obtained from the control
experiments (Figure 5) and crossover experiment (Figure 2A)
indicated that the reaction proceeds via selective trans-
formation of the morpholino group over the tosyl group to
afford SS-aryl 4-toluene(dithioperoxo)sulfonate18 followed by
sulfur extrusion.12a
This mechanistic insight was supported by density functional
theory (DFT) calculations. On the basis of the reaction
mechanism previously proposed,12b we performed geometry
optimizations and vibrational frequency calculations at the
B3LYP/6-31+G(d,p) level of theory to obtain the structures of
intermediates RC1−PC7 and those of transition states TS1−
TS7 (Figure 6). The results indicated that the activation of the
morpholino group occurs to form PC1, which subsequently
reacts with anisole (1b) in an electrophilic aromatic
substitution reaction to afford SS-aryl 4-toluene(dithioperoxo)-
sulfonate (PC3). Sulfur extrusion of PC3 via thiosulfoxide
PC6 affords thiosulfonate 3b. These results suggest the
possibility of a pathway from 7 to 3b, which involves C−S
bond formation and desulfurization.
In conclusion, we have developed a TFA-mediated
desulfurilative sulfonylthiolation of arenes using SS-morpholi-
no 4-toluene(dithioperoxo)sulfonate (7) as a doubly trans-
formable sulfur platform. The wide substrate scope of this
reaction and the ability to transform the resulting thiosulfo-
nates enables rapid access to various combinations of sulfides
or the conjugation of functional molecules via double C−S
bond formation. Control experiments and theoretical calcu-
lations suggested that the reaction proceeds via the electro-
philic aromatic substitution mechanism and subsequent sulfur
extrusion with selective activation of the morpholino group.
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04289.
Experimental details and characterization data for all
new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Kazuya Kanemoto − Faculty of Science and Engineering, Chuo
University, Tokyo 112-8551, Japan; orcid.org/0000-
0002-3958-7369; Email: k-kanemoto.18n@g.chuo-u.ac.jp
Shin-ichi Fukuzawa − Faculty of Science and Engineering,
Chuo University, Tokyo 112-8551, Japan; orcid.org/
0000-0001-8108-3829; Email: orgsynth@kc.chuo-u.ac.jp
Authors
Koudai Furuhashi − Faculty of Science and Engineering, Chuo
University, Tokyo 112-8551, Japan
Yoshitsugu Morita − Faculty of Science and Engineering,
Chuo University, Tokyo 112-8551, Japan; orcid.org/
0000-0001-9288-4840
Teruyuki Komatsu − Faculty of Science and Engineering,
Chuo University, Tokyo 112-8551, Japan; orcid.org/
0000-0002-7622-3433
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c04289
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Kato Memorial Bioscience
Foundation (K.K.), JSPS KAKENHI grant numbers
JP19K23637 (Research Activity Start-up; K.K.) and
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