Cross-Coupling of Chloro(hetero)arenes with Thiolates Employing a Ni(0)-Precatalyst

Article abstract of DOI:10.1021/acs.orglett.8b03476

A general and efficient Ni-catalyzed coupling of challenging aryl chlorides and in situ generated aliphatic and aromatic thiolates is described. The employed on-cycle, air-stable defined Ni precatalysts allow for transformation of a broad scope of substrates. A variety of functional groups and heterocyclic motifs as well as structurally varied thiols are tolerated at unprecedented moderate catalyst loadings and reaction temperatures. Depending on reaction conditions, aryl thiols can selectively undergo C-S or C-C couplings.

Full text of DOI:10.1021/acs.orglett.8b03476

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cross-Coupling of Chloro(hetero)arenes with Thiolates Employing a
Ni(0)-Precatalyst
‡
‡
̌
Paul H. Gehrtz, Valentin Geiger, Tanno Schmidt, Laura Srsan, and Ivana Fleischer*
Institute of Organic Chemistry, Faculty of Science and Mathematics, Eberhard-Karls University Tu
72076 Tubingen, Germany
̈
bingen, Auf der Morgenstelle 18,
̈
S
* Supporting Information
ABSTRACT: A general and efficient Ni-catalyzed coupling of challenging aryl chlorides
and in situ generated aliphatic and aromatic thiolates is described. The employed on-
cycle, air-stable defined Ni precatalysts allow for transformation of a broad scope of
substrates. A variety of functional groups and heterocyclic motifs as well as structurally
varied thiols are tolerated at unprecedented moderate catalyst loadings and reaction
temperatures. Depending on reaction conditions, aryl thiols can selectively undergo
C−S or C−C couplings.
Scheme 1. Methods for Aryl Thioether Synthesis and Our Ni-
Catalyzed Migita Reaction
he Migita reaction (MR) is the transition-metal catalyzed
Tcross-coupling of haloarenes and thiols under basic
conditions to yield aryl thioethers.1 This structural motif
belongs to the classical series of bivalent isosteres (−CH2−,
−NH−, −O−, −S−) and is thus valuable when modification of
a lead structure in an agrochemical, pharmaceutical, or material
chemistry context is necessary.2 It can also be accessed in a
noncatalytic manner by nucleophilic (aromatic) substitution,
charge transfer-mediated radical−radical coupling,3 or numer-
ous conceptually different catalytic approaches (Scheme 1a),
including (metallo)photoredox catalysis,4 cross-electrophile or
-nucleophile couplings,5 decarbonylation,6 single-bond meta-
thesis,7 and (photocatalytic) radical−nucleophilic aromatic
substitutions.8 However, the Pd-catalyzed Migita reaction
remains prevalent due to its generality and modularity. For
example, it was successfully employed on multi-kilogram scale
for the production of pharmaceuticals.9 Besides the typical Pd0/II
mechanism, dinuclear PdI catalysts have been employed in a MR
of thiolates with high selectivity toward the activation of
bromoarenes.10
a
A large interest in the activation of aryl chlorides exists since
these electrophiles are generally of low cost and high stability
compared to other aryl halides. Second, such methods allow
sequential cross-coupling sequences based on the bond
dissociation energy order (PhCl, 408.4 kJ mol−1; PhBr, 345.6
kJ mol−1; PhI, 281.2 kJ mol−1) of aryl halides,11 which generally
correlates with reactivity as explained by the distortion
interaction model.12
a
PRC, photoredox catalyst; [TM], transition metal; xant, xantphos; X,
(pseudo)halide.
Some methods for the thiolation of chloroarenes have been
developed employing Pd-based systems, which required air
sensitive ferrocenylphosphine ligands.13 Since oxidative addi-
tion of Ni0 complexes into electrophiles is more facile than with
Received: October 31, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03476
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Organic Letters
Letter
Pd0 complexes,14 chloroarene activation should be favored for
Ni catalysts. In addition, earth-abundant Ni catalysts could
emerge as replacements for expensive Pd-complexes if the
drawback of the relatively higher metal loadings (often 5−20
mol %) could be overcome.15
Table 1. MR of Chlorobenzene with Heptanethiol under Ni
Catalysis as a Model Reaction
a
Only few reports on Ni-catalyzed C−S cross couplings with
̈
chloroarenes appeared. In 2015, Schonebeck and co-workers
conducted a detailed study on the trifluoromethylthiolation of
chloro(hetero)arenes under Ni catalysis (10 mol %) using
(Me4N)SCF3.16 In 2018, Stewart employed a high-throughput
ligand screening method, which allowed the identification of
several bidentate phosphines for C−S cross couplings of
chloro(hetero)arenes (10 mol % Ni metal) with arylthiols
under reducing conditions (Zn), whereas alkylthiols were less
competent coupling partners (although aryl bromides were
reported to be working, only one reported example with
chlorides was disclosed with a yield of 20%).17 In addition, Ni-
Schiff base complexes catalyzed (5 mol %) reactions of aryl
thiols and chlorides.18
During our study on the Ni-catalyzed Fukuyama coupling, we
observed a MR of chloroarenes resulting from the liberated zinc
thiolate.19 Herein, this Ni-catalyzed side reaction was studied in
more detail, which resulted in the discovery of an efficient
catalytic system for the MR of chloroarenes (Scheme 1b). It
operates at exceptionally low catalyst loading and mild
conditions compared to competitive Ni-based catalysts. For
the first time, alkylthiols can be efficiently coupled with aryl
chlorides under Ni catalysis. Moreover, a divergent behavior was
observed for aryl thiols, which can undergo C−S or C−C
coupling depending on reaction conditions.
The reaction of chlorobenzene (1) with equimolar amounts
of heptane-1-thiol (2, HeptSH) and the established precatalyst
C1 was selected as a model system (Table 1, entry 1).20
PhMgBr·LiCl (3) was employed as a stoichiometric base to
generate a reactive Mg thiolate.21 With a loading of 0.5 mol %
C1, the reaction was completed within 15 min, providing the
product 4 in an excellent yield. A shorter reaction time of 5 min
was less satisfactory. Various control experiments confirmed the
necessity of inert atmosphere, phosphine ligation, and a
molecular precatalyst (entries 2−5). A strong ligand effect was
suspected, and thus other literature-known Ni complexes of the
type L2Ni(oTol)Cl were evaluated, featuring a small bite-angle
bidentate phosphine in C2, a monodentate phosphine in C3,
and a similar large bite-angle bidentate phosphine in C4. In all
cases, no significant product formation occurred (entries 6−8).
The use of a Grignard reagent as an organometallic base requires
temperature control and dropwise addition to avoid a competing
Kumada coupling. To circumvent this problem, 3 was replaced
by the corresponding zinc reagent 5, which again resulted in an
excellent yield of the product after 15 min with no cooling
required (entry 9). Base 5 was prepared from a fresh solution of
3 by transmetalation with ZnCl2 in THF. In contrast, the use of a
preformed HeptSZnCl·LiCl solution led to a disappointing
result (entry 10). This indicates that a stoichiometric amount of
organometallic reagent is required for an efficient trans-
formation. It fulfils a dual role of base and reductant. In
addition, commercially available iPrMgCl·LiCl failed to initiate
efficient catalysis (entry 11).
b
b
entry
deviation from standard conditions
5 min
conv. 1 (%)
4 (%)
1
2
3
4
5
6
7
8
36
13
35
6
31
2
10
8
96
18
3
33
13
0
1
0
0
0
7
reaction conducted in air
c
catalytic NiCl2
c
no metal, no ligand
cd
,
catalytic NiB nanoparticles
catalytic C2
catalytic C3
c
catalytic C4
9
10
11
PhZnCl·LiCl (5, 2.0 equiv), 15 min, rt
HeptSZnCl·LiCl (1.3 equiv), 10 min, rt
iPrMgCl·LiCl (1.1 equiv), 60 min
96
18
2
e
a
Standard reaction conditions: PhCl (50 μL, 500 μmol), heptane-1-
thiol (80 μL, 500 μmol), PhZnCl·LiCl (1.2 mmol based on titer
[typically 0.5 M], in THF), C1 (2.0 mg, 2.5 μmol, 0.5 mol %), dry
THF (500 μL), 0 °C to rt, 15 min. Determined by quant. GC-FID
analysis. Formation of biphenyl. Prepared as a THF slurry by a
literature procedure (SI). HeptSZnCl·LiCl was generated from thiol
and PhZnCl·LiCl, which was prepared from PhMgBr·LiCl.
b
c
d
e
tolerated in the para- or meta-position generally resulting in
good to excellent yields after 0.5−4 h either at room temperature
or 60 °C with C1 loadings from 0.5 to 2 mol %. An outlier is the
moderate performance of electron-poor 4-chloro-pentafluor-
osulfanylbenzene to give 12. Electron-rich chloroarenes are
tolerated, but generally require harsher reaction conditions and
higher loadings of C1. However, thiolations of ortho-substituted
chloroarenes did not proceed when catalysis with C1 was
attempted. The use of analogue catalyst C5 introduced by
Stradiotto showed again excellent activity for these substrates
(leading to compounds 13 and 14).22 Some chloroarenes with
Lewis basic substituents were unreactive, possibly due to
coordination-induced catalyst poisoning. The addition of
̈
MeCN, which was demonstrated by Schonebeck to have a
positive effect on couplings of challenging ArCl, was unfruitful in
our case.16 However, we found that NMP had a positive effect as
cosolvent. For example, in THF alone, no product formation of
10 and 17 was observed under standard conditions.
In contrast, by using NMP as a cosolvent in conjunction with a
catalyst loading of 2 mol % at 60 °C, the products were obtained
in good to excellent yield. With these more robust conditions in
hand, we were able to convert a range of diverse chloro-
heteroarenes to the corresponding sulfides (15−24), including
pyrimidine and purine motifs, in moderate to excellent yields. A
limitation is the presence of a Michael acceptor as in the
structure leading to product 22 (the full set of limitations is
disclosed in the SI). After oxidation, the sulfide 21 is an entry
point for desulfonylative olefinations or cross-coupling reac-
Following these preliminary investigations, the scope of
coupling partners was evaluated by reaction of monosubstituted
chloro(hetero)arenes with 2 (Scheme 2). Various electrophilic
(e.g., ketone in 7, nitrile in 11) and Lewis basic (e.g., tertiary
amine in 6, amide in 10) functional groups on chloroarenes are
B
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Letter
a
Scheme 2. Scope of the Ni-Catalyzed MR of Chloroarenes with Alkylthiols
a
Isolated yields. Conditions: chloroarene (1.0 mmol), thiol (1.0 mmol), PhZnCl·LiCl or PhMgBr·LiCl (1.2 mmol of a titrated solution in THF),
dry NMP or THF (400 μL), C1 or C5 (0.5−2.0 mol %), 0.5 to 4.0 h, RT−60 °C (for RZnX) or 0 °C−RT (for RMgX, removal of ice−water bath
b
c
after Grignard addition). 0.5 mmol scale. Contains unknown impurities.
tions.23 Notably, the catalytic system also operates on more
complex chlorinated compounds, such as 8-chlorocaffeine to
give 25 in moderate yield or indomethacin ethyl ester leading to
26 in good yield. The reaction of electron-poor chloroarenes
leading to 7, 11, and 17 was performed without the catalyst. No
products were obtained, which suggests that the SNAr
mechanism can be ruled out.
performed well (sulfides 27 to 31), while tertiary thiols gave
lower yields (33 and 34). The synthesis of 31 was repeated on a
10 mmol scale with isolated yield of 80%. A bifunctional thiol
could also be employed, giving the aryl sulfide 29. Electronically
less activated thiols performed poorly in catalysis (e.g., leading to
32).
Notably, the keto-sulfide 36 was obtained in moderate yield
Next, the reactivity of structurally varied thiols was
investigated. It was found that primary and secondary alkylthiols
from an atom-economical tandem intramolecular Fukuyama−
C
DOI: 10.1021/acs.orglett.8b03476
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Migita reaction (Scheme 3), which formally corresponds to
insertion of a 1,4-phenylene spacer into the thioester C−S bond.
base at 110 °C with 1 h reaction time. However, biaryls and
symmetrical sulfides were also produced. The formation of
symmetrical sulfides was independently explained by Percec and
Kentaro as a result of reinsertion of LnNi0 into the product
sulfide, followed by thiolate scrambling.26 Yang and Wang
reported a transition-metal-free cross coupling of aryl zinc
halides with thiophenols under thermal conditions.27 Thus,
nBuZnCl·LiCl was used instead, leading to an improved
selectivity profile (Scheme 5).
Scheme 3. Example of a Tandem Fukuyama−Migita
a
Reaction
Scheme 5. Ni-Catalyzed MR of Chloroarenes with
a
Thiophenols Driven by Alkylzinc Bases
a
Conditions: 35 (0.5 mmol), 4-Cl-C6H4ZnCl·LiCl (3.6 mL of a
0.25 M THF solution), C1 (2 mol %), THF (0.5 mL), 1.5 h, rt.
Unfortunately, arylthiols gave no conversion using PhZnCl·
LiCl as the base under mild conditions. It was investigated if the
choice of organometallic base affects the reaction outcome.
Using Grignard reagents as the base and thiophenols as potential
nucleophiles, a desulfenylative Kumada-type cross-coupling24
was observed even in the presence of chloroarenes, together with
formation of the Migita product and symmetrical sulfides. The
use of sterically encumbered Grignard bases to disfavor C−C
coupling did not lead to a clearer reaction outcome. Thus, the
scope of the so far unexplored reaction of aryl thiols and
Grignard reagents using C1 was studied (Scheme 4). Several
biaryls (37−45) were obtained in fair to good yields. The
combination of electron-rich nucleophile and electron-poor
electrophile appears to provide the best results, as expected for a
cross-coupling reaction.25
During further screening of reaction conditions, it was found
that toluene was the optimal cosolvent using PhZnCl·LiCl as the
Scheme 4. Ni-Catalyzed Desulfenylative Kumada Coupling of
Thiophenols with Grignard Reagents
a
Conditions: chloroarene (1.0 mmol), arenethiol (1.0 mmol),
a
BuZnCl·LiCl (1.2 mmol of a THF solution [typically 0.5 M]), C1
(2 mol %), toluene (usually 2.4 mL, equal to THF volume), 1 h,
110 °C.
While the method is excellent for challenging electron-rich
aryl chlorides (providing 46, 49, 50, and 53), electron-poor
reactants still lead to the formation of symmetrical sulfides,
which decreases overall yield (e.g., 48). Thus, our method is
complementary to the visible-light driven chloroarene thio-
phenolation,3 which works best with the latter class of
electrophiles.
In conclusion, an efficient Ni-catalyzed coupling of in situ
generated zinc thiolates with aryl chlorides was developed. The
method is characterized by short reaction times and low catalyst
loadings for unfunctionalized coupling partners (TOF of
800 h−1). Even under robust conditions for challenging
heterocyclic and Lewis basic coupling partners, the catalytic
system surpasses in many parameters the known methods
involving the activation of chloroarenes and should be of general
interest to the practicing synthetic chemist. While the MR of
thiophenols requires thermally harsher conditions, short
reaction times (1 h) can be achieved with challenging,
electron-rich aryl chlorides. In the absence of other electro-
philes, catalyst C1 can be also employed for a desulfenylative
Kumada-type reaction of thiophenols with Grignard reagents.
a
Conditions: arenethiol (1.0 mmol), ArMgBr·LiCl (2.2 mmol of a
THF solution [typically 1 M]), C1 (2 mol %), THF (0.5−1.0 mL),
4.0 h, 60 °C. The formation of sulfide was proven by lead acetate
b
paper test. The product could not be completely purified (NMR
yields are given).
D
DOI: 10.1021/acs.orglett.8b03476
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(7) 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.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b03476.
■
S
Experimental procedures, analytical data, and mechanistic
discussion (PDF)
(9) (a) Norris, T.; Leeman, K. Development of a New Variant of the
Migita Reaction for Carbon−Sulfur Bond Formation Used in the
Manufacture of Tetrahydro-4-[3-[4-(2-methyl-1H-imidazol-1-yl)-
phenyl]thio]phenyl-2H-pyran-4-carboxamide. Org. Process Res. Dev.
2008, 12, 869−876. (b) de Koning, P. D.; Murtagh, L.; Lawson, J. P.;
Vonder Embse, R. A.; Kunda, S. A.; Kong, W. Development an Efficient
Route to the 5-Lipoxygenase Inhibitor PF-04191834. Org. Process Res.
Dev. 2011, 15, 1046−1051.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ivana.fleischer@uni-tuebingen.de.
ORCID
Ivana Fleischer: 0000-0002-2609-6536
(10) Scattolin, T.; Senol, E.; Yin, G.; Guo, Q.; Schoenebeck, F. Site-
Selective C-S Bond Formation at C-Br over C-OTf and C-Cl Enabled
by an Air-Stable, Easy-to-Recover & Recyclable Pd(I) Catalyst. Angew.
Chem., Int. Ed. 2018, 57, 12425.
Author Contributions
‡These authors contributed equally. All authors have given
approval to the final version of the manuscript.
(11) Galli, C.; Pau, T. The dehalogenation reaction of organic halides
by tributyltin radical: The energy of activation vs. the BDE of the C-X
bond. Tetrahedron 1998, 54, 2893−2904.
Notes
The authors declare no competing financial interest.
(12) (a) Legault, C. Y.; Garcia, Y.; Merlic, C. A.; Houk, K. N. Origin of
Regioselectivity in Palladium-Catalyzed Cross-Coupling Reactions of
Polyhalogenated Heterocycles. J. Am. Chem. Soc. 2007, 129, 12664−
12665. (b) Bickelhaupt, F. M.; Houk, K. N. Analyzing Reaction Rates
with the Distortion/Interaction-Activation Strain Model. Angew.
Chem., Int. Ed. 2017, 56, 10070−10086.
ACKNOWLEDGMENTS
■
We thank B. Ciszek (University of Tu
discussions. Financial support from Boehringer Ingelheim
̈
Stiftung (Exploration Grant) and the University of Tubingen
(Institutional Strategy: Deutsche Forschungsgemeinschaft ZUK
63) is gratefully acknowledged.
̈
bingen) for helpful
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F
DOI: 10.1021/acs.orglett.8b03476
Org. Lett. XXXX, XXX, XXX−XXX