Nickel-Catalyzed Negishi-Type Arylation of Trialkylsulfonium Salts

Article abstract of DOI:10.1055/s-0040-1707817

Negishi-type arylation of trialkylsulfonium salts with arylzinc reagents has been accomplished under nickel catalysis. The use of cyclohexanethiol as an additional ligand was found to be particularly important to promote C-S cleavage. The present reaction accommodates one-pot arylation of dialkyl sulfides by combining with S -methylation with MeOTf. Mechanistic experiments suggest that C-S cleavage would proceed via single-electron transfer (SET) to generate the most stable carbon-centered radical and that the thiolate ligand would promote the C-S cleavage and radical recombination step.

Full text of DOI:10.1055/s-0040-1707817

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© Georg Thieme Verlag Stuttgart · New York
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Nickel-Catalyzed Negishi-Type Arylation of Trialkylsulfonium Salts
Hiroko Minami
Keisuke Nogi
Ar Zn
cat. NiCl2(bpy)
cat. CySH
OTf
MeOTf
alkyl Ar
alkyl SMe
alkyl SMe2
Hideki Yorimitsu*
0
0
0
0-0
0
0
2-0
1
5
3-1
8
8
8
DMA/THF
15 examples
up to 85% yield
Department of Chemistry, Graduate School of Science,
Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan
yori@kuchem.kyoto-u.ac.jp
Published as part of the Cluster Modern Nickel-Catalyzed
Reactions
Received: 10.04.2020
Accepted after revision: 28.04.2020
Published online: 16.04.2020
fairly restrict the reaction scope (Scheme 1, a).8 In 2018, Ba-
ran accomplished Negishi-type arylation of diverse alkyl
sulfones with wider functional group tolerance by means of
a tetrazolylsulfonyl leaving group (Scheme 1, b).9,10
DOI: 10.1055/s-0040-1707817; Art ID: st-2020-k0201-c
Abstract Negishi-type arylation of trialkylsulfonium salts with arylzinc
reagents has been accomplished under nickel catalysis. The use of cy-
clohexanethiol as an additional ligand was found to be particularly im-
portant to promote C–S cleavage. The present reaction accommodates
one-pot arylation of dialkyl sulfides by combining with S-methylation
with MeOTf. Mechanistic experiments suggest that C–S cleavage would
proceed via single-electron transfer (SET) to generate the most stable
carbon-centered radical and that the thiolate ligand would promote the
C–S cleavage and radical recombination step.
(a) Denmark’s arylation of alkyl sulfide and sulfones
Me
N
Me
or
cat. Fe
ArMgBr
Ph
S
Ph
Ar
or
R2
R2
CPME
R1
(b) Baran’s arylation of alkyl sulfones
SO2Ph
R1
Ar
Key words Negishi coupling, trialkylsulfonium salt, nickel catalysis,
thiolate ligand, radical
R2
N
N
cat. Ni/bpy
ArZnCl
R2
N
R1
S
N
R1
Ar
THF/NMP
O
O
Ph
Transition-metal-catalyzed cross-coupling represents a
privileged class of molecular transformations for the con-
struction of C–C bonds and is regarded as an indispensable
tool in many scientific disciplines that employ organic mol-
ecules.1 Conventionally, aryl and alkenyl (pseudo)halides
having C(sp2)–halogen bonds have been used as electro-
philic coupling partners.
(c) This work: Arylation of trialkylsulfonium salts
cat. NiCl2(bpy)
cat. CySH
ArZnBr·MgCl2·LiCl
R2
R2
R2
OTf
MeOTf
R1
SR3
R1
SR3Me
R1
Ar
THF/DMA
Scheme 1 Cross-coupling of aliphatic organosulfur compounds
For the last two decades, cross-coupling of sp3-hybrid-
ized carbon electrophiles with organometallic reagents has
been emerging as a powerful strategy for the synthesis of
diverse saturated hydrocarbon frameworks.2 While alkyl
halides are generally employed for such transformations,
cross-coupling of aliphatic organosulfur compounds of high
accessibility has received far less attention despite continu-
ous reports on C(sp2)–S cleaving transformations of aro-
matic and vinylic organosulfur compounds.3 Moreover, a
limited range of organosulfur compounds including rela-
tively reactive benzylic,4 allylic,5 difluoromethyl,6 and -
carbonyl-activated4b,7 C(sp3)–S electrophiles are applicable
to the reactions.
Recently, we have focused on sulfonium salts as compe-
tent electrophiles for catalytic C–S cleaving transforma-
tions.11–13 We envisioned that trialkylsulfonium salts can
participate in C(sp3)–S cleaving cross-coupling, which can
expand the repertoire of sp3-hybridized carbon electro-
philes. Herein we report Negishi-type arylation of trialkyl-
sulfonium triflates with arylzinc reagents under nickel ca-
talysis.14 The use of cyclohexanethiol as an additional li-
gand was found to be particularly important for promotion
of the C–S cleavage. Our arylation is applicable to one-pot
transformation of dialkyl sulfides by combining with S-
methylation with MeOTf, which showcases the synthetic
utility of the present system.
As a seminal work on C(sp3)–S cleaving cross-coupling,
Denmark developed Fe-catalyzed arylation of unactivated
alkyl sulfide and sulfones whereas arylmagnesium reagents
The arylation of dimethyldodecylsulfonium triflate (1a)
with arylzinc 2a prepared from the corresponding arylmag-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
H. Minami et al.
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nesium bromide, ZnCl2, and LiCl15 in THF was chosen as a
model reaction (Table 1).16 Since nickel catalysts often show
good catalytic activity for cross-coupling of alkyl electro-
philes,2a,f,h,l,m we evaluated several nickel catalysts. Based on
brief screening of ligands (see Table S1 in the Supporting In-
formation), the reaction was conducted with 10 mol% of
NiCl2(bpy) (bpy = 2,2′-bipyridyl), and the desired product
3aa was obtained in 26% yield (Table 1, entry 1). During the
initial screening, we suffered from low reproducibility. Af-
ter careful survey of the reaction system, sulfur impurities
proved to provide a positive effect for the reaction. We thus
attempted additions of thiols, sulfides, and disulfides to the
reaction system. Gratifyingly, the yield of 3aa dramatically
increased to 81% by means of 20 mol% of cyclohexanethiol
(CySH, Table 1, entry 2). Of note, the C(sp3)–S cleavage se-
lectively proceeded at the C12H25–S bond; 4-methylanisole
generated through the cleavage of the Me–S bond was not
observed. This selectivity suggests that the reaction would
proceed via generation of alkyl radical initiated by single-
electron transfer (SET) from low-valent nickel species to the
sulfonium salt (see Scheme 7). Other alkane- and arenethi-
ols were less effective compared to CySH (Table 1, entries
3–5). Although we tested Zn and Mn powders to generate
low-valent nickel species, no positive effect was observed
(entries 6 and 7). The use of amide cosolvent was crucial for
the arylation, and only a 6% yield of the product was ob-
tained without DMA (entry 8). Employment of NMP and
DMF instead of DMA slightly lowered the yield of 3aa (en-
tries 9 and 10). Decreasing the reaction temperature to 0 °C
improved the yield to 86% (entry 11). An 86% yield of 3aa
was obtained with lower catalyst loadings, 5 mol% of
NiCl2(bpy) and 10 mol% of CySH, and 3aa was isolated in
82% yield under the reaction conditions (entry 12).
Table 1 Screening of Conditions
C12H25
Me
S
10 mol% NiCl2(bpy)
20 mol% additive
Me
+
C12H25
OTf
1a
BrZn
·MgCl2
·LiCl
cosolvent/THF
r.t., 12 h
OMe
3aa
OMe
(2 equiv)
2a
Entry
Additive
Cosolvent
NMR yield (%)
1
2
none
DMA
DMA
DMA
DMA
DMA
DMA
DMA
26
CySH
81
3
c-C5H9SH
BuSH
79
4
69
5
PhSH
37
6
Zn powder
Mn powder
CySH
26
7
29
8
none (THF)
NMP
6
9
CySH
59
10
11a
12a,b
CySH
DMF
68
CySH
DMA
86
CySH
DMA
86 (82)c
a At 0 °C.
b With 5 mol% of NiCl2(bpy) and 10 mol% of CySH.
c Isolated yield.
mild reactivity of arylzinc, sulfide 4b having an ester func-
tionality could be involved in the reaction to afford 3ba18 in
60% yield. Although cyano-substituted 4c underwent the
reaction with 2a, the yield of 3ca was not high despite full
conversion of the substrate. The present arylation preferen-
tially occurred at the C–SMe2+ bond of sulfonium triflate 1d
over the C–Cl bond to afford 3da in 41% yield. Allyl and ben-
zyl sulfides 4e and 4f took part in the arylation to afford
3ea and 3fa. On the other hand, tert-butyl methyl sulfide
(4g) did not undergo the reaction; the desired product was
not obtained and only anisole and 4,4′-dimethoxybiphenyl
were observed. Instead of 4-methoxyphenylzinc 2a, 2-
naphthylzinc (2b) uneventfully reacted with 4-phenoxybu-
tylsulfonium triflate (1h) to furnish 3hb in 63% yield. The
reactions of 2-phenoxyethylsulfononium (1i) with 2-naph-
thyl- and 4-fluorophenylzinc reagents afforded arylation
products 3ib and 3ic in moderate yields. In both cases, phe-
nol was obtained as a byproduct in ca. 20% yield. This by-
product would be generated by -oxygen elimination from
a 2-phenoxyethylnickel intermediate. Alkyl sulfide 4j hav-
ing a 2,3-dihydrobenzofuryl moiety underwent the reac-
tion with 4-methylphenylzinc (2d) to provide desired prod-
uct 3jd in 68% yield accompanied by a 22% NMR yield of 2-
allylphenol formed by the -oxygen elimination.
The present catalysis is applicable to one-pot arylation
of dialkyl sulfides as is the case with our previous one-pot
transformations of aryl sulfides.11d–f,11h,i After methylation
of dodecyl methyl sulfide (4a) with MeOTf and removal of
all volatiles, sulfonium triflate 1a generated was arylated
with arylzinc 2a in a one-pot manner to afford 3aa in 82%
yield (Scheme 2).17
OTf
1.3 equiv MeOTf
SMe2
C
12H25 SMe
C12H25
1a
C12H25
DCE, 60 °C, 12 h
4a
5 mol% NiCl2(bpy)
10 mol% CySH
2 equiv 2a
OMe
DMA/THF, 0 °C, 12 h
3aa 82%
Scheme 2 One-pot arylation of alkyl sulfide 4a
Having the one-pot procedure in hand, we then ex-
plored the reaction scope with respect to alkyl methyl sul-
fides 4 and arylzinc reagents 2 (Scheme 3). Owing to the
As shown in Schemes 2 and 3, the arylation of alkyldi-
methylsulfonium salts selectively proceeded via cleavage of
+
the C(alkyl)–SMe2 bonds. To further explore the regiose-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

C
H. Minami et al.
Cluster
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cal, the reaction of 1m provided only a 2% yield of the cy-
clized product 3ma′ (Scheme 5, b). Instead, the linear prod-
uct 3ma was obtained as the major product in 74% yield.
These results indicate that recombination of radical species
with nickel (see Scheme 7) would proceed faster than the 5-
exo cyclization of 5-hexenyl radical (rate constant: 1.0105
s–1),19 but slower than the ring opening of cyclopropylmeth-
yl radical (rate constant: 1.3108 s–1).19
1.3 equiv MeOTf
DCE, 60 °C, 12 h
OTf
SMe2
R
SMe
R
4
1
5 mol% NiCl2(bpy)
10 mol% CySH
2 equiv ArZnBr·MgCl2·LiCl (2)
R
Ar
DMA/THF, 0 °C, 12 h
3
EtO2C(CH2)5
NC(CH2)3
Cl(CH2)4
(a)
10 mol% NiCl2(bpy)
20 mol% CySH
OMe
OMe
OMe
OMe
3ba 60%
3ca 32%a
3da 41%
3la 5% (NMR)
2 equiv 2a
SMe2
OTf
+
DMA/THF, 0 °C, 12 h
1l
OMe
OMe
OMe
OMe
3la' 77% (NMR)
3fa 50%
3ga 0%
3ea 60%
(b)
PhO(CH2)2
O
PhO(CH2)n
F
Me
10 mol% NiCl2(bpy)
20 mol% CySH
2 equiv 2a
OMe
3ma 74% (NMR)
3ic 62%b
3jd 68%c
3hb (n = 4) 63%
3ib (n = 2) 54%b
OTf
+
SMe2
DMA/THF, 0 °C, 12 h
Scheme 3 Scope of arylation. a With 10 mol% NiCl2(bpy) and 20 mol%
CySH. b Phenol was obtained in ca. 20% yield. c 2-Allylphenol was ob-
tained in 22% yield.
1m
OMe
3ma' 2% (NMR)
Scheme 5 Mechanistic experiments with radical probes
lectivity of the C–S cleavage, we conducted the arylation of
trialkylsulfonium triflate 1k having three different alkyl
groups: cyclohexyl, hexyl, and methyl groups (Scheme 4).
As a result, 4-cyclohexylanisole (3ka) was obtained in 85%
yield along with a 3% yield of 4-hexylanisole (3ka′), and
none of 4-methylanisole was detected. This result indicates
that the C–S cleavage would proceed via SET from low-va-
lent nickel species to form the most stable carbon-centered
radical preferentially (see Scheme 7).
We next carried out the reaction with didodecylmethyl-
sulfonium triflate 1a-C12 to understand the effect of CySH
(Scheme 6). Under the standard conditions, 1a-C12 was fully
consumed, and a 74% yield of 4-dodecylanisole (3aa) was
obtained along with a 90% yield of departed dodecyl methyl
sulfide (4a). On the other hand, in the absence of CySH, 1a-
C12 was recovered in 47% yield, which suggests that CySH
might assist the C–S cleaving step. Of note, although a 46%
yield of 4a was generated, the yield of arylation product 3aa
was only 18%. This result implies that recombination of rad-
ical species after the C–S cleavage might also be assisted by
CySH.
5 mol% NiCl2(bpy)
10 mol% CySH
OMe
C6H13
OTf
2 equiv 2a
S
3ka 85%
10 mol% NiCl2(bpy)
0 or 20 mol% CySH
DMA/THF, 0 °C, 12 h
Me
1k
C6H13
2 equiv 2a
H25C12
OTf
C12H25
H25C12 Ar
S
4a
OMe
+
DMA/THF
0 °C, 12 h
3ka’ 3%
(Ar = 4-MeOC6H4)
Me
3aa
1a-C12
Scheme 4 Regioselective C–S arylation of trialkylsulfonium triflate 1k
20 mol% CySH
0 mol% CySH
74%
90%
46%
18%
(47% recovery of 1a-C12
)
To verify the intermediacy of radical species, we con-
ducted a radical clock experiment using (cyclopropylmeth-
yl)sulfonium triflate 1l. The reaction of 1l with arylzinc 2a
provided ring-opening product 3la' in 77% yield as the ma-
jor product, which would be consistent with the intermedi-
acy of radical species (Scheme 5, a). We also conducted the
arylation with another radical probe, (5-hexen-1-yl)sulfo-
nium triflate (1m). Although 5-hexenyl radical is known to
undergo 5-exo cyclization to afford cyclopentylmethyl radi-
Scheme 6 Effect of CySH for arylation
Although further mechanistic studies should be re-
quired for elucidating the reaction mechanism, we suppose
the reaction proceeds through a Ni(I)/Ni(III) catalytic cycle
involving a SET process (Scheme 7).2f,20 Initial reduction of
the Ni(II) precatalyst to Ni(0) followed by comproportion-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

D
H. Minami et al.
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Synlett
ation with other Ni(II) species in the presence of CyS– anion
would generate Ni(I)–SCy A (step a). Subsequent SET from A
to trialkylsulfonium triflate 1 would provide an alkyl radi-
cal and a Ni(II) intermediate (step b). The thiolate ligand on
A might assist the SET process from the nickel center to 1 as
an electron-rich donor-type ligand. Subsequently, recombi-
nation of the radical and Ni(II) would afford cationic alkyl-
nickel(III) B which might be trapped by another CyS– anion
to generate alkylnickel(III) dithiolate C (steps c and d). Final-
ly, transmetalation of C with arylzinc 2 (step e) followed by
reductive elimination from D would provide coupling prod-
uct 3 with regeneration of Ni(I)–SCy A (step f). Instead of
the formation of nickel(III) dithiolate C, transmetalation of
cationic species B with arylzinc 2 can also generate alky-
larylnickel(III) D (step g).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707817.
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References and Notes
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jere, A.; Diederich, F., Ed.; Wiley-VCH: Weinheim, 2004.
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(g) Nakamura, E.; Hatakeyama, T.; Ito, S.; Ishizuka, K.; Ilies, L.;
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(4) A review on the reaction with benzylic dithioacetals: (a) Luh, T.
Y. Acc. Chem. Res. 1991, 24, 257. The reactions with benzyl sul-
fones: (b) Wu, J.-C.; Gong, L.-B.; Xia, Y.; Song, R.-J.; Xie, Y.-X.; Li,
J.-H. Angew. Chem. Int. Ed. 2012, 51, 9909. (c) Nambo, M.;
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N
N
N
N
Ni0
NiIICl2
+
SCy
2
+
step a
OTf
SMe2
N
N
R
Ar
R
NiI SCy
3
1
A
step b
SMe2
step f
Ar
R
•
N
N
R
N
NiIII
Zn
NiII SCy
OTf
OTf
SCy
N
D
ArZn
2
step g
step e
step c
ZnSCy
SCy
ArZn
N
N
R
N
N
R
NiIII
NiIII
SCy
SCy
B
C
OTf
step d
Zn OTf
Scheme 7 A possible reaction mechanism
In conclusion, we developed Negishi-type cross-cou-
pling of trialkylsulfonium salts with arylzinc reagents un-
der nickel–thiolate catalysis. The present system was appli-
cable to one-pot arylation of dialkyl sulfides by combining
with S-methylation with MeOTf. The C–S cleavage would
proceed via single-electron transfer (SET) by low-valent
nickel species, which leads to regioselective C–S cleavage
that provides the most stable carbon-centered radical.
Mechanistic experiments revealed that the thiolate ligand
would promote the C–S cleavage as well as the radical re-
combination step, while further mechanistic studies are
necessary.
(5) For examples: (a) Gendreau, Y.; Normant, J. F.; Villieras, J.
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Funding Information
This work was supported by the Japan Society for the Promotion of
Science (JSPS KAKENHI, Grant Numbers JP18H04254, JP18H04409,
JP19H00895, and JP18K14212) as well as the Japan Science and Tech-
(6) Miao, W.; Zhao, Y.; Ni, C.; Gao, B.; Zhang, W.; Hu, J. J. Am. Chem.
Soc. 2018, 140, 880.
nology Agency (JST CREST, Grant Number JPMJCR19R4).
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(7) As -carbonyl-activated organosulfur compounds, C–S cleavage
of -ketothioesters has been reported recently: Wang, M.; Dai,
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yield was lower than that with the corresponding arylzinc
reagent. See Scheme S1 in the Supporting Information.
(17) 4-Dodecylanisole (3aa) – Typical Procedure for One-Pot Ary-
lation
A 10 mL Schlenk tube was charged with dodecyl methyl sulfide
(4a, 0.11 g, 0.50 mmol) and DCE (1.0 mL) before an addition of
MeOTf (74 L, 0.65 mmol). The resulting mixture was stirred for
12 h at 60 °C. After removal of all volatiles under reduced pres-
sure (ca. 1 Torr), NiCl2(bpy) (7.1 mg, 0.025 mmol), CySH (6 L,
0.050 mmol), and DMA (3.0 mL) were subsequently added to
the tube. The resulting mixture was cooled to 0 °C, and a solu-
tion of 4-methoxyphenylzinc (2a, 0.56 M in THF, 1.8 mL, 1.0
mmol) was then added dropwise. The resulting mixture was
stirred for 12 h at 0 °C before an addition of aqueous HCl (2 M).
The resulting biphasic solution was extracted with a mixture of
hexane and EtOAc (v/v = 10:1, 3 × 10 mL). The combined organic
layer was dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by column chroma-
tography on silica gel (eluent: hexane/EtOAc = 100:1) to give
3aa (0.11 g, 0.41 mmol, 82%) as a colorless oil. All the reso-
nances in 1H NMR and 13C NMR spectra were consistent with
the reported values in the literature: Komeyama, K.; Ohata, R.;
Kiguchi, S.; Osaka, I. Chem. Commun. 2017, 53, 6401.
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(18) Ethyl 6-(4-Methoxyphenyl)hexanoate (3ba)
1
Colorless oil (76 mg, 0.30 mmol, 60%). H NMR (594 MHz):  =
7.08 (d, J = 8.8 Hz, 2 H), 6.82 (d, J = 8.8 Hz, 2 H), 4.12 (q, J = 7.3
Hz, 2 H), 3.79 (s, 3 H), 2.55 (t, J = 7.5 Hz, 2 H), 2.28 (t, J = 7.5 Hz, 2
H), 1.68–1.57 (m, 4 H), 1.38–1.33 (m, 2 H), 1.25 (t, J = 7.3 Hz, 3
H). 13C NMR (149 MHz):  = 174.0, 157.8, 134.8, 129.4, 113.8,
60.3, 55.4, 34.9, 34.4, 31.5, 28.8, 25.0, 14.4. HRMS (APCI-MS,
positive): m/z calcd for C15H23O3: 251.1642 [M + H]+; found:
251.1645.
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© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E