Copper-Catalyzed Carbene Insertion into the Sulfur-Sulfur Bond of RS-SCF 2 H/SCF 3 under Mild Conditions

Article abstract of DOI:10.1055/s-0037-1611839

A copper-catalyzed carbene insertion into the sulfur-sulfur bond of trifluoromethyl/difluoromethyl/diphenyldisulfides under mild conditions has been developed. Diverse dithioketal derivatives were synthesized in moderate to good yields in an atom-economic

Full text of DOI:10.1055/s-0037-1611839

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
en
X. Hong et al.
Letter
Synlett
Copper-Catalyzed Carbene Insertion into the Sulfur–Sulfur Bond
of RS–SCF2H/SCF3 under Mild Conditions
Xin Honga
Long Lu*b
Qilong Shen*a
N2
2.5 mol% Cu(OTf)2
SRf
RS
R1
+
RS SRf
0
0
0
0-
0
0
0
1-5
1
2
7-9
5
8
0
R1
CO2Et
DCE
30 °C, 2 h
CO2Et
0
0
0
0-0
0
0
1-
5
6
2
2-1
5
3
X
R, R1 = aryl or alkyl
Rf = CF3 or CF2H
23 examples
34–90%
a Key Laboratory of Organofluorine Chemistry, Center for Excellence
in Molecular Synthesis, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, P. R. of China
cnshenql@sioc.ac.cn
b Shanghai Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, P. R. of China
lulong@sioc.ac
Received: 20.03.2019
Accepted after revision: 04.05.2019
Published online: 03.07.2019
More specifically, insertion of metal carbenoid into the S–S
bond for the simultaneous formation of two C–S bonds at
one carbon represents an intriguing yet attractive method.
In this respect, the Kawamura group reported the first di-
insertion reaction of fluorenylidene, which was generated
from 9-diazofluorene upon irradiation with a Xenon lamp,
into the S–S bond of diaryl disulfides.10 It was proposed that
the reaction proceeded via a double Stevens rearrangement.
Shortly after, similar 1,1-insertion of the S–S bond into a
carbene was observed by Hamaguchi during their investiga-
tion of vinylcarbenoid with cyclic disulfides.11 In 2016, Bao,
Xu and co-workers reported a catalyst-free, donor/acceptor
free carbene insertion into a S–S bond of diaryl disulfide.12
Crossover experiments as well as DFT calculations indicated
that the reaction proceeded through a radical pathway.
Shortly after, Arunprasath and Sekar reported that the car-
bene from N-tosylhydrazone generated in situ in the pres-
ence of a base was able to insert into the S–S bond of diaryl
disulfide, although the reaction was proposed to proceed
via a sulfonium ylide, followed by 1,2-migration or Stevens
rearrangement.13 Very recently, Song14 and Xu15 inde-
pendently described a rhodium- or copper-catalyzed carbe-
ne insertion into the S–S bond of benzenesulfonothioate,
although two different mechanisms were proposed.
Inspired by these reports and our interests in the devel-
opment of efficient methods for the incorporation of fluo-
roalkylthio groups,16 we envisaged that the S–S bond of flu-
oroalkyl-substituted disulfide may undergo insertion upon
reaction with carbene to generate fluoroalkylthiolated ace-
tal, which is otherwise difficult to access. Herein, we report
our preliminary results on copper-catalyzed carbene inser-
tion into the S–S bond of RS–SCF2H/SCF3.
We initially chose the reaction of difluoromethyl-
phenyldisulfide (1a) and phenyldiazoacetate (2a) as a mod-
el system to optimize the reaction conditions (Table 1). Var-
ious copper and rhodium catalysts that are commonly used
for the generation of metal carbenoid were initially
screened and it was found that all of them were able to pro-
DOI: 10.1055/s-0037-1611839; Art ID: st-2019-w0159-l
Abstract A copper-catalyzed carbene insertion into the sulfur–sulfur
bond of trifluoromethyl/difluoromethyl/diphenyldisulfides under mild
conditions has been developed. Diverse dithioketal derivatives were
synthesized in moderate to good yields in an atom-economic process.
Key words copper, carbene, difluoromethylthio, dithioketal
Recently, the trifluoromethylthio group (–SCF3) and di-
fluoromethylthio group (–SCF2H) have attracted much at-
tention from both academia and industry, mainly because
of their beneficial properties such as high yet tunable lipo-
philicity (Hansch’s hydrophobicity parameter for SCF3:  =
1.44; SCF2H:  = 0.68) that are important in fine-tuning the
pharmacokinetic and pharmacodynamic properties of lead
compound.1 Moreover, the difluoromethylthio group bears
a slightly acidic proton that can act as a hydrogen-bond do-
nor, which could increase the binding strength and selectiv-
ity between the lead compound and the host enzyme.2 Con-
sequently, in the last decade, synthetic methods that could
form the C–SCF3 or C–SCF2H bonds have been extensively
investigated.3 Nevertheless, new trifluoromethylthiolat-
ing/difluoromethylthiolating methods are still urgently
needed to strengthen the medicinal chemists’ arsenal for
new drug discovery.
Diazo compounds are readily available, powerful build-
ing blocks for the construction of carbon–carbon or car-
bon–heteroatom bonds.5 It is well known that a highly reac-
tive intermediate carbene or metal carbenoid can be gener-
ated in situ from the diazo compound, which then
undergoes a wide range of synthetic transformations in-
cluding C–H and X–H insertion (X = N, O, S, P, and Si),6 cyclo-
propanation7 and ylide formation.8 More recently, the met-
al-catalyzed insertion of carbenoid species into X–Y bonds
(X, Y = C, N, O, Si, S, etc.) has emerged as a powerful method
for the construction of versatile chemical frameworks.9
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

B
X. Hong et al.
Letter
Synlett
mote the reaction to give the desired product in 10–72%
yields, although the rhodium catalyst typically showed
higher reactivity than the copper catalyst (entries 1–4).
Considering that the rhodium complexes were much more
expensive than the copper salts, we chose to use Cu(OTf)2
as the catalyst for further optimization. The choice of sol-
vent was crucial for the conversion of the reaction. When
the reaction was conducted in non-coordinating less polar
solvent such as 1,2-dichloroethane (DCE) or toluene, the re-
action occurred in 70–72% yields, whereas the formation of
the desired product was not observed using coordinating,
more polar solvents such as THF or DMF (Table 1, entries 5,
6, 8, and 9).
With the optimized conditions established as indicated
in Table 1, entry 15, we next studied the substrate scope. As
shown in Scheme 1, vaious difluoromethyl-substituted di-
sulfide were prepared and subjected in the optimized reac-
tion conditions, affording the corresponding products 3a–q
in moderate to high yields. In general, substrates with ei-
ther electron-withdrawing or electron-donating groups
(fluoro, chloro, bromo, tBu and methoxyl) at the para-posi-
tion of the phenyl ring were well tolerated, giving the corre-
sponding products in high yields (Scheme 1, 3a–e). Sub-
strates with strong electron-withdrawing group such as ni-
tro at the para-position, however, did not react with diazo
compound at all, likely due to the low nucleophilicity of the
sulfur of the substrate (Scheme 1, 3f). In addition, difluoro-
methyl-substituted aryldisulfide substrates with different
substituents at the ortho- or meta-position also reacted to
give the corresponding products in moderate to good yields
(Scheme 1, 3g–m). Furthermore, difluoromethyl-substitut-
ed alkyldisulfides also reacted under the standard condi-
tions, leading to the desired product 3n in 64% yield and 3o
in 80% yield. However, reaction of difluoromethyl-substi-
tuted heteroaryldisufide occurred in low yield (Scheme 1,
3p–q). Next, we also investigated the scope of diazo com-
pounds and it was found that methyl or isopropyl phenyldi-
azoacetates also reacted to give the corresponding products
in 76% and 92% yield, respectively (Scheme 1, 3r–s). In addi-
tion, reactions of aryldiazoacetate with different functional
groups such as Cl, Br, CF3 also occurred smoothly to give the
corresponding products in good yields (Scheme 1, 3t–w).
The structure of compound 3t was confirmed by X-ray dif-
fraction analysis of its single crystals.
Encouraged by the board scope of the reaction, we next
tried to extend the reaction to other substituted disulfides.
As summarized in Scheme 2, under the standard condi-
tions, reaction of trifluoromethyl-substituted disulfide also
reacted with diazo compound to give the corresponding tri-
fluoromethylthiolated acetal in high yields. For example, re-
actions of 1-(trifluoromethyl)-2-(2-methoxyphenyl)disul-
fide or 1-(4-bromophenyl)-2-(difluoromethyl)disulfide
with ethyl phenyldiazoacetate afforded the trifluorometh-
ylthiolated acetal 3x and 3y in 75% and 77% yields, respec-
tively (Scheme 2). Likewise, diphenyl disulfide also reacted to
give the phenylthiolated acetal 3z in 73% yield (Scheme 2).
Notably, the product of the carbene insertion reaction
bears a chiral carbon center, which indicates the possibility
of an asymmetric carbene insertion into the S–S bond of
the disulfide. In a preliminary screening of chiral diamine
ligands, it was found that the highest enantioselectivity of
40% ee could be achieved when L1 was used as the ligand
(Scheme 3). Clearly, further efforts are needed to improve
the enantioselectivity of reaction before it becomes appli-
cable.
Table 1 Optimization of Reaction Conditions for Carbene Insertion
into the ArS–SCF2H Bonda
S
y mol% catalyst
S
SCF2H
CO2Et
SCF2H
+
N2
solvent, 30 °C, 2 h
Ph
Br
Ph
CO2Et
Br
1a
2a (x equiv)
3a
Entry Catalyst
Solvent
x
y
Yield (%)b
1
2
Rh2(esp)2
Rh2(OAc)4
DCE
DCE
DCE
DCE
toluene
MeCN
THF
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:2
1
1
64
72
10
72
70
50
0
3
Cu(MeCN)4PF6
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
10
10
10
10
10
10
10
10
10
5
4
5
6
7
8
DMF
DCE
DCE
DCE
DCE
DCE
DCE
DCE
0
9
80
76
90c
92c
82c
90d
94e
10
11
12
13
14
15
1:2.5
1:2
1:2
1:2
2.5
1:2
2.5
2.5
1:2
a Reaction conditions: compound 1a (0.10 mmol), diazo compound 2a
(0.12 mmol), catalyst and solvent as indicated, at room temperature for
2.0 h.
b Yields were determined by 19F NMR spectroscopy using PhCF3 as an inter-
nal standard.
c The diazo compound was added in two portions.
d The concentration of compound 1a was 0.2 M.
e The concentration of compound 1a was 0.5 M.
Interestingly, reaction in acetonitrile also occurred in
moderate yield, even though acetonitrile is a coordinating
polar solvent (Table 1, entry 6). Further adjusting the equiv-
alents of the diazo compound, the loading of the catalyst
and the concentration of the reaction mixture led to the op-
timized conditions that generated the desired product 3a in
94% yield (entries 9–15).
In summary, we have developed a copper-catalyzed car-
bene insertion reaction between disulfides including triflu-
oromethyl-/difluoromethyl-/phenyl-substituted disulfides
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

C
X. Hong et al.
Letter
Synlett
N2
2.5 mol% Cu(OTf)2
SCF2H
CO2Et
RS
R1
+
RSSCF2H
R1
CO2Et
DCE
30 °C, 2 h
1
2
3a
Cl
Me
S
SCF2H
S
SCF2H
S
SCF2H
Ph CO2Et
R = F, 68%, 3a
Ph CO2Et
Ph CO2Et
R
67%, 3g
68%, 3h
Cl, 86%, 3b
OMe
Br, 82%, 3c
S
SCF2H
S
SCF2H
OMe, 82%, 3d
tBu, 86%, 3e
NO2, <5%, 3fc
Ph CO2Et
Ph CO2Et
68%, 3i
76%, 3j
Cl
Cl
Me
Me
S
SCF2H
S
SCF2H
S
SCF2H
Ph CO2Et
Ph CO2Et
Ph CO2Et
Cl
Cl
Cl
72%, 3k
78%, 3l
48%, 3m
N
S
X
S
SCF2H
S
SCF2H
16
Ph CO2Et
Ph
SCF2H
Ph CO2Et
Ph CO2Et
X = O, 30%, 3pa
S, 24%, 3qa
78%, 3n
80%, 3o
EtO2C SCF2H
S
S
SCF2H
Ph CO2R
Br
Cl
Br
R = Me, 76%, 3r
iPr, 92%, 3s
70%, 3t
EtO2C SCF2H
S
EtO2C SCF2H
S
EtO2C SCF2H
Me
Br
S
Br
F3C
Br
Br
Me
63%, 3u
60%, 3v
60%, 3w
Scheme 1 Scope of carbene insertion into ArS–SCF2H bond. Reagents and conditions: compound 1a (0.30 mmol), diazo compound 2a (0.60 mmol),
Cu(OTf)2 (2.5 mol%) in DCE (0.6 mL) at room temperature for 2.0 h; Isolated yields. a Yields were determined by 19F NMR spectroscopy using PhCF3 as an
internal standard.
S
S
SR’
N2
2.5 mol% Cu(OTf)2
S
SR’
10 mol% Cu(CH3CN)4
10 mol% L1
S
SCF2H
SCF2H
+
R
R
N2
R1 CO2R’’
+
R1
CO2R’’
DCE
30 °C, 2 h
Ph CO2Et
Br
Ph
CO2Et
DCE
rt, 2 h
Br
1
2
3x–z
1a
2a (1.5 equiv)
3a
OMe
S
SCF3
S
SCF3
S
SPh
Ph CO2Et
Ph CO2Et
Ph CO2Et
Br
Br
N
N
Br
L1 =
77%, 3y
75%, 3x
73%, 3z
Br
Br
Scheme 2 Scope for reaction of ethyl phenyldiazoacetates with substi-
tuted disulfides. Reagents and conditions: compound 1 (0.30 mmol), di-
azo compound 2a (0.60 mmol), Cu(OTf)2 (2.5 mol%) in DCE (0.6 mL) at
room temperature for 2.0 h; Isolated yields.
Scheme 3 Copper-catalyzed asymmetric insertion of carbene into the
S–S bond of difluoromethyl-substituted disulfide
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

D
X. Hong et al.
Letter
Synlett
and diazo compounds under mild conditions.17 Two new C–
S bonds were formed simultaneously at one carbon. Various
common functional groups such as fluoride, chloride, bro-
mide, methoxy, trifluoromethyl were compatible. When a
chiral ligand was employed, moderate enantioselectivity
was observed. Further extension of the scope of the reac-
tion to other types of carbene precursors is under way in
our laboratory.
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Funding Information
The authors gratefully acknowledge the financial support from Na-
tional Natural Science Foundation of China (21572258) and the Stra-
tegic Priority Research Program of the Chinese Academy of Sciences
(XDB20000000).
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611839.
S
u
p
p
orti
n
gInformati
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n
S
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p
p
orit
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(10) Kawamura, Y.; Akitomo, K.; Oe, M.; Horie, T.; Tsukayama, M.
Tetrahedron Lett. 1997, 38, 8989.
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(17) General procedure for copper-catalyzed carbene insertion of
disulfides (3a–e, 3g–o, 3r–z). In a flame-dried glass tube, under
an argon atmosphere, a mixture of disulfide (0.3 mmol) and
Cu(OTf)2 (2.7 mg, 0.0075 mmol, 2.5 mol%) was added to DCE
(0.6 mL) at room temperature. Diazo compound (0.3 mmol) was
then added in one portion. The mixture was stirred for 1 h and
then additional diazo compound (0.3 mmol) was added. The
mixture was stirred for another 1 h and subsequently filtered
through a short plug of Celite and the solvent was evaporated
under reduced pressure. The residue was purified by flash chro-
matography (EtOAc/PE) to give the product.
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Ethyl 2-((Difluoromethyl)thio)-2-((4-fluorophenyl)thio)-2-
phenylacetate (3a). Rf = 0.5 (EtOAc/PE, 1:20); yield: 76 mg
(68%); yellow oil. 1H NMR (400 MHz, CDCl3, 293 K, TMS):  =
7.33–7.20 (m, 5 H), 7.17–7.13 (m, 2 H), 6.93 (dd, J = 56.2,
54.1 Hz, 1 H), 6.89 (t, J = 8.6 Hz, 2 H), 4.35–4.23 (m, 2 H), 1.27 (t,
J = 7.1 Hz, 3 H). 19F NMR (375 MHz, CDCl3):  = –92.72 (dd, J =
252.6, 56.2 Hz, 1 F), –95.60 (dd, J = 252.7, 54.3 Hz, 1 F), –109.87
(s, 1 F). 13C NMR (100.7 MHz, CDCl3):  = 169.4, 164.2 (d, J =
251.6 Hz), 139.6 (d, J = 8.8 Hz), 136.3, 128.8, 128.3, 127.6, 124.4
(d, J = 3.2 Hz), 122.7 (t, J = 269.9 Hz), 115.7 (d, J = 21.9 Hz), 70.6,
63.5, 13.7. IR (KBr): max = 2984, 1728, 1589, 1489, 1446, 1232,
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Nikolaienko, P.; Rueping, M. Chem. Commun. 2014, 50, 6617.
(d) Matheis, C.; Krause, T.; Bragoni, V.; Goossen, L. J. Chem. Eur. J.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

E
X. Hong et al.
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1067, 1041, 864 cm–1. MS (ESI): m/z = 390.0 [M + NH4+]. HRMS
(ESI): m/z calcd for C17H19NF3O2S2 [M + NH4+]: 390.0809; found:
390.0803.
C17H19NF2ClO2S2 [M + NH4+]: 406.0514; found: 406.0508.
Ethyl 2-((4-Bromophenyl)thio)-2-((difluoromethyl)thio)-2-
phenylacetate 3c. Rf = 0.5 (EtOAc/PE, 1:20); yield: 107 mg
(82%); yellow oil. 1H NMR (400 MHz, CDCl3, 293 K, TMS):  =
7.25 (d, J = 8.4 Hz, 2 H), 7.23–7.16 (m, 5 H), 6.95 (d, J = 8.4 Hz,
2 H), 6.85 (dd, J = 56.2, 54.1 Hz, 1 H), 4.28–4.16 (m, 2 H), 1.19 (t,
J = 7.1 Hz, 3 H). 19F NMR (375 MHz, CDCl3):  = –92.64 (dd, J =
252.7, 56.3 Hz, 1 F), –95.67 (dd, J = 252.7, 54.1 Hz, 1 F). 13C NMR
(100.7 MHz, CDCl3):  = 169.3, 138.8, 136.2, 131.7, 128.8, 128.4,
128.1, 127.5, 125.2, 122.6 (t, J = 270.1 Hz), 70.5, 65.8, 63.5. IR
(KBr): max = 2982, 1727, 1473, 1446, 1232, 1068, 1041, 815,
769 cm–1. MS (ESI): m/z = 449.9 [M + NH4+]. HRMS (ESI): m/z
Ethyl 2-((4-Cchlorophenyl)thio)-2-((difluoromethyl)thio)-2-
phenylacetate (3b). Rf = 0.5 (EtOAc/PE, 1:20); yield: 100 mg
(86%); yellow oil. 1H NMR (400 MHz, CDCl3, 293 K, TMS):  =
7.30–7.22 (m, 5 H), 7.16 (d, J = 8.4 Hz, 2 H), 7.08 (d, J = 8.6 Hz,
2 H), 6.92 (dd, J = 56.2, 54.1 Hz, 1 H), 4.34–4.22 (m, 2 H), 1.25 (t,
J = 7.1 Hz, 3 H). 19F NMR (375 MHz, CDCl3):  = 92.65 (dd, J =
252.7, 56.2 Hz, 1 F), –95.65 (dd, J = 252.7, 54.1 Hz, 1 F). 13C NMR
(100.7 MHz, CDCl3):  = 169.3, 138.6, 136.8, 136.3, 128.9, 128.8,
128.4, 127.6, 122.6 (t, J = 269.9 Hz), 70.6, 63.5, 13.7. IR (KBr):

max = 2983, 1728, 1573, 1475, 1301, 1233, 1067, 1042, 796 cm–1
MS (ESI): m/z = 406.0 [M + NH4+]. HRMS (ESI): m/z calcd for
.
calcd for
450.0003
C17H19NF2BrO2S2 [M +
NH4+]: 450.0009; found:
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E