Ni-Catalyzed Aryl Sulfide Synthesis through an Aryl Exchange Reaction

Article abstract of DOI:10.1021/jacs.1c04215

A Ni-catalyzed aryl sulfide synthesis through an aryl exchange reaction between aryl sulfides and a variety of aryl electrophiles was developed. By using 2-pyridyl sulfide as a sulfide donor, this reaction achieved the synthesis of aryl sulfides without using odorous and toxic thiols. The use of a Ni/dcypt catalyst capable of cleaving and forming aryl-S bonds was important for the aryl exchange reaction between 2-pyridyl sulfides and aryl electrophiles, which include aromatic esters, arenol derivatives, and aryl halides. Mechanistic studies revealed that Ni/dcypt can simultaneously undergo oxidative additions of aryl sulfides and aromatic esters, followed by ligand exchange between the generated aryl-Ni-SR and aryl-Ni-OAr species to furnish aryl exchanged compounds.

Full text of DOI:10.1021/jacs.1c04215

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Ni-Catalyzed Aryl Sulfide Synthesis through an Aryl Exchange
Reaction
Ryota Isshiki, Miki B. Kurosawa, Kei Muto, and Junichiro Yamaguchi*
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ABSTRACT: A Ni-catalyzed aryl sulfide synthesis through an aryl
exchange reaction between aryl sulfides and a variety of aryl
electrophiles was developed. By using 2-pyridyl sulfide as a sulfide
donor, this reaction achieved the synthesis of aryl sulfides without
using odorous and toxic thiols. The use of a Ni/dcypt catalyst capable
of cleaving and forming aryl−S bonds was important for the aryl
exchange reaction between 2-pyridyl sulfides and aryl electrophiles,
which include aromatic esters, arenol derivatives, and aryl halides.
Mechanistic studies revealed that Ni/dcypt can simultaneously
undergo oxidative additions of aryl sulfides and aromatic esters,
followed by ligand exchange between the generated aryl−Ni−SR and
aryl−Ni−OAr species to furnish aryl exchanged compounds.
In related work, our group developed a Ni-catalyzed aryl
exchange reaction between aryl halides and aromatic esters
(Figure 1B).11 The key for this reaction was the high bond-
cleaving ability of Ni/dcypt catalyst, which also allowed the
reaction of challenging arenol derivatives instead of aryl
halides.12 However, this reaction afforded only aromatic esters
as a product, not aryl halides and arenols. We assumed that this
is due to the difficulty of reductive elimination of C−X bonds
from the Ar−Ni/dcypt−X intermediate (X = halogen and
OR). Because it is known that C−S bond reductive elimination
is a relatively facile process in metal catalysis,13 we envisioned
that aryl sulfide synthesis by a catalytic aryl exchange reaction
would be reasonable and possible. Herein, we report a new aryl
sulfide synthesis by means of a Ni/dcypt-catalyzed aryl
exchange between aryl sulfides and aromatic esters (Figure
1C). Moreover, this nickel catalysis was revealed to be viable
for various aryl electrophiles such as aryl halides and arenols
other than aromatic esters. During the preparation of this
manuscript, Morandi reported a similar aryl sulfide synthesis
using an aryl exchange reaction between aryl sulfides with aryl
nitriles.14
INTRODUCTION
■
Aryl sulfide is an important chemical motif that is widely seen
in biologically active compounds as well as in chemical
materials.1 Due to this importance, there has been interest
among chemists to expand the methodology toward the
synthesis of aryl sulfides. Conventionally, metal-catalyzed C−S
bond formations of aryl electrophiles with thiols have been
utilized (Figure 1A).2,3 Contrary to the high reliability of this
method, the use of thiols is often shunned because of their
odor and toxicity. The reaction of aryl halides with disulfides4
and the decarbonylation reaction of thioesters have been
developed as alternatives.5 Recently, a reaction using alkyl
sulfides as a sulfide source has emerged using palladium
catalysis under strongly basic conditions.6 Despite the progress
in this area, the development of C−S bond formation without
thiols is still a topic in its infancy.7
Meanwhile, transition-metal-catalyzed aryl exchange reac-
tions between two different aryl electrophiles have gained
attention in recent years.8,9 This type of transformation is not
only conceptually interesting but also synthetically valuable
because it is possible to avoid the use of nucleophilic
counterparts, which often triggers poor functional group
tolerance and catalyst deactivation. As a pioneering work,
Morandi and Arndtsen independently reported a Pd-catalyzed
aryl exchange reaction between aryl iodides and aroyl chlorides
(Figure 1B).10 Commonly, the development of these reactions
requires a high level of design. It is important to choose and/or
develop an appropriate metal catalyst enabling both the
cleavage and formation of two distinct chemical bonds.
Another consideration is the design of a set of substrates to
control the equilibrium of the reaction.
Received: April 22, 2021
Published: June 28, 2021
© 2021 The Authors. Published by
American Chemical Society
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a
Table 1. Optimization of Reaction Conditions
b
b
entry
R
ligand
dcypt
additive
yield of 4Aa/% yield of 5/%
1
2
H
43
58
24
58
80 (80)
51
71
33
24
7
16
23
17
24
24
19
16
5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
dcypt
dcypt
dcypt
dcypt
dcypt
dcypt
dcypt
dcype
dppe
c
3
c
4
Zn(OAc)2
Zn(OAc)2
f
5
d
6
d
7
e
Zn(OAc)2
8
9
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
trace
0
10
11
12
Xantphos
PnBu3
0
0
0
0
a
Figure 1. (A) Conventional catalytic C−S bond formations. (B)
Catalytic aryl exchange reactions. (C) Ni-catalyzed aryl sulfide
synthesis via the aryl exchange reaction.
Conditions: 1A (0.20 mmol), 2 (2.0 equiv), Ni(OAc)2 (10 mol %),
ligand (bidentate: 15 mol %, monodentate: 30 mol %), Na3PO4 (2.0
b
c
equiv), toluene (0.80 mL), 150 °C, and 24 h. NMR yield. Ni(cod)2
d
e
instead of Ni(OAc)2. Without Na3PO4. Pd(OAc)2 instead of
f
Ni(OAc)2. Isolated yield.
RESULTS AND DISUCUSSION
■
To initiate the study, 4-tolyl sulfide 1A and 4-phenylbenzoate
2a were reacted under the conditions for our previous aryl
exchange reaction (Ni(OAc)2/dcypt catalyst, Zn, and Na3PO4)
(Table 1). To our delight, the desired aryl sulfide 4Aa was
obtained in 43% yield along with 16% yield of aromatic ester 5
(Table 1, entry 1). In this case, phenyl propyl sulfide was also
generated as a major byproduct, which is derived from the
phenol moiety on 2a through an undesired C(aryl)−O bond
cleavage (details in Supporting Information).11,12a−d In order
to suppress this undesired pathway, we utilized tolyl ester 3a
with the expectation that the ortho-methyl group can block the
C(aryl)−O bond oxidative addition (Table 1, entry 2). As
expected, the yield of 4Aa was improved to 58%, and
significantly decreased the formation of phenyl propyl sulfide.
A change from Ni(OAc)2 to Ni(cod)2 decreased the yields of
4Aa and 5 (Table 1, entry 3). Hypothesizing that the
conditions using Ni(OAc)2 and Zn produces Zn(OAc)2
which might promote this reaction, we added a semicatalytic
amount of Zn(OAc)2 into the reaction with Ni(cod)2. As
expected, we obtained a comparable result with the conditions
using Ni(OAc)2 (Table 1, entries 2 and 4). Moreover, the
addition of Zn(OAc)2 to the conditions using Ni(OAc)2
improved the yield of 3Aa to 80% whereas the yield of 5
remained the same (Table 1, entry 5). Removing Na3PO4 from
these conditions decreased the yields of 4Aa and 5 (Table 1,
entries 6 and 7). It was revealed that Pd/dcypt catalyst can also
work without Zn(OAc)2 to give 4Aa and 5 albeit in lower
yields (Table 1, entry 8). Finally, it was found that the choice
of ligand was crucial. Our dcypt ligand effectively worked well,
yet other diphosphines and monophosphines were totally
ineffective (Table 1, entries 9−12). With these studies,
Ni(OAc)2/dcypt/Zn/Zn(OAc)2 catalysis was identified as
our optimized conditions. Of note, a similar Ni/Zn catalysis
was often employed for reductive biaryl coupling of two aryl
electrophiles, but such a cross-biaryl formation did not occur in
this case.15
Although we established the optimized conditions, the two
following questions arose. Can two distinct oxidative additions
to the same Ni/dcypt catalyst can occur? Can the two
generated nickel complexes engage in the exchange reaction?
To answer these questions, we next carried out several
mechanistic studies. We first confirmed the oxidative addition
reaction of aryl sulfide 6A to Ni(cod)/dcypt complex (Figure
2A).16 The reaction of equimolar Ni(cod)2, dcypt, and aryl
sulfide 6A (2.0 equiv) in toluene at 80 °C smoothly furnished
oxidative addition complex 7 in 83% yield. The structure of 7
was unambiguously confirmed by X-ray crystallographic
analysis. With complex 7 in hand, we conducted the
stoichiometric reaction of 7 with 3b in toluene at 90 °C to
gain insight on this double oxidative addition of sulfide 1 and
ester 3 (Figure 2B). As a result, we obtained Ni−arenoxo
complex 8 and nickel dicarbonyl 9 in 23% total yield (details in
the SI). Encouraged by this result, we further studied this
process by monitoring the oxidative addition of aryl sulfide 6A
and aromatic ester 3b to Ni(cod)2/dcypt at 80 °C, and the
time course plot is shown in Figure 2C (details in the SI). It
was observed that 6A undergoes a much faster oxidative
addition than 3b. Interestingly, during this reaction, the
amount of 8 and 9 constantly increased, and that of 7 and
Ni(cod)/dcypt decreased, giving 49% yields of 8 and 9 after 42
h. With these studies, we concluded that one of the key aspects
of these two simultaneous oxidative additions would be the
reversible oxidative addition and reductive elimination of C−S
bonds. This reversibility would allow for aromatic esters to
undergo oxidative additions to the Ni(0) species albeit at a
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Figure 2. Mechanistic studies. (A) Oxidative addition of 6A. (B) Reversibility of the C−S bond oxidative addition and reductive elimination. (C)
Double oxidative addition of 6A and 3b and its time-course plot. (D) Reaction of nickel complexes 7 with 8. (E and F) Effects of Zn and
Zn(OAc)2. (G) Plausible catalytic cycle.
slow reaction rate. Finally, the reaction of 7 and 8 furnished
4Ab (59% yield) along with 6A, showing that an exchange
reaction between two nickel intermediates is possible (Figure
2D).
accelerated only when both Zn and Zn(OAc)2 were used
(Figure 2F, entries 2−4). Thus, the main role of Zn and
Zn(OAc)2 in this catalysis is the induction of the reductive
decomposition of the aryl−Ni−arenoxo complex to regenerate
the Ni(0) species. However, the H-atom source and detailed
action of these zinc reagents were still unclear.
Our next interest was to clarify why this reaction provides
aryl sulfide 4 as a major product and not aromatic esters. We
assumed that the elucidation of the role of Zn/Zn(OAc)2
might give insight into this question. Thus, the aryl exchange
reaction between 6A and 3b in the presence and absence of
Zn/Zn(OAc)2 was performed by using nickel complexes 7, 8,
and 9 (30 mol %) in toluene at 150 °C (Figure 2E). Without
Zn/Zn(OAc)2, nickel complexes 7 and 9 delivered 4Ab in 21
and 36%, respectively. However, 8 gave only an 8% yield of
4Ab. By the addition of Zn and Zn(OAc)2 to these reactions,
the yield of 4Ab was improved to over 40% in all cases. Judging
from these results, we postulated that a Ni−arenoxo complex
such as 8 would be a resting-state intermediate. To gain further
insight into the effects of Zn and Zn(OAc)2 particularly on the
aryl−Ni−arenoxo complex, the reaction of aromatic ester 3c
with the Ni(cod)2/dcypt catalyst was performed (Figure 2F,
entry 1). As a result, we obtained arene 10 in 8% yield, which
was thought to be a decomposed compound from the aryl−
Ni−arenoxo species. Furthermore, the formation of 10 was
Combining the results from these mechanistic studies, a
postulated catalytic cycle is illustrated in Figure 2G. The
Ni(0)dcypt complex can undergo two separate oxidative
addition pathways, onto aryl sulfide 1 and onto aromatic
ester 3, to generate aryl−Ni−SR species B and aryl−Ni−
arenoxo species C, respectively. These complexes can react
with each other, namely, via an exchange reaction, to give D
and E. The reductive elimination of D can furnish aryl-
exchanged product 4. On the other hand, intermediate E can
be decomposed by Zn and Zn(OAc)2 to afford an arene and
regenerate Ni(0) species A. In this catalytic cycle, all of the
steps except for the oxidative addition of 3 to A and the
decomposition of E (and C) are thought to be reversible.
These mechanistic studies informed us that the Ni(0)
regeneration step from intermediate E would be a turnover-
limiting step. Although Zn and Zn(OAc)2 enhanced this
process, these zinc reagents also effected the undesired
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decomposition of Ni−arenoxo intermediate C. Probably due
to this difficulty, the substrate generality of this reaction turned
out to be narrow (Scheme 1). For instance, the reactions of
the aryl exchange reaction by using Ni(cod)2/dcypt in toluene
at 150 °C (Figure 3B). Delightfully, the reaction furnished aryl
sulfide 4Ab in 48% yield together with decarbonylative
etherification product 12 in 53% yield. The reverse reaction
was also conducted, generating only a tiny amount of 11A.
This suggested that the reaction is no longer reversible with
11A. In contrast, when 1A was subjected to these conditions
instead of 11A, we confirmed that the reaction was completely
reversible (details in the SI).
Scheme 1. Substrate Scope of the Reaction Using 1A and
a
6A
Encouraged by this result, we optimized the reaction
conditions by using 11A and 3d (Table 2). The use of
a
Table 2. Optimization of Reaction Conditions Using 11A
Zn 60
mol %
Zn(OAc)2
50 mol %
Na3PO4
yield of
yield of
b
a
b
Conditions: 1A or 6A (0.20 mmol), 3 (2.0 equiv), Ni(OAc)2 (10
entry
2.0 equiv
4Ad/%
12/%
mol %), dcypt (15 mol %), Zn (60 mol %), Zn(OAc)2 (50 mol %),
Na3PO4 (2.0 equiv), toluene (0.80 mL), 150 °C, and 24 h.
1
2
3
4
5
23
26
30
46
49
66
20
4
33
54
54
81
○
○
○
○
○
○
○
○
electron-rich (3c) as well as electron-deficient (3d) aromatic
esters with 1A gave the corresponding aryl sulfides 4 in low
yields. Even when we changed sulfide donor 1A to electron-
deficient 6A, the yield of 4Ae did not improve. In order to
solve this issue, we sought an alternative protocol capable of
accelerating the turnover-limiting decomposition of E
selectively.
c
d
c
6
a
Conditions: 11A (0.20 mmol), 3d (2.0 equiv), Ni(cod)2 (10 mol
%), dcypt (15 mol %), toluene (0.80 mL), 150 °C, and 12 h.
Determined by H NMR analysis. Zn (1.0 equiv). 24 h.
b
c
d
1
To this end, we focused on employing 2-pyridyl sulfide as a
sulfide donor (Figure 3A). We previously developed a
Ni(cod)2/dcypt afforded 4Ad in 23% yield and 12 in 20% yield
(Table 2, entry 1). When 11A was used as a sulfide donor, the
addition of Zn(OAc)2 and Na3PO4 was not effective, but the
addition of only Zn improved the yields of 4Ad and 12 (Table
2, entries 2−4). Increasing the amount of Zn slightly improved
the yield (Table 2, entry 5).19 Finally, a longer reaction time
gave the best result (Table 2, entry 6).
With the optimized conditions in hand, we then evaluated
the substrate scope of the present reaction (Scheme 2). First,
we examined the scope of sulfide groups. This reaction
successfully transferred primary, secondary, and tertiary alkyl
sulfide groups to give the corresponding aryl sulfides in
moderate yields (4Bb, 4Cb, and 4Db). Of note, for methyl
sulfide 4Bb synthesis, the present method is more advanta-
geous than typical cross-coupling methods using methanethiol
because methanethiol is a gaseous (bp = 6 °C) and strongly
odorous reagent, often associated with cumbersome handling.
Other alkyl sulfides bearing CF3 (4Eb), cyclobutyl (4Fb, 4Ff),
and arenes (4Gb) were synthesized in acceptable yields.
Nitrogen substituents on sulfide groups were compatible with
the present reaction (4Hb, 4Ib, and 4Ig). The scope of arenes
was next investigated. It was revealed that para and meta
substituents did not effect on this reaction significantly (4Aa
and 4Ah); however, ortho substituents inhibited the reaction
due to steric repulsions with the catalyst (4Ai). With respect to
the electronic nature of substituents, both electron-donating
and electron-withdrawing groups at the para position were
applicable to the present reaction. Aryl sulfides bearing methyl
(4Aj), methoxy (4Ad), phenoxy (4Ak), and dioxole (4Al)
were obtained in moderate yields. Compared to Morandi’s
recent method that was mainly effective for the synthesis of
aryl sulfides with electron-withdrawing groups,14 it is note-
worthy that our present reaction can also synthesize highly
Figure 3. (A) 2-Pyridyl sulfide for a funneling strategy. (B) Forward
reaction and reverse reaction of 11A. See the SI for details.
decarbonylative synthesis of diarylethers, where we found
that only the reductive elimination of 2-azinyl−O bonds from a
Ni/dcypt complex was facile but that of other aryl−O bonds
was difficult.17,18 Accordingly, the use of 2-pyridyl sulfide can
“funnel” this reversible catalytic cycle into desired products 4
by the selective enhancement of the reductive elimination of
intermediate E. To support this funneling strategy, we first
subjected 2-pyridyl sulfide 11A, which can be synthesized from
pyridine-2-thiol with alkyl bromides, with aromatic ester 3b to
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a
Scheme 2. Substrate Scope of the Reaction Using 11
a
In the scheme: aConditions: 11 (0.40 mmol), 3 (2.0 equiv), Ni(cod)2 (10 mol %), dcypt (15 mol %), Zn (1.0 equiv), toluene (1.6 mL), 150 °C,
b
c
and 24 h. Yields of isolated products are shown. Obtained as a sulfone after oxidation by mCPBA. Obtained as a sulfoxide after oxidation by
oxone.
electron-rich arenes such as methoxy and phenoxy aryl sulfides
(4Ad and 4Ak). Several electron-withdrawing groups including
highly reactive functional groups such as alkyl ester (4Ae),
cyano (4An), ketone (4Ao), and amide (4Ap) were tolerated.
Naphthyl sulfides (4Ab and 4Aq) were obtained in good to
moderate yields. The exchange reaction of heteroaromatic
esters was also viable to this reaction, furnishing the
corresponding heteroaryl sulfides in moderate yields (4Ff,
4Ar, 4As, and 4At).
Scheme 3. (A) Intramolecular Reaction of 13 and (B) the
Reaction Using Thioester 15
We then performed this reaction in an intramolecular
setting. Pyridine 13 bearing both a sulfide and a tolylester was
treated under the optimized conditions (Scheme 3A). As a
result, we obtained 2-arenoxylated 3-pyridyl sulfide 14 in 35%
yield. This transformation proceeds through a double exchange
reaction on the pyridine ring, which is rare in other exchange
reactions.10 Next, we expected that thioester 15 can be used as
a sulfide donor through our previously developed Ni-catalyzed
decarbonylation5e to form 2-pyridyl sulfide in situ (Scheme
3B). Delightfully, under the Ni/dcypt catalysis, we obtained
aryl sulfide product 16 in 62% yield along with 2-
arenoxypyridine 12 in 69% yield.
Because the Ni/dcypt catalyst is known to be effective for
the oxidative addition of aryl halides as well as arenol
derivatives, we thought that it is possible to utilize aryl
electrophiles other than aromatic esters (Scheme 4).12
Delightfully, Ni/dcypt/Zn catalysis was found to be applicable
to aryl pivalate, carbamate, carbonate, sulfonate, bromide, and
chlorides, giving desired aryl sulfide 4Ab in generally good
yields.20 We evaluated the substrate generality of the reaction
using aryl pivalates 17 and aryl carbamates 18. Pivalates 17
bearing both electron-donating groups (17j, 17u, and 17v) and
phenyl (17h) engaged in this reaction to give the
corresponding aryl sulfides. Sensitive functional groups such
as esters (17e), ketones (17w and 17x), secondary amides
(17y), and boronic esters (17z) were tolerated. Pyridyl (18r)
and quinolinyl (18aa) carbamates were also suitable substrates,
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a
Scheme 4. Scope of Sulfide Acceptors
Scheme 5. Late-Stage C−S Bond Formation via Functional
a
Group Interconversion
a
(In the scheme) aConditions: 11 (0.40 mmol), 23 (2.0 equiv),
Ni(cod)2 (10 mol %), dcypt (15 mol %), Zn (1.0 equiv), toluene (1.6
a
a
In the scheme: Conditions: 11A (0.40 mmol), 17−22 (2.0 equiv),
mL), 150 °C, and 24 h. Yields of isolated products are shown.
c
bObtained as a sulfone after oxidation by oxone. Obtained as a
Ni(cod)2 (10 mol %), dcypt (15 mol %), Zn (1.0 equiv), toluene (1.6
mL), 150 °C, and 24 h. Yields of isolated products are shown.
bObtained as a sulfone after oxidation by mCPBA.
d
sulfoxide after oxidation by mCPBA. Obtained as a sulfone after
e
oxidation by mCPBA. Ni(OAc)2 (10 mol %), dcypt (15 mol %),
Na3PO4 (2.0 equiv), Zn (60 mol %), and Zn(OAc)2 (50 mol %).
being converted to the corresponding aryl sulfides in good
yields. Furthermore, naphthalene with both pivalate and aryl
ester (17ab) was tested to examine which group reacts faster.
As a result, aromatic ester 4Aab was obtained as a major
product in 56% yield (details in the SI).
aryl sulfide synthesis without using highly nucleophilic and
odorous thiols. Mechanistic studies confirmed that this
reaction proceeded through two oxidative additions of aryl
sulfides and aromatic esters at the same time, followed by an
exchange reaction between the resulting nickel complexes.
Further studies to develop other aryl exchange reactions and
detailed mechanistic studies are ongoing in our laboratory.22
Aromatic esters, arenols, and aryl halides are frequently seen
in natural products and pharmaceuticals. Expecting that the
present method can be applied to a late-stage C−S bond
formation via functional group interconversion, we performed
reactions on known substrates with many functional groups.21
As a result, we succeeded in derivatizing biologically active
molecules such as probenecid aryl ester, flavone, estrone,
phenylalanine, umbelliferone, and β-isocupreidine pivalates in
good yields (Scheme 5). Drug molecules containing an aryl
chloride moiety were also transformed to the corresponding
aryl sulfides in good yields. Of note, in these demonstrations, it
was shown that the present method was compatible with
reactive functional groups such as ketones, imides, esters,
tertiary amines, and tertiary alcohol groups.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c04215.
■
sı
Experimental procedures and spectroscopic data for
compounds including 1H, 13C, 19F, and 31P NMR
spectra and crystallographic data. (PDF)
Accession Codes
CCDC 2074846 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
CONCLUSIONS
■
We have developed a Ni-catalyzed aryl sulfide synthesis
through an aryl exchange. By using 2-pyridyl sulfide as a sulfide
donor, not only aromatic esters but also arenols and haloarenes
can be used as a sulfide acceptor. This method presents a new
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2006, 128, 2180−2181. (d) Sayah, M.; Organ, M. G. Carbon-Sulfur
Bond Formation of Challenging Substrates at Low Temperature by
Using Pd-PEPPSI-IPent. Chem. - Eur. J. 2011, 17, 11719−11722.
(e) Kwong, F. Y.; Buchwald, S. L. A General, Efficient, and
Inexpensive Catalyst System for the Coupling of Aryl Iodides and
Thiols. Org. Lett. 2002, 4, 3517−3520. (f) Liu, B.; Lim, C.-H.;
Miyake, G. M. Visible-Light-Promoted C-S Cross-Coupling via
Intermolecular Charge Transfer. J. Am. Chem. Soc. 2017, 139,
13616−13619. (g) Wang, X.; Cuny, G. D.; Noël, T. A Mild, One-Pot
Stadler-Ziegler Synthesis of Arylsulfides Facilitated by Photoredox
Catalysis in Batch and Continuous-Flow. Angew. Chem., Int. Ed. 2013,
52, 7860−7864. (h) Uyeda, C.; Tan, Y.; Fu, G. C.; Peters, J. C. A New
Family of Nucleophiles for Photoinduced, Copper-Catalyzed Cross-
Couplings via Single-Electron Transfer: Reactions of Thiols with Aryl
Halides Under Mild Conditions (0 °C). J. Am. Chem. Soc. 2013, 135,
9548−9552. (I) Yin, G.; Kalvet, I.; Englert, U.; Schoenebeck, F.
Fundamental Studies and Development of Nickel-Catalyzed Tri-
fluoromethylthiolation of Aryl Chlorides: Active Catalytic Species and
Key Roles of Ligand and Traceless MeCN Additive Revealed. J. Am.
Chem. Soc. 2015, 137, 4164−4172. (j) Oderinde, M. S.; Frenette, M.;
Robbins, D. W.; Aquila, B.; Johannes, J. W. Photoredox Mediated
Nickel Catalyzed Cross-Coupling of Thiols with Aryl and Heteroaryl
Iodides via Thiyl Radicals. J. Am. Chem. Soc. 2016, 138, 1760−1763.
(4) (a) Taniguchi, N. Alkyl- or Arylthiolation of Aryl Iodide via
Cleavage of the S-S Bond of Disulfide Compound by Nickel Catalyst
and Zinc. J. Org. Chem. 2004, 69, 6904−6906. (b) Taniguchi, N.;
Onami, T. Magnesium-Induced Copper-Catalyzed Synthesis of
Unsymmetrical Diaryl Chalcogenide Compounds from Aryl Iodide
via Cleavage of the Se-Se or S-S Bond. J. Org. Chem. 2004, 69, 915−
920.
AUTHOR INFORMATION
Corresponding Author
Junichiro Yamaguchi − Department of Applied Chemistry,
Waseda University, Shinjuku, Tokyo 162-0041, Japan;
orcid.org/0000-0002-3896-5882;
■
Email: junyamaguchi@waseda.jp
Authors
Ryota Isshiki − Department of Applied Chemistry, Waseda
University, Shinjuku, Tokyo 162-0041, Japan
Miki B. Kurosawa − Department of Applied Chemistry,
Waseda University, Shinjuku, Tokyo 162-0041, Japan;
orcid.org/0000-0002-8995-5377
Kei Muto − Waseda Institute for Advanced Study, Waseda
University, Shinjuku, Tokyo 162-0041, Japan; orcid.org/
0000-0001-8301-4384
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c04215
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI grant numbers
JP JP19H02726 (to J.Y.), JP21K05079 and JP20H04829
(hybrid catalysis) (to K.M.), and JP19J23053 and a Waseda
Research Institute for Science and Engineering Grant in Aid
for Young Scientists (Early Bird) (to R.I.). This work was also
partially supported by JST ERATO grant number
JPMJER1901 (to J.Y.). We thank Dr. Kenta Kato (Waseda
University) for assistance with X-ray crystallographic analysis.
We also thank the National Institute of Health Sciences in
Japan for the support of NMR measurements. The Materials
Characterization Central Laboratory in Waseda University is
acknowledged for the support of the HRMS measurement.
(5) (a) Osakada, K.; Yamamoto, T.; Yamamoto, A. Decarbonylation
of Thiol Esters to Give Sulfides Promoted by Transition Metal
Complexes. Tetrahedron Lett. 1987, 28, 6321−6324. (b) Ichiishi, N.;
́
Malapit, C. A.; Wozniak, Ł.; Sanford, M. S. Palladium- and Nickel-
Catalyzed Decarbonylative C-S Coupling to Convert Thioesters to
Thioethers. Org. Lett. 2018, 20, 44−47. (c) Lee, S.-C.; Liao, H.-H.;
Chatupheeraphat, A.; Rueping, M. Nickel-Catalyzed C-S Bond
Formation via Decarbonylative Thioetherification of Esters, Amides
and Intramolecular Recombination Fragment Coupling of Thioesters.
Chem. - Eur. J. 2018, 24, 3608−3612. (d) Liu, C.; Szostak, M.
Decarbonylative Thioetherification by Nickel Catalysis using Air- and
Moisture-stable Nickel Precatalysts. Chem. Commun. 2018, 54, 2130−
2133. (e) Ishitobi, K.; Isshiki, R.; Asahara, K. K.; Lim, C.; Muto, K.;
Yamaguchi, J. Decarbonylative Aryl Thioether Synthesis by Ni
Catalysis. Chem. Lett. 2018, 47, 756−759.
REFERENCES
■
(1) (a) Dunbar, K. L.; Scharf, D. H.; Litomska, A.; Hertweck, C.
Enzymatic Carbon-Sulfur Bond Formation in Natural Product
Biosynthesis. Chem. Rev. 2017, 117, 5521−5577. (b) Ilardi, E. A.;
Vitaku, E.; Njardarson, J. T. Data-Mining for Sulfur and Fluorine: An
Evaluation of Pharmaceuticals to Reveal Opportunities for Drug
Design and Discovery. J. Med. Chem. 2014, 57, 2832−2842. (c) Zhao,
C.; Rakesh, K. P.; Ravidar, L.; Fang, W.-Y.; Qin, H.-L. Pharmaceutical
and Medicinal Significance of Sulfur (SVI)-Containing Motifs for Drug
Discovery: A Critical Review. Eur. J. Med. Chem. 2019, 162, 679−734.
(2) For selected reviews of C−S bond formation, see (a) Kondo, T.;
Mitsudo, T. Metal-Catalyzed Carbon-Sulfur Bond Formation. Chem.
Rev. 2000, 100, 3205−3220. (b) Ley, S. V.; Thomas, A. W. Modern
Synthetic Methods for Copper-Mediated C(aryl)-O, C(aryl)-N, and
C(aryl)-S Bond Formation. Angew. Chem., Int. Ed. 2003, 42, 5400−
5449. (c) Beletskaya, I. P.; Ananikov, V. P. Transition-Metal-
Catalyzed C-S, C-Se, and C-Te Bond Formation via Cross-Coupling
and Atom-Economic Addition Reactions. Chem. Rev. 2011, 111,
1596−1636.
(3) For representative examples of C−S bond-forming cross-
coupling, see (a) Kosugi, M.; Shimizu, T.; Migita, T. Reactions of
Aryl Halides with Thiolate Anions in the Presence of Catalytic
Amounts of Tetrakis(Triphenylphosphine)Palladium Preparation of
Aryl Sulfides. Chem. Lett. 1978, 7, 13−14. (b) Murata, M.; Buchwald,
S. L. A General and Efficient Method for the Palladium-Catalyzed
Cross-Coupling of Thiols and Secondary Phosphines. Tetrahedron
2004, 60, 7397−7403. (c) Fernández-Rodríguez, M. A.; Shen, Q.;
Hartwig, J. F. A General and Long-Lived Catalyst for the Palladium-
Catalyzed Coupling of Aryl Halides with Thiols. J. Am. Chem. Soc.
(6) (a) Mao, J.; Jia, T.; Frensch, G.; Walsh, P. J. Palladium-Catalyzed
Debenzylative Cross-Coupling of Aryl Benzyl Sulfides with Aryl
Bromides: Synthesis of Diaryl Sulfides. Org. Lett. 2014, 16, 5304−
5307. (b) Li, Y.; Bao, G.; Wu, X.-F. Palladium-Catalyzed
Intermolecular Transthioetherification of Aryl Halides with Thio-
ethers and Thioesters. Chem. Sci. 2020, 11, 2187−2192.
(7) Cham−Lam−Evans-type aryl sulfide synthesis using arylboronic
acids with sulfur imides was also reported. Savarin, C.; Srogl, J.;
Liebeskind, L. S. A Mild, Nonbasic Synthesis of Thioethers. The
Copper-Catalyzed Coupling of Boronic Acids with N-Thio(alkyl, aryl,
heteroaryl)imides. Org. Lett. 2002, 4, 4309−4312.
(8) For reviews on a functional group transfer reaction, see
(a) Bhawal, B. N.; Morandi, B. Catalytic Isofunctional Reactions
Expanding the Repertoire of Shuttle and Metathesis Reactions. Angew.
Chem., Int. Ed. 2019, 58, 10074−10103. (b) Boehm, P.; Morandi, B.
New Catalysis Concepts for Molecular Design and Feedstocks
Valorization. Chimia 2020, 74, 724−729.
(9) Conceptually similar transfer reactions were also known. (a) Jun,
C.-H.; Lee, H. Catalytic Carbon-Carbon Bond Activation of
Unstrained Ketone by Soluble Transition-Metal Complex. J. Am.
Chem. Soc. 1999, 121, 880−881. (b) Arisawa, M.; Igarashi, Y.;
Kobayashi, H.; Yamada, T.; Bando, K.; Ichikawa, T.; Yamaguchi, M.
Equilibrium Shift in the Rhodium-Catalyzed Acyl Transfer Reactions.
Tetrahedron 2011, 67, 7846−7859. (c) Murphy, S. K.; Park, J.-W.;
10339
https://doi.org/10.1021/jacs.1c04215
J. Am. Chem. Soc. 2021, 143, 10333−10340

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Cruz, F. A.; Dong, V. M. Rh-Catalyzed C-C Bond Cleavage by
Transfer Hydroformylation. Science 2015, 347, 56−60. (d) Fang, X.;
Yu, P.; Morandi, B. Catalytic Reversible Alkene-Nitrile Interconver-
sion Through Controllable Transfer Hydrocyanation. Science 2016,
351, 832−836. (e) Fan, C.; Lv, X.-Y.; Xiao, L.-J.; Xie, J.-H.; Zhou, Q.-
L. Alkenyl Exchange of Allylamines via Nickel(0)-Catalyzed C-C
Bond Cleavage. J. Am. Chem. Soc. 2019, 141, 2889−2893. (f) Kanda,
T.; Naraoka, A.; Naka, H. Catalytic Transfer Hydration of
Cyanohydrins to α-Hydroxyamides. J. Am. Chem. Soc. 2019, 141,
825−830.
(10) (a) Lee, Y. H.; Morandi, B. Metathesis-Active Ligands Enable a
Catalytic Functional Group Metathesis Between Aroyl Chlorides and
Aryl Iodides. Nat. Chem. 2018, 10, 1016−1022. (b) De La Higuera
Macias, M.; Arndtsen, B. A. Functional Group Transposition: A
Palladium-Catalyzed Metathesis of Ar-X σ-Bonds and Acid Chloride
Synthesis. J. Am. Chem. Soc. 2018, 140, 10140−10144.
(11) Isshiki, R.; Inayama, N.; Muto, K.; Yamaguchi, J. Ester Transfer
Reaction of Aromatic Esters with Haloarenes and Arenols by a Nickel
Catalyst. ACS Catal. 2020, 10, 3490−3494.
(12) For examples of the Ni/dcypt-catalyzed reaction involving the
cleavage of inert bonds, see (a) Takise, R.; Muto, K.; Yamaguchi, J.;
Itami, K. Nickel-Catalyzed α-Arylation of Ketones with Phenol
Derivatives. Angew. Chem., Int. Ed. 2014, 53, 6791−6794. (b) Koch,
E.; Takise, R.; Studer, A.; Yamaguchi, J.; Itami, K. Ni-Catalyzed α-
Arylation of Esters and Amides with Phenol Derivatives. Chem.
Commun. 2015, 51, 855−857. (c) Takise, R.; Itami, K.; Yamaguchi, J.
Cyanation of Phenol Derivatives with Aminoacetonitriles by Nickel
Catalysis. Org. Lett. 2016, 18, 4428−4431. (d) Muto, K.; Hatakeyama,
T.; Yamaguchi, J.; Itami, K. C-H Arylation and Alkenylation of
Imidazoles by Nickel Catalysis: Solvent-Accelerated Imidazole C-H
Activation. Chem. Sci. 2015, 6, 6792−6798. (e) Isshiki, R.; Muto, K.;
Yamaguchi, J. Decarbonylative C-P Bond Formation Using Aromatic
Esters and Organophosphorus Compounds. Org. Lett. 2018, 20,
1150−1153. (f) Okita, T.; Muto, K.; Yamaguchi, J. Decarbonylative
Methylation of Aromatic Esters by a Nickel Catalyst. Org. Lett. 2018,
20, 3132−3135. (g) Iizumi, K.; Kurosawa, M. B.; Isshiki, R.; Muto, K.;
Yamaguchi, J. Decarbonylative Synthesis of Aryl Nitriles from
Aromatic Esters and Organocyanides by a Nickel Catalyst. Synlett
2020, eFirst. DOI: 10.1055/s-0040-1705943.
2013, 42, 599−621. (d) Barbero, N.; Martin, R. Ligand-Free Ni-
Catalyzed Reductive Cleavage of Inert Carbon-Sulfur Bonds. Org.
Lett. 2012, 14, 796−799 For selected examples, see. (e) Sugahara, T.;
Murakami, K.; Yorimitsu, H.; Osuka, A. Palladium-Catalyzed
Amination of Aryl Sulfides with Anilines. Angew. Chem., Int. Ed.
2014, 53, 9329−9333. (f) Tobisu, M.; Masuya, Y.; Baba, K.; Chatani,
N. Palladium(ii)-Catalyzed Synthesis of Dibenzothiophene Deriva-
tives via the Cleavage of Carbon-Sulfur and Carbon-Hydrogen Bonds.
Chem. Sci. 2016, 7, 2587−2591. (g) Ma, Y.; Cammarata, J.; Cornella,
J. Ni-Catalyzed Reductive Liebeskind-Srogl Alkylation of Hetero-
cycles. J. Am. Chem. Soc. 2019, 141, 1918−1922. (h) Lian, Z.; Bhawal,
B. N.; Yu, P.; Morandi, B. Palladium-Catalyzed Carbon-Sulfur or
Carbon-Phosphorus Bond Metathesis by Reversible Arylation. Science
2017, 356, 1059−1063. (i) Delcaillau, T.; Bismuto, A.; Lian, Z.;
Morandi, B. Nickel-Catalyzed Inter- and Intramolecular Aryl
Thioether Metathesis by Reversible Arylation. Angew. Chem., Int.
Ed. 2020, 59, 2110−2114. (j) Bismuto, A.; Delcaillau, T.; Muller, P.;
̈
Morandi, B. Nickel-Catalyzed Amination of Aryl Thioethers: A
Combined Synthetic and Mechanistic Study. ACS Catal. 2020, 10,
4630−4639.
(17) Takise, R.; Isshiki, R.; Muto, K.; Itami, K.; Yamaguchi, J.
Decarbonylative Diaryl Ether Synthesis by Pd and Ni Catalysis. J. Am.
Chem. Soc. 2017, 139, 3340−3343.
(18) For selected reviews on catalytic decarbonylative trans-
formation, see (a) Takise, R.; Muto, K.; Yamaguchi, J. Cross-
Coupling of Aromatic Esters and Amides. Chem. Soc. Rev. 2017, 46,
5864−5888. (b) Lu, H.; Yu, T.-Y.; Xu, P.-F.; Wei, H. Selective
Decarbonylation via Transition-Metal-Catalyzed Carbon-Carbon
Bond Cleavage. Chem. Rev. 2021, 121, 365−411.
(19) It was found that 12 inhibits this present reaction by
coordinating to a nickel catalyst. The addition of Zn(0) can form
an insoluble zinc-12 complex to maintain the catalytic activity of
nickel. See the SI for details.
(20) When these aryl electrophiles were used, the corresponding 2-
pyridine−X (X = halogen, OR, etc) species were generated, albeit in
much lower yields than aryl sulfide products. (See the SI for details.)
(21) (a) Dominguez-Huerta, A.; Dai, X.-J.; Zhou, F.; Querard, P.;
Qiu, Z.; Ung, S.; Liu, W.; Li, J.; Li, C.-J. Exploration of New Reaction
Tools for Late-Stage Functionalization of Complex Chemicals. Can. J.
Chem. 2019, 97, 67−85. (b) Cannalire, R.; Pelliccia, S.; Sancineto, L.;
Novellino, E.; Tron, G. C.; Giustiniano, M. Visible Light Photo-
catalysis in the Late-Stage Functionalization of Pharmaceutically
Relevant Compounds. Chem. Soc. Rev. 2021, 50, 766−897. (c) Hong,
B.; Luo, T.; Lei, X. Late-Stage Diversification of Natural Products.
ACS Cent. Sci. 2020, 6, 622−635. (d) Cernak, T.; Dykstra, K. D.;
Tyagarajan, S.; Vachal, P.; Krska, S. W. The Medicinal Chemist’s
Toolbox for Late Stage Functionalization of Drug-like Molecules.
Chem. Soc. Rev. 2016, 45, 546−576.
(13) (a) Mann, G.; Baranano, D.; Hartwig, J. F.; Rheingold, A. L.;
Guzei, I. A. Carbon-Sulfur Bond-Forming Reductive Elimination
Involving sp-, sp2-, and sp3-Hybridized Carbon. Mechanism, Steric
Effects, and Electronic Effect on Sulfide Formation. J. Am. Chem. Soc.
1998, 120, 9205−9219. (b) Alvaro, E.; Hartwig, J. F. Resting State
and Elementary Steps of the Coupling of Aryl Halides with Thiols
Catalyzed by Alkylbisphosphine Complexes of Palladium. J. Am.
Chem. Soc. 2009, 131, 7858−7868.
(14) Delcaillau, T.; Boehm, P.; Morandi, B. Nickel-Catalyzed
Reversible Functional Group Metathesis between Aryl Nitriles and
Aryl Thioethers. J. Am. Chem. Soc. 2021, 143, 3723−3728.
(22) A prior version of the present article was deposited as a preprint
on ChemRxiv: Isshiki, R.; Kurosawa, M. B.; Muto, K.; Yamaguchi, J.
Ni-Catalyzed Aryl Sulfide Synthesis through an Aryl Exchange
Reaction. ChemRxiv Preprint 2021, DOI: 10.26434/chem-
rxiv.14462376.
(15) For reductive biaryl couplings using Ni/Zn catalysis, see
(a) Ackerman, L. K. G.; Lovell, M. M.; Weix, D. J. Multimetallic
Catalysed Cross-Coupling of Aryl Bromides with Aryl Triflates.
Nature 2015, 524, 454−457. (b) Huang, L.; Ackerman, L. K. G.;
Kang, K.; Parsons, A. M.; Weix, D. J. LiCl-Accelerated Multimetallic
Cross-Coupling of Aryl Chlorides with Aryl Triflates. J. Am. Chem.
Soc. 2019, 141, 10978−10983. (c) Kang, K.; Huang, L.; Weix, D. J.
Sulfonate versus Sulfonate: Nickel and Palladium Multimetallic Cross-
Electrophile Coupling of Aryl Triflates with Aryl Tosylates. J. Am.
Chem. Soc. 2020, 142, 10634−10640.
(16) For reviews of catalytic reactions through C(aryl)−S bond
oxidative addition, see (a) Dubbaka, S. R.; Vogel, P. Organosulfur
Compounds: Electrophilic Reagents in Transition-Metal-Catalyzed
Carbon-Carbon Bond-Forming Reactions. Angew. Chem., Int. Ed.
2005, 44, 7674−7684. (b) Modha, S. G.; Mehta, V. P.; Van der
Eycken, E. V. Transition Metal-Catalyzed C-C Bond Formation via C-
S Bond Cleavage: An Overview. Chem. Soc. Rev. 2013, 42, 5042−
5055. (c) Wang, L.; He, W.; Yu, Z. Transition-Metal Mediated
Carbon-Sulfur Bond Activation and Transformations. Chem. Soc. Rev.
10340
https://doi.org/10.1021/jacs.1c04215
J. Am. Chem. Soc. 2021, 143, 10333−10340