Ni(II) Precatalysts Enable Thioetherification of (Hetero)Aryl Halides and Tosylates and Tandem C?S/C?N Couplings

Article abstract of DOI:10.1002/chem.202101906

Ni-catalyzed C?S cross-coupling reactions have received less attention compared with other C-heteroatom couplings. Most reported examples comprise the thioetherification of most reactive aryl iodides with aromatic thiols. The use of C?O electrophiles in this context is almost uncharted. Here, we describe that preformed Ni(II) precatalysts of the type NiCl(allyl)(PMe₂Ar’) (Ar’=terphenyl group) efficiently couple a wide range of (hetero)aryl halides, including challenging aryl chlorides, with a variety of aromatic and aliphatic thiols. Aryl and alkenyl tosylates are also well tolerated, demonstrating, for the first time, to be competent electrophilic partners in Ni-catalyzed C?S bond formation. The chemoselective functionalization of the C?I bond in the presence of a C?Cl bond allows for designing site-selective tandem C?S/C?N couplings. The formation of the two C-heteroatom bonds takes place in a single operation and represents a rare example of dual electrophile/nucleophile chemoselective process.

Full text of DOI:10.1002/chem.202101906

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Ni(II) Precatalysts Enable Thioetherification of (Hetero)Aryl
Halides and Tosylates and Tandem CÀ S/CÀ N Couplings
M. Trinidad Martín,[a] Mario Marín,[a] Celia Maya,[b] Auxiliadora Prieto,*[c] and
M. Carmen Nicasio*[a]
Abstract: Ni-catalyzed CÀ S cross-coupling reactions have
received less attention compared with other C-heteroatom
couplings. Most reported examples comprise the thioether-
ification of most reactive aryl iodides with aromatic thiols. The
use of CÀ O electrophiles in this context is almost uncharted.
Here, we describe that preformed Ni(II) precatalysts of the
type NiCl(allyl)(PMe2Ar’) (Ar’=terphenyl group) efficiently
aliphatic thiols. Aryl and alkenyl tosylates are also well
tolerated, demonstrating, for the first time, to be competent
electrophilic partners in Ni-catalyzed CÀ S bond formation.
The chemoselective functionalization of the CÀ I bond in the
presence of a CÀ Cl bond allows for designing site-selective
tandem CÀ S/CÀ N couplings. The formation of the two C-
heteroatom bonds takes place in a single operation and
represents a rare example of dual electrophile/nucleophile
chemoselective process.
couple
a wide range of (hetero)aryl halides, including
challenging aryl chlorides, with a variety of aromatic and
Introduction
both copper- and palladium-based catalyst systems have
proven to be very effective and versatile in terms of functional
group tolerance.[5] However, an important limitation of the less
expensive copper approach is the inefficiency to couple
chloroarenes or phenol-derived electrophiles in a reliable
manner.[6] Conversely, thioetherification of challenging aryl
chlorides has been successfully accomplished with palladium
using bisphosphines[7–8] and N-heterocyclic carbene ligands.[9]
However, so far, only limited examples of the use aryl
triflates[7a,10] as electrophilic coupling partners and a single case
illustrating the coupling between phenyl tosylate[7a] with 1-
octanethiol under palladium catalysis have been reported. The
synthesis of alkenyl sulfides through Pd-catalyzed coupling of
alkenyl tosylates and thiols have been recently described.[11]
Nickel is able to activate those bonds that are less reactive
with copper and palladium.[12] However, it is noticeable the
scarcity of protocols developed for using aryl chlorides as
electrophiles in CÀ S bond forming reactions.[13] In these
reported examples, chelating ligands (i.e. diamines,[13a] Schiff
bases,[13e] bisphosphines[13b–d]) were employed to stabilize Ni
species and, in some cases, stoichiometric amount of a
reductant (i.e. Zn,[13c] organomagnesium or organozinc
reagents[13d]) were required to achieve an efficient transforma-
tion. Very recently, electrochemical Ni-catalyzed thioetherifica-
tion of aryl bromides and chlorides has been described,[14] but
only electron-deficient chloroarenes are successfully coupled
under these conditions.[14a] Regarding the use of phenol-derived
electrophiles in Ni-catalyzed CÀ S cross-coupling, in 1995, Percec
and co-workers[15] outlined the first and, to our knowledge, the
only application of phenol-derived electrophiles in the synthesis
of diaryl sulfides catalyzed by Ni(0) species. High yield of the
CÀ S coupling product was obtained when combining phenyl
mesylate with sodium benzenethiolate. However, attempts to
extend the scope to p-substituted aryl mesylates resulted in low
yields of non-symmetrical disulfides together with considerable
Thioethers are prevalent in many natural products,[1] in addition
to being valuable intermediates for pharmaceutical[2] and
material science[3] applications. Moreover, the rising interest in
the activation of CÀ S bonds by transition metals has opened up
new opportunities to transform thioethers into diverse function-
alized organic compounds.[4] A general approach for the
synthesis of thioethers relies on the use of transition metal-
catalyzed CÀ S cross-coupling reactions between organic halides
and thiols under basic conditions.[5] In these transformations,
[a] M. T. Martín, Dr. M. Marín, Prof. M. C. Nicasio
Departamento de Química Inorgánica
Universidad de Sevilla
Aptdo 1203, 41071 Sevilla (Spain)
E-mail: mnicasio@us.es
[b] Dr. C. Maya
Instituto de Investigaciones Químicas (IIQ)
Departamento de Química Inorgánica and Centro de Innovación en
Química Avanzada (ORFEO-CINQA)
Consejo Superior de Investigaciones Científicas (CSIC)
Universidad de Sevilla
Avda. Américo Vespucio 49, 41092 Sevilla (Spain)
[c] Dr. A. Prieto
Laboratorio de Catálisis Homogénea
Unidad Asociada al CSIC
CIQSO-Centro de Investigación en Química Sostenible and Departamento
de Química
Campus de El Carmen s/n, Universidad de Huelva
21007 Huelva (Spain)
E-mail: maria.prieto@diq.uhu.es
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/chem.202101906
© 2021 The Authors. Chemistry - A European Journal published by Wiley-
VCH GmbH. This is an open access article under the terms of the Creative
Commons Attribution Non-Commercial NoDerivs License, which permits use
and distribution in any medium, provided the original work is properly cited,
the use is non-commercial and no modifications or adaptations are made.
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amounts of side products (i.e. diphenyl sulfide and arene
resulting from reduction or aryl mesylate).
Monodentate ancillary ligands are rarely used to support
nickel catalysts for CÀ S bond forming reactions, the exception
being Ni complexes with N-heterocyclic carbenes (NHCs).[16]
Among the latter, well-defined complexes of the type (NHC)
Ni(allyl)Cl with a 1:1 nickel to ligand ratio described by us[16b] as
well as the group of Nolan,[16d] displayed excellent activities in
the coupling of aryl iodides and bromides with thiophenols,
although aryl chlorides were much less reactive. We wondered
whether analogous Ni(II)-allyl complexes ligated by electron-
rich and sterically-hindered monophosphine ligands might be
better candidates to promote the CÀ S coupling of problematic
substrates such as aryl chlorides and phenol-derived electro-
philes. In this vein, it has been recently shown the efficient
coupling of aryl bromides with thiols at room temperature
promoted by a monophosphine-based Pd catalyst.[17] Our group
has recently developed a family of strong electron-donating
and sterically demanding dialkylterphenyl phosphine ligands.[18]
The bulky terphenyl moiety in these phosphines provides
effective steric protection to the metal center along with
additional stabilization through weak MÀ Carene interactions
involving one of the flanking aryl rings.[19] These ligand features
could improve the Ni catalyst lifetime in CÀ S cross-coupling,
preventing thiolate-mediated deactivation.[20] With this in mind,
we prepared and structurally characterized a series of NiCl
(allyl)(PMe2Ar’) complexes (Ar’=terphenyl group). Their catalytic
activity have been examined in the S-arylation of aromatic and
aliphatic thiols with a variety of electrophiles, including aryl and
heteroaryl chlorides, bromides and iodides and, for the first
time, tosylates. In addition, a protocol for tandem CÀ S/CÀ N
couplings in a single reaction has been devised.
Scheme 1. Synthesis of complexes 1–3.
the two PÀ Me bound groups give rise to two distinct doublets
in the low-frequency region of the spectra (2JHP �8 Hz and JCP
1
�27 Hz). In turn, all these compounds show five distinct 1H
resonances for the allyl protons, consistent with an η3-bound
allyl ligand in a C1-symmetric molecule.[21] The terminal allylic
protons bound to the carbon atom in pseudo-trans position to
the phosphine appear at higher frequency (ca. 3.6–2.4 Hz) than
those in pseudo-trans position to the chloride (ca. 2.3–0.8 Hz).
The molecular structures of 1–3 were confirmed by X-ray
diffraction studies (Figure 1 and Figure S1). In these com-
pounds, the coordination sphere about the Ni atom is formed
by the phosphine ligand, the chloride and the three carbon
atoms of an η3-allyl group. As a result of the trans influence
exerted by the phosphine ligand, the NiÀ C1 bond distances
(2.053–2.078 Å) for the allyl carbon atoms pseudo-trans to the
phosphine are slightly longer than the NiÀ C3 bond distances
(1.982–1.997 Å) pseudo-trans to the chloride. In addition, the
C1–C2 separations are ca. 0.04 shorter than the C2–C3
(significant disorder at the allyl group in the structure of 3
precludes an accurate comparison of such bond distances). The
NiÀ P and NiÀ Cl bond lengths are similar to those reported for
Ni(II)-allyl complexes.[22]
Results and Discussion
Synthesis and structural characterization of Ni(II) complexes
The synthesis of NiCl(allyl)(PMe2Ar’) complexes 1–3 was accom-
plished by the addition of one equivalent of the dialkylterphen-
yl phosphine L1–L3 to a THF solution of (allyl)Ni(II) chloride-
bridged dimer, generated in situ via oxidative addition of allyl
chloride to Ni(COD)2 (COD=1,5-cyclooctadiene) (Scheme 1).
Compounds 1–3 were isolated in good yields (63–72%) as
orange crystalline materials by recrystallization from petroleum
Catalytic studies
The catalytic activity of compounds 1–3 in the CÀ S coupling of
iodobenzene with thiophenol, the model reaction, was eval-
uated. Complex 1 was selected as the precatalyst to optimize
the reaction conditions. Quantitative yield of the diphenyl
sulfide product was obtained when the trial was conducted in
°
ether : dichloromethane (2:1) mixtures at À 20 C. They were
moderately air stable as solids but decomposed in solution
when exposed to air.
°
dioxane at 110 C for 24 h, using 5 mol% catalyst loading and
Complexes 1–3 were characterized by elemental analyses
and NMR spectroscopy. In the 31P{1H} NMR spectra, the
resonances of the P nuclei are significantly shifted (ca. 30–
35 ppm) to higher frequencies with respect to the uncoordi-
NaOtBu as the base (see Table 1, entry 1). Decreasing the
reaction time up to 16 h does not erode the yield, whereas
incomplete conversions were observed when running the CÀ S
coupling for 8 h (Table 1, entries 2 and 3). The yield over the
same period of time (16 h) was not affected when the reaction
1
nated phosphine ligands. The room-temperature H and 13C{1H}
°
NMR spectra of these complexes are in agreement with a
monodentate coordination mode of the P ligand in conjunction
with fast rotation along PÀ Caryl bond on the NMR time scale.
However, the rotation around the PÀ Ni bond is hindered and
was performed at 100 C, but at lower temperature inferior
results were noted (entries 4 and 5). A set of experiments were
accomplished to adjust the catalyst loading. With 3 mol% of 1
full conversion of the iodobenzene was attained (entry 6), but a
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formation of the disulfide byproduct in any of experiments
discussed above.
Having identified the best performing Ni(II) precatalysts and
the suitable reaction conditions for the efficient thioetherifica-
tion of iodobenzene,[23] we tested other haloarenes as potential
coupling partners for the CÀ S coupling with thiophenol
(Table 2). Bromobenzene is somewhat less reactive than the
parent iodobenzene and a catalyst loading of 5 mol% was
required to ensure full conversion (Table 2, entries 1–3). The
more challenging chlorobenzene produced a sluggish reaction
in DMF even at higher loadings (10 mol%) and extended
reaction times (entries 4 and 5). However, we observed that
when the CÀ S coupling was undertaken in NMP (NMP=N-
°
methylpyrrolidone) at 120 C with
a catalyst loading of
10 mol%, the expected diphenyl sulfide was obtained in
excellent yield with both precatalysts (entries 6 and 7).
Following the optimization studies, complexes 1 and 2 were
selected for exploring the scope of these CÀ S couplings. As
summarized in Table 3, a collection of (hetero)aryl chlorides/
bromides/iodides reacted with a variety of thiophenols afford-
ing the coupling products in good-to-excellent yields. Both,
electron-rich (Table 3, 4b–f, 4h, 4i and 4t) and electron-
withdrawing substituents (Table 3, 4g, 4k, 4l) on the aryl
halides were well tolerated providing access to the correspond-
ing diarylsulfides in useful synthetic yields under the optimal
reaction conditions. Moreover, this catalytic protocol is also
compatible with ortho-substitution on both coupling partners
without the need of increasing the catalyst loading (4e, 4h–i,
4q, 4t). Interestingly, aryl iodides could be selectively coupled
with thiophenols in the presence of a chloride or a bromide
functionality (Table 3, 4k–l), allowing further derivatizations of
the corresponding sulfides (see below). Moreover, (p-
phenylene) sulfide oligomers (Table 3, 4m–n) were prepared
through two CÀ S bond formations from the reaction of 1-
chloro-4-iodobenzene with two equivalents of the correspond-
ing thiophenol, using the reaction conditions optimized for the
thiotherification of aryl chlorides. Compounds of this kind
exhibit interesting thermal and conducting properties.[24] Finally,
nitrogen-containing heteroaryl halides could be efficiently
Figure 1. Solid-state structures of complexes 1 (top) and 2 (bottom). Hydro-
gen atoms are omitted for clarity. Thermal ellipsoids are shown at 50%
°
probability. Selected bond lengths [Å] and angles [ ] for 1: Ni1-P1 2.1904(5),
Ni-Cl1 2.2047(5), Ni1-C1 2.078(2), Ni-C2 1.994(2), Ni-C3 1.982(2), C1-C2
1.362(4), C2-C3 1.405(4), C1-C2-C3 120.3(3), P1-Ni-Cl1 102.28(2); for 2: Ni1-P1
2.1989(5), Ni-Cl1 2.2034(5), Ni1-C1 2.053(2), Ni-C2 1.984(2), Ni-C3 1.997(2),
C1-C2 1.377(4), C2-C3 1.409(3), C1-C2-C3 120.2(2), P1-Ni-Cl1 96.17(2).
further reduction of the catalyst loading to 2 mol% led to a
substantial drop in the yield (entry 7). Furthermore, the use of
DMF as the solvent facilitated the CÀ S coupling in a shorter
time of 6 h (Table 1, entry 8). Among the three Ni(II) precatalysts
tested, complex 3 displayed the lower activity (entry 10). Finally,
control experiments revealed no reaction in the absence of the
nickel complex (entry 13). Interestingly, we do not detect the
Table 1. Optimization of reaction conditions and screening of precatalysts for the model reaction.[a]
°
Entry
[Ni]
[Ni] (mol%)
T ( C)
Solvent
Time (h)
Yield (%)[b]
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
2
3
-
5
5
5
5
5
3
2
3
3
3
-
110
110
110
100
80
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DMF
24
16
8
16
16
16
16
6
99
98
52
98
89
97
61
98
98
85
0
100
100
100
100
100
100
9
10
11
dioxane
dioxane
DMF
16
16
6
[a] Reaction conditions: iodobenzene (1.0 mmol), thiophenol (1.1 mmol), NaOtBu (1.2 mmol), solvent (1 mL). [b] Isolated yields (average of two runs).
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applied as electrophilic coupling partners furnishing the desired
products in high yields (Table 3, 4o–s, 4u–v).
Table 2. Screening of conditions for the coupling of bromobenzene and
chlorobenzene with thiophenol catalyzed by complexes 1 and 2.
Concerning the nucleophile scope, aryl thiols bearing either
electron-withdrawing (Table 3, 4s) or electron-donating (Ta-
ble 3, 4t–4v) para-substituents were equally effective delivering
the corresponding products in comparable yields. Perhaps
more significantly, reactions involving thiols containing func-
tional groups subjected to being arylated, such as free hydroxyl
or amine groups, occurred with complete chemoselectivity
towards the CÀ S coupling products (Table 3, 4t, 4u), avoiding
the need of protecting groups.
The thioetherification of aliphatic thiols is usually problem-
atic due to their enhanced nucleophilicity compared to that of
aromatic thiols.[13c,25] Only few Ni-based catalysts systems that
allow the effective coupling of aliphatic thiols with aryl halides,
primarily iodides and bromides, have been described in the
literature.[13d,26] On that basis, we decided to probe the arylation
of aliphatic thiols using the reaction conditions already
developed for aromatic thiols. As shown in Table 4, primary (5a,
5b), secondary (5c–k) and tertiary alkyl thiols (5l–n) could be
readily coupled with an array of (hetero)aryl halides, including
less reactive chloroarenes (Table 4, 5d, 5j), demonstrating the
broad utility of this transformation.
Entry
ArX
Deviation from standard conditions[a]
Yield (%)[b]
1
2
3
4
5
6
7
PhBr
PhBr
PhBr
PhCl
PhCl
PhCl
PhCl
None
89
96
97
14
32
92
90
1 (5 mol%), 6 h
2 (5 mol%), 6 h
1 (5 mol%), 16 h
1 (10 mol%), 24 h
1 (10 mol%), NMP, 120 C, 16 h
2 (10 mol%), NMP, 120 C, 16 h
°
°
[a] Standard conditions: aryl halide (1.0 mmol), thiophenol (1.1 mmol),
NaOtBu (1.2 mmol), 1 (3 mol%), DMF (1 mL), 100 C, 6 h. [b] Isolated yields
(average of two runs).
°
Table 3. Scope of the CÀ S coupling of (hetero)aryl halides with thiophe-
nols catalyzed by complexes 1 and 2.[a]
Table 4. Scope of the CÀ S coupling of (hetero)aryl halides with aliphatic
thiols catalyzed by complexes 1 and 2.[a]
[a] Standard conditions: aryl halide (1.0 mmol), thiophenol (1.1 mmol),
°
NaOtBu (1.2 mmol), 1 or 2 (3 mol%), DMF (1 mL), 100 C, 6 h. Isolated
yields of pure products. [b] Reaction performed with 5 mol% catalyst
loading. [c] Reaction performed with 10 mol% catalyst loading in NMP
[a] Standard conditions: aryl halide (1.0 mmol), thiophenol (1.1 mmol),
°
NaOtBu (1.2 mmol), 1 or 2 (3 mol%), DMF (1 mL), 100 C, 6 h. Isolated
°
(1 mL), at 120 C for 16 h. [d] aryl halide (1.1 mmol), thiophenol (1.0 mmol).
[e] 1-chloro-4-iodobenzene (0.5 mmol), thiol (1.1 mmol), NaOtBu
yields of pure products. [b] Reaction performed with 5 mol% catalyst
loading. [c] Reaction performed with 10 mol% catalyst loading in NMP
°
(1.2 mmol), 1 or 2 (10 mol%) NMP (1 mL), 120 C, 16 h.
°
(1 mL), at 120 C for 16 h. [d] aryl halide (1.1 mmol), thiophenol (1.0 mmol).
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To further expand the range of electrophilic partners
compatible with this nickel-catalyzed CÀ S coupling protocol, we
focused our attention on aryl sulfonates. Disappointingly,
phenyl mesylate, the only phenol-derived electrophile success-
fully tested in nickel-catalyzed CÀ S couplings,[15] failed to react
with thiophenol under the standard conditions (see Table 2),
even in the presence of higher catalyst loadings (10 mol%).
However, the coupling of p-tolyl tosylate with thiophenol under
the standard conditions delivered the corresponding thioether
in 58% yield. Further screening experiments revealed that
replacing NaOtBu by LiOtBu as the base, the CÀ S coupling
product was isolated in 89% yield with only 5 mol% of the
nickel source. Unfortunately, under these optimized conditions
other CÀ O electrophiles, such as aryl mesylates, sulfamates or
carbamates, appeared to be completely ineffective.
Next, the scope of this novel transformation was evaluated.
A variety of aryl tosylates were successfully coupled with a
diverse range of thiophenols in yields ranging from 57 to 89%
(Table 5). Deactivated aryl tosylates proved to be suitable
substrates (Table 5, 4c, 4f, 4w–x, 4z), although reactions
involving strongly deactivated 4-methoxyphenyl tosylate gave
the sulfide product 4d only in moderate yields (57 and 59%).
Gratifyingly, thioetherification of 4-chlorophenyl tosylate oc-
curred exclusively at the tosylate group (Table 5, 4k). Further-
more, 2-pyridyl tosylate underwent efficient coupling with
electron-rich (Table 5, 4u), electron-withdrawing (Table 5, 4s)
and hindered (Table 5, 4y) thiophenols. It is remarkable the
tolerance of potentially reactive functional groups, such as OH
(Table 5, 4ab) and NH2 (Table 5, 4u, 4z) to the reaction
conditions. Moreover, the protocol could be applied to the
synthesis of alkenyl sulfides, as exemplified by the trisubstituted
alkenyl thioether 4ac. Disappointingly, all attempts to couple
aliphatic thiols with aryl tosylates failed.
Taking advantage of the selective thioetherification of CÀ I
bond over CÀ Cl functionalization and recalling that aryl iodides
proved to be problematic in the Buchwald-Hartwig
amination,[27] we explored the potential to combine both CÀ S
and CÀ N couplings in a one-pot reaction using the same Ni-
based catalyst precursor. First, we evaluated the performance of
complexes 1 and 2 as precatalysts in the Buchwald-Hartwig
amination reaction. Taking (4-chlorophenyl)(phenyl)sulfane (see
Table 3, 4k) as the electrophilic partner, the amination of the
CÀ Cl bond with primary and secondary amines (i.e. hexylamine
or morpholine) was successfully accomplished in the presence
of both Ni precatalysts (see Supporting Information for details).
We found that dioxane was the solvent of choice to perform
the tandem CÀ S/CÀ N couplings since the amination did not
work in DMF and, on the other hand, the CÀ S coupling of aryl
chlorides required polar solvents. To our delight, the reaction of
1-chloro-4-iodobenzene with thiophenol and an amine in the
°
presence of 5 mol% of 1 or 2 at 100 C in dioxane led to the
formation of the highly functionalized products in good yields
(Scheme 2, 6a–b). The catalytic efficiency of the one-step
catalytic procedure compares well to that of the two-steps
reaction (i.e. 90% overall yield for catalyst 1). Moreover, tandem
CÀ S and CÀ N bond formations could also be accomplished
through two consecutive arylations of 4-aminobenzenethiol
with iodo and chloroarenes (Scheme 2, 6c–d). In all these
couplings, the thiolation occurred exclusively on CÀ I bond and
the amination on the CÀ Cl bond, disclosing an exquisite
simultaneous chemoselectivity both at the electrophilic and the
nucleophilic sites. Intermolecular cross-coupling reactions tak-
ing place in a single step with dual nucleophile and electrophile
selectivity are very uncommon.[28] Usually, sequential
couplings[29] are accomplished in two steps,[27,30–32] being
necessary to change the solvent polarity,[30a–b,31b] use protecting
Table 5. CÀ S coupling of aryl and alkenyl tosylates with thiophenols
catalyzed by complexes 1 and 2.[a]
Scheme 2. Tandem CÀ S/CÀ N couplings. Isolated yields of pure products. [a].
1-chloro-4-iodobenzene (1.0 mmol), thiol (1.1 mmol), amine (1.2 mmol),
[a] Reaction conditions: aryl/alkenyl tosylate (1.0 mmol), thiophenol
°
NaOtBu (2.4 mmol), 1 or 2 (5 mol%), dioxane (1 mL), T=100 C, 16 h. [b] aryl
°
(1.5 mmol), LiOtBu (1.5 mmol), 1 or 2 (5 mol%), DMF (1 mL), 100 C, 6 h.
iodide (0.5 mmol), aryl chloride (0.5 mmol), 4-aminobenzenethiol (0.6 mmol),
°
Isolated yields of pure products.
NaOtBu (1.2 mmol), 1 or 2 (5 mol%), dioxane (1 mL), 100 C, 16 h.
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groups, or different catalyst systems[30c,33] to reach high levels of
chemoselectivity.
under a nitrogen atmosphere. The mixture was stirred at certain
°
°
temperature (100 for aryl iodides/bromides or 120 C for aryl
chlorides) for 6–16 h in an oil bath. The reaction mixture was
allowed to cool to room temperature, diluted with ethyl acetate
(10 mL) and filtered through a Celite plug. The conversion was
determined by GC analysis. Pure products were obtained after
purification by flash chromatography on silica gel with petroleum
ether.
Conclusion
In summary, we have developed a versatile protocol for the
arylation of aromatic and aliphatic thiols compatible with a
wide variety of electrophiles, including aryl and heteroaryl
iodides/bromides/chlorides and, for the first time tosylates. The
success of this strategy lies in the use of preformed Ni(II)-allyl
precatalysts supported by hindered terphenyl phosphine
ligands. No reductant or excess ligand are required to obtain
high yields of coupling products. Tandem CÀ S and CÀ N
couplings of multi-electrophile/nucleophile combinations are
Crystallographic data: Deposition numbers 2084432 (for 2),
2084433 (for 3) and 2084434 (for 1) contain the supplementary
crystallographic data for this paper. These data are provided free of
charge by the joint Cambridge Crystallographic Data Centre and
Fachinformationszentrum Karlsruhe Access Structures service
www.ccdc.cam.ac.uk/structures.
achieved in a completely chemoselective manner leading to Acknowledgements
highly functionalized products. To our knowledge, this is the
first example of dual electrophile/nucleophile selectivity in
cross-coupling reactions not involving the formation of CÀ C
bonds.
We thank FEDER/Ministerio de Ciencia, Innovación y Universi-
dades-Agencia Estatal de Investigación (Grant CTQ2017-82893-
C2-2-R) and US/FEDER/JUNTA, UE (Grant, US126226) for finan-
cial support.
Experimental Section
Conflict of Interest
All preparations and manipulations were carried out under an
oxygen-free nitrogen atmosphere using standard Schlenk techni-
ques. Solvents were rigorously dried and degassed before use.
Reagents were purchased from commercial suppliers and used
The authors declare no conflict of interest.
without further purification. Dimethylterphenyl phosphines
[34]
PMe2ArPh2 [18a]
,
L1 and PMe2ArXyl2 [18a]
,
L2 and Ni(COD)2
were
Keywords: CÀ S bond formation · Ni catalysis · phosphine
complexes · dual chemoselectivity · tandem cross-couplings
synthesized following described procedures. Solution NMR spectra
were recorded on Bruker Avance DPX-300, Avance DRX-400, Avance
DRX-500 and 400 Ascend/R spectrometers. The 1H and 13C
resonances of the solvent were used as the internal standard and
the chemical shifts are reported relative to TMS while 31P was
referenced to external H3PO4. Elemental analyses were performed
by the Servicio de Microanálisis of the Instituto de Investigaciones
Químicas (IIQ). X-ray diffraction studies were accomplished at
Centro de Investigación, Tecnología e Innovación de la Universidad
de Sevilla (CITIUS). High resolution mass spectra were registered on
Orbitrap Elite Mass Spectrometer at CITIUS (Universidad de Sevilla).
Complete synthetic and catalytic procedures are provided in the
Supporting Information. A selection of representative synthesis of
Ni(II) complexes and catalytic reactions are reported below.
[1] K. L. Dunbar, D. H. Scharf, A. Litomska, C. Hertweck, Chem. Rev. 2017,
117, 5521–5577.
[2] a) M. Feng, B. Tang, S. H. Liang, X. Jiang, Curr. Top. Med. Chem. 2016, 16,
1200–1216; b) E. A. Ilardi, E. Vitaku, J. T. Njardarson, J. Med. Chem. 2014,
57, 2832–2842.
[3] a) D. A. Boyd, Angew. Chem. Int. Ed. 2016, 55, 15486–15502; Angew.
Chem. 2016, 128, 15712–15729; b) X. Du, F. Kleitz, X. Li, H. Huang, X.
Zhang, S.-Z. Qiao, Adv. Funct. Mater. 2018, 28, 1707325–1707359; c) H.
Mutlu, E. B. Ceper, X. Li, J. Yang, W. Dong, M. M. Ozmen, P. Theato,
Macromol. Rapid Commun. 2019, 40, 1800650–1800700.
[4] a) S. G. Modha, V. P. Mehtaz, E. V. Van der Eycken, Chem. Soc. Rev. 2013,
42, 5042–5055; b) F. Pana, Z.-J. Shiab, ACS Catal. 2014, 4, 280–288; c) J.
Lou, Q. Wang, P. Wu, H. Wang, Y.-G. Zhou, Z. Yu, Chem. Soc. Rev. 2020,
49, 4307–4359 and references therein; d) Y. Ma, J. Cammarata, J.
Cornella, J. Am. Chem. Soc. 2019, 141, 5, 1918–1922; e) Y. Li, G. Bao, X.-F-
Wu, Chem. Sci. 2020, 11, 2187–2192.
Synthesis of NiCl(allyl)(PMe2ArPh2), 1: To a suspension of Ni(COD)2
(200 mg, 0.722 mmol) in THF (20 mL), allyl chloride (59 μL,
0.724 mmol) was added. The reaction was stirred for 1 h at room
temperature, after which
a ’
solution of the ligand PMe2APh2
[5] a) T. Kondo, T. Mitsudo, Chem. Rev. 2000, 100, 3205–3220; b) P. Bilcher,
J. A. Love, Top. Organomet. Chem. 2010, 31, 39–64; c) I. P. Beletskaya,
V. P. Ananikov, Chem. Rev. 2011, 111, 1596–1636; d) C. C. Eichman, J. P.
Stambuli, Molecules 2011, 16, 590–608; e) C.-F. Lee, Y.-C. Liu, S. S.
Badsara, Chem. Asian J. 2014, 9, 706–722; f) A. Sujatha, A. M. Thomas,
A. P. Thankachan, G. Anilkumar, Arkivoc 2015, 1–28; g) A. Ghaderi,
Tetrahedron 2016, 72, 4758–4782; h) A. V. Murashkina, A. Y. Mitrofanov,
I. P. Beletskaya, Russ. J. Org. Chem. 2019, 55, 1629–1641; i) N. Sundar-
avelu, S. Sangeetha, G. Sekar, Org. Biomol. Chem. 2021, 19, 1459–1482.
[6] I. P. Beletskaya, A. V. Cheprakov, Organometallics 2012, 31, 7753–7808.
[7] a) M. A. Fernández-Rodríguez, Q. Shen, J. F. Hartwig, J. Am. Chem. Soc.
2006, 128, 2180–2181; b) M. A. Fernández-Rodríguez, Q. Shen, J. F.
Hartwig, Chem. Eur. J. 2006, 12, 7782–7796.
(210 mg, 0.722 mmol) in THF (5 mL) was added. The mixture was
stirred for 1 h and then, the solvent was evaporated under vacuum.
The solid residue was extracted with CH2Cl2, filtered through a
Celite plug and the solution was taken to dryness. The complex was
purified by recrystallization from CH2Cl2: petroleum ether (1:2)
mixtures, rendering compound 1 as reddish orange crystals. Yield:
221 mg (72%). Elemental analysis calculated (found) for C27H32ClNiP:
C, 64.76 (64.58); H, 5.91 (5.75).
General catalytic procedures for the C-S coupling of aryl iodides/
bromides/chlorides with aromatic/aliphatic thiols: The catalyst 1
or 2 (0.03–0.1 mmol) and the base NaOtBu (1.2 mmol) were
dissolved in the solvent (DMF or NMP, 1 mL) into a vial equipped
with a J Young tap containing a magnetic bar. The thiol (1.1 mmol)
and the aryl iodide/bromide/chloride (1 mmol) were added, in turn,
[8] M. Murata, S. L. Buchwald, Tetrahedron 2004, 60, 7397–7403.
[9] a) Y. Shi, Z. Cai, P. Guan, G. Pang, Synlett 2011, 2090; b) M. Sayah, M. G.
Organ, Chem. Eur. J. 2011, 19, 2749–2756; c) G. Bastug, S. P. Nolan, J.
Org. Chem. 2013, 78, 9303–9308.
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doi.org/10.1002/chem.202101906
Chemistry—A European Journal
[10] a) N. Zheng, J. C. McWilliams, F. J. Fleitz, J. D. Armstrong III, R. P. Volante,
J. Org. Chem. 1998, 63, 9606–9607; b) T. Itoh, T. Mase, Org. Lett. 2004, 6,
4587–4590; c) C. Mispelaere-Canivet, J.-F. Spindler, S. Perrio, P. Beslin,
Tetrahedron 2005, 61, 5253–5259.
[11] N. Velasco, C. Virumbrales, R. Sanz, S. Suárez-Pantiga, M. A. Fernández-
Rodríguez, Org. Lett. 2018, 20, 2848–2852.
[12] a) B. M. Rosen, K. W. Quasdorf, D. A. Wilson, N. Zhang, A.-M. Resmerita,
N. K. Garg, V. Percec, Chem. Rev. 2011, 111, 1346–1416; b) F.-S. Han,
Chem. Soc. Rev. 2013, 42, 5270–5298; c) S. Z. Tasker, E. A. Standley, T. F.
Jamison, Nature 2014, 504, 299–309; d) V. P. Ananikov, ACS Catal. 2015,
5, 1964–1971; e) C. Zarate, M. van Gemmeren, R. Somerville, R. Martin,
Adv. Organomet. Chem. 2016, 66, 143–222.
[13] a) P. Gogoi, S. Hazarika, M. J. Sarma, K. Sarma, Tetrahedron 2014, 70,
1784–7489; b) G. Yin, I. Kalvet, U. Englert, F. Schoenebeck, J. Am. Chem.
Soc. 2015, 137, 4164–4172; c) K. D. Jones, D. J. Power, D. Bierer, K. M.
Gericke, S. G. Stewart, Org. Lett. 2018, 20, 208–211; d) P. H. Gehrtz, V.
Geiger, T. Schmidt, L. Sršan, I. Fleischer, Org. Lett. 2019, 21, 50–55; e) R.
Sikari, S. Sinha, S. Das, A. Saha, G. Chackraborty, R. Mondal, N. D. Paul, J.
Org. Chem. 2019, 84, 4072–4085.
[23] a) M. Basauri-Molina, S. Hernández-Ortega, D. Morales-Morales, Eur. J.
Inorg. Chem. 2014, 2014, 4619–4625; b) J. M. Serrano-Becerra, H. Valdés,
D. Canseco-González, V. Gómez-Benítez, S. Hernández-Ortega, D.
Morales-Morales, Tetrahedron Lett. 2018, 59, 3377–3380; c) M. A.
Rodríguez-Cruz, S. Hernández-Ortega, H. Valdés, E. Rufino-Felipe, D.
Morales-Morales, J. Catal. 2020, 383, 193–198; d) B. X. Valderrama-
García, E. Rufino-Felipe, H. Valdés, S. Hernández-Ortega, B. A. Aguilar-
Castillo, D. Morales-Morales, Inorg. Chim. Acta 2020, 502, 119283.
[24] a) A. S. Rahate, K. R. Nemade, S. A. Waghuley, Rev. Chem. Eng. 2013, 29,
471–489; b) O. Goyot, M. Gingras, Tetrahedron Lett. 2009, 50, 1977–
1981.
[25] a) J. P. Stambuli, T. J. Colacot, New Trends in Cross-Coupling: Theory and
Applications, RSC Publishing, Cambridge, 2015, p 254–275; b) A. Correa,
M. Carril, C. Bolm, Angew. Chem. Int. Ed. 2008, 47, 2880–2883; Angew.
Chem. 2008, 120, 2922–2925.
[26] a) X.-B. Xu, J. Liu, J.-J. Zhang, Y.-W. Wang, Y. Peng, Org. Lett. 2013, 15,
550–553; b) F.-J. Guo, J. Sun, Z.-Q. Xu, F. E. Kühn, S.-L. Zang, M.-D. Zhou,
Catal. Commun. 2017, 96, 11–14; c) Y. Fang, T. Rogge, L. Ackermann, S.-
Y. Wang, S.-J. Ji, Nat. Commun. 2018, 9, 2240; d) T.-Y. Yu, H. Pang, Y.
Cao, F. Gallou, B. H. Lipshutz, Angew. Chem. Int. Ed. 2021, 60, 3708–3713;
Angew. Chem. 2021, 133, 3752–3757; e) M. M. Talukder, J. T. Miller,
J. M. O. Cue, C. M. Udamulle, A. Bhadran, M. C. Biever, M. C. Stefan,
Organometallics 2021, 40, 83–94.
[14] a) D. Liu, H.-X. Ma, P. Fang, T.-S. Mei, Angew. Chem. Int. Ed. 2019, 58,
5033–5037; Angew. Chem. 2019, 131, 5087–5091; b) N. W. J. Ang, L.
Ackermann, Chem. Eur. J. 2021, 27, 4883–4887.
[15] V. Percec, J.-Y. Bae, D. H. Hill, J. Org. Chem. 1995, 60, 6895–6903.
[16] See for example: a) Y. Zhang, K. C. Ngeow, J. Y. Ying, Org. Lett. 2007, 9,
3495–3498; b) M. J. Iglesias, A. Prieto, M. C. Nicasio, Adv. Synth. Catal.
2010, 352, 1949–1954; c) P. Guan, C. Cao, Y. Liu, Y. Li, P. He, Q. Chen, G.
Liu, Y. Shi, Tetrahedron Lett. 2012, 53, 5987–5992; d) A. R. Martin, D. J.
Nelson, S. Meiries, A. M. Z. Slawin, S. P. Nolan, Eur. J. Org. Chem. 2014,
2014, 3127–3131; e) F.-J. Guo, J. Sun, Z.-Q. Xu, F. E. Kühn, S.-L. Zang, M.-
D. Zhou, Catal. Commun. 2017, 96, 11–14.
[27] D. S. Surry and S. L. Buchwald, Chem. Sci. 2011, 2, 27–50.
[28] a) C. P. Seath, J. W. B. Fyfe, J. J. Molloy, A. J. B. Watson, Angew. Chem. Int.
Ed. 2015, 54, 9976–9979; Angew. Chem. 2015, 127, 10114–10117;
b) J. W. B. Fyfe, N. J. Fazakerley, A. J. B. Watson, Angew. Chem. Int. Ed.
2017, 56, 1249–1253; Angew. Chem. 2017, 129, 1269–1273.
[29] a) C. Wang, F. Glorius, Angew. Chem. Int. Ed. 2009, 48, 5240–5244;
Angew. Chem. 2009, 121, 5342–5346; b) P. Dobrounig, M. Trobe, R.
Breinbauer, Monatsh. Chem. 2017, 148, 3–35.
[17] J. Xu, R. Y. Liu, C. S. Yeung, S. L. Buchwald, ACS Catal. 2019, 9, 6461–
6466.
[30] a) N. Hadei, G. T. Achonduh, C. Valente, C. J. O’Brien, M. G. Organ,
Angew. Chem. Int. Ed. 2011, 50, 3896–3899; Angew. Chem. 2011, 123,
3982–3985; b) S. T. Keaveney, G. Kundu, F. Schoenebeck, Angew. Chem.
Int. Ed. 2018, 57, 12573–12577; Angew. Chem. 2018, 130, 12753–12757;
c) N. Sinha, D. Heijnen, B. L. Feringa, M. G. Organ, Chem. Eur. J. 2019, 25,
9180–9184; d) P. Chatelain, A. Sau, C. N. Rowley, J. Moran, Angew. Chem.
Int. Ed. 2019, 58, 14959–14963; Angew. Chem. 2019, 131, 9941–9945.
[31] a) E. Sperotto, G. P. M. van Klink, J. G. de Vries, G. van Koten, Tetrahedron
2010, 66, 9009–9020; b) D. N. Rao, Sk. Rasheed, R. A. Vishwakarmab, P.
Das, Chem. Commun. 2014, 50, 12911–12914.
[18] a) L. Ortega-Moreno, M. Fernández-Espada, J. J. Moreno, C. Navarro-
Gilabert, J. Campos, S. Conejero, J. López-Serrano, C. Maya, R. Peloso, E.
Carmona, Polyhedron 2016, 116, 170–181; b) M. Marín, J. J. Moreno, C.
Navarro-Gilabert, E. Álvarez, C. Maya, R. Peloso, M. C. Nicasio, E.
Carmona, Chem. Eur. J. 2019, 25, 260–272; c) M. Marín, J. J. Moreno,
M. M. Alcaide, E. Álvarez, J. López-Serrano, J. Campos, M. C. Nicasio, E.
Carmona, J. Organomet. Chem. 2019, 896, 120–128.
[19] a) L. Ortega-Moreno, R. Peloso, C. Maya, A. Ortega, E. Carmona, Chem.
Commun. 2015, 51, 17008–17011; b) R. J. Rama, C. Maya, M. C. Nicasio,
Chem. Eur. J. 2020, 26, 1064–1073; c) M. T. Martín, M. Marín, R. J. Rama,
E. Álvarez, C. Maya, F. Molina, M. C. Nicasio, Chem. Commun. 2021, 57,
3083–3086.
[32] C. M. Crudden, C. Ziebenhaus, J. P. G. Rygus, K. Ghozati, P. J. Unsworth,
M. Nambo, S. Voth, M. Hutchinson, V. S. Laberge, Y. Maekawa, D. Imao,
Nat. Commun. 2016, 7, 11065–11071.
[20] For Pd-catalyzed CÀ S coupling reactions, the formation of anionic or
bridging thiolates complexes is accounted for deactivation of the
catalyst system. See references 5d and 7.
[21] a) E. Carmona, P. Palma, M. L. Poveda, Polyhedron 1990, 9, 757–761;
b) L–C. Silva, P. T. Gomes, L. F. Veiros, S. I. Pascu, M. T. Duarte, S.
Namorado, J. R. Ascenso, A. R. Dias, Organometallics 2006, 25, 4391–
4403; c) S. Filipuzzi, P. S. Pregosin, A Albinati, S. Rizzato, Organometallics
2008, 27, 437–444; d) E. A. Bielinski, W. Dai, L. M. Guard, N. Hazari, M. T.
Takase, Organometallics 2013, 32, 4025–4037.
[33] a) H. Nogushi, K. Hojo, M. Suginome, J. Am. Chem. Soc. 2007, 129, 758–
759; b) E. P. Gillis, M. D. Burke, J. Am. Chem. Soc. 2007, 129, 6716–6717;
c) J. E. Grob, M. A. Dechantsreiter, R. B. Tichkule, M. K. Connolly, A.
Honda, R. C. Tomlinson, L. G. Hamann, Org. Lett. 2012, 14, 5578–5581.
[34] M. M. Colqhoun, J. Holton, D. J. Thompson, M. V. Twiggs in New
Pathways for Organic Synthesis. Practical Applications of Transition
Metals, Plenum Press, New York, 1984.
[22] a) N. M. Brunkan, W. D. Jones, J. Organomet. Chem. 2003, 683, 77–82;
b) I. Hyder, M. Jiménez-Tenorio, M. C. Puerta, P. Valerga, Dalton Trans.
2007, 3000–3009; c) B. R. Dibble, M. S. Sigman, Inorg. Chem. 2006, 45,
8430–8441; d) J. Frosch, M. Feytag, P. G. Jones, M. Tamm, J. Organomet.
Chem. 2020, 918, 121311.
Manuscript received: May 31, 2021
Accepted manuscript online: June 30, 2021
Version of record online: ■■■, ■■■■
Chem. Eur. J. 2021, 27, 1–8
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© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH
��
These are not the final page numbers!

FULL PAPER
Ni(II)-allyl complexes supported by
bulky terphenyl phosphine ligands
have been prepared and character-
ized. These complexes have been
used as precatalysts in the formation
of CÀ S bonds, allowing the efficient
coupling between a variety of electro-
philes, including aryl chlorides and,
for the first time, tosylates, with
aromatic and aliphatic thiols.
M. T. Martín, Dr. M. Marín, Dr. C. Maya,
Dr. A. Prieto*, Prof. M. C. Nicasio*
1 – 8
Ni(II) Precatalysts Enable Thioetheri-
fication of (Hetero)Aryl Halides and
Tosylates and Tandem CÀ S/CÀ N
Couplings
Moreover, differentiated reactivity of
the electrophilic partners enables
tandem formation of CÀ S and CÀ N
bonds in a single step.