C-S cross-coupling of aryl halides with alkyl thiols catalyzed by in-situ generated nickel(II) N-heterocyclic carbene complexes

Article abstract of DOI:10.1016/j.catcom.2017.02.007

The C-S cross-coupling of aryl halides with alkyl thiols catalyzed by in-situ generated Ni (II) N-heterocyclic carbene (NHC) complexes is investigated. Good to excellent yields can be obtained for a variety of aryl halides when using 5 mol% of the Ni (II)-NHC catalyst and 1.5 eq. of KO^tBu. Both the electronic and steric effects of the NHC ligands on the catalytic performance of Ni (II)-NHC, as well as the electronic effects of aryl halides on coupling reactivity are examined. The mechanism for Ni (II)-NHC catalyzed coupling reactions is also discussed.

Full text of DOI:10.1016/j.catcom.2017.02.007

Accepted Manuscript
C-S cross-coupling of aryl halides with alkyl thiols catalyzed by
in-situ generated nickel(II) N-heterocyclic carbene complexes
Fang-Jie Guo, Jing Sun, Zhao-Qing Xu, Fritz E. Kühn, Shu-Liang
Zang, Ming-Dong Zhou
PII:
DOI:
Reference:
S1566-7367(17)30052-3
doi: 10.1016/j.catcom.2017.02.007
CATCOM 4935
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Catalysis Communications
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17 December 2016
7 February 2017
7 February 2017
Please cite this article as: Fang-Jie Guo, Jing Sun, Zhao-Qing Xu, Fritz E. Kühn, Shu-
Liang Zang, Ming-Dong Zhou , C-S cross-coupling of aryl halides with alkyl thiols
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ACCEPTED MANUSCRIPT
C-S cross-coupling of aryl halides with alkyl thiols catalyzed by in-situ
generated nickel(II) N-heterocyclic carbene complexes
Fang-Jie Guoa, Jing Suna,*, Zhao-Qing Xub, Fritz E. Kühnc, Shu-Liang Zanga and
Ming-Dong Zhoua,*
a School of Chemistry and Materials Science, Liaoning Shihua University, Dandong
Road, No. 1, Fushun 113001, China. Tel: +86 24 56863837, Fax: +86 24 56863837.
E-mail: sunjing@lnpu.edu.cn, mingdong.zhou@lnpu.edu.cn.
b Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of
Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China. E-mail:
zqxu@lzu.edu.cn.
c
Molecular Catalysis, Catalysis Research Center, Department of Chemistry,
Technische Universität München, Lichtenberg str. 4, D-85747 Garching bei München,
Germany. Tel: +49 89 289 13096. Fax: +49 89 289 13247. E-mail:
fritz.kuehn@ch.tum.de.
Abstract: The C-S cross-coupling of aryl halides with alkyl thiols catalyzed by in-situ
generated Ni (II) N-heterocyclic carbene (NHC) complexes is investigated. Good to
excellent yields can be obtained for a variety of aryl halides when using 5 mol% of
the Ni (II)-NHC catalyst and 1.5 eq. of KOtBu. Both the electronic and steric effects
of the NHC ligands on the catalytic performance of Ni (II)-NHC, as well as the
electronic effects of aryl halides on coupling reactivity are examined. The mechanism
for Ni (II)-NHC catalyzed coupling reactions is also discussed.
Keywords: C-S cross coupling; Nickel catalysis; N-heterocyclic carbene; Aryl
sulfides
Introduction
C-S coupling is a very important transformation in modern organic synthesis.
Catalytic cross-coupling of aryl halide and thiol provides a simple and efficient
protocol for the synthesis of aryl sulfides. The latter are important synthetic
intermediates in biochemistry and in pharmaceutical industry.1,2
Among various reported procedures, palladium3,4 and copper5-7 based catalysts are
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most commonly used under basic conditions. In addition, nickel,8-11 iron,12 indium13,14
and other metal compounds15-18 are also found to be effective catalysts. However, in
contrast to the large number of reports on palladium catalysts, the C-S coupling
catalyzed by nickel and other transition metal complexes is so far rather limited in
scope. Since nickel is cheaper and also shows a reduced tendency to deposit metallic
nanoparticles (as compared to Pd),8-11 the C-S cross-coupling using Ni complex
appears to be an attractive field of study.
Additionally, N-heterocyclic carbenes (NHCs) have received much attention as
ligands in transition-metal catalysis during the last two decades.19-25 Ni-NHC
complexes, for example, are known to be excellent catalysts for numerous
transformations such as Kumada-Corriu cross-coupling26, Suzuki-Miyaura
cross-coupling27, hydrosilylation reactions28, the amination of arylamines29, and the
oligomerization of olefins.30 However, to the best of our knowledge, the C-S
cross-coupling using Ni-NHC complexes, has not yet been extensively studied.31-33
Zhang et. al. have described a Ni (0)-NHC catalyzed C-S coupling using
1,3-dibenzylimidazol-2-ylidene as the NHC precursor,31 and good to excellent yields
could be achieved for a variety of aryl halides. However, in this reaction protocol the
coupling of aryl halides with alkyl thiols were not investigated.31 Considering that
alkyl phenyl thioethers are also important synthetic intermediates, and Ni (II)-NHC
complexes may represent better stability in the catalytic system than Ni (0) complexes,
we were interested in studying the C-S cross-coupling of aryl halides with alkyl thiols
using in-situ generated Ni (II)-NHC complexes as the catalysts. Therefore, we wish to
report our primary results of this work herein.
Results and discussion
Scheme 1. NHC ligand precursors.
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NHCs L1-L6 were investigated as ligands for Ni catalysts in C-S coupling
reactions (Scheme 1). In the presence of KOtBu as deprotonating reagent,
L1-L6 readily coordinate with NiCl2 forming the corresponding nickel
bis-carbene complexes, which can be proven by the isolated X-ray single
crystal structures of Ni(II)-NHCs bearing L1, L2 and L4 (Figure 1). Details on
the synthesis, crystallization procedures and characterization data of
Ni(II)-NHCs can be found in the ESI.
Figure 1. ORTEP diagram showing the coordination environment for Ni atoms of Ni-NHCs.
Thermal ellipsoids are given on a 50% probability level. H-atoms have been omitted. CCDC:
1433176 (L1), 1433177 (L2), 1433179 (L4).
To explore the reactivity, coupling of 4-bromotoluene with butanethiol was studied
first (Table 1). Blank reaction resulted in only trace amounts of
butyl(4-methylphenyl)sulfane 3aa in the absence of catalyst. When using 5 mol% of
NiCl2 without involving a NHC ligand, 35% of 3aa could be obtained (entry 1). After
applying 10 mol% NHC ligands L1-L6, the reaction readily formed the respective
nickel bis-carbene complexes. As compared to NiCl2, the in-situ generated Ni
(II)-NHC compounds showed much better solubility in the reaction system. However,
different ligand precursors displayed very different catalytic activities (entries 2-7). It
seems that both electronic and steric effects of the NHC ligands played important roles
on catalytic performance. For L2 and L3 bearing strong electron-donating p-CH3 and
p-OCH3 groups on the benzene ring, the yields of 3aa were lower than that using
merely NiCl2 (entries 3 and 4). This may be due to the strong electron-donating ability
of L2 and L3, leading to a strong decrease of Lewis acidity of the Ni center. For Ni
(II)-NHC L1 without a functional group on the NHC ligand, the reaction showed a
comparable 3aa yield as when using NiCl2 (entry 2). Ni (II)-NHC (L4) with an
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electron-withdrawing p-Cl group resulted in the highest 3aa yield (53%, entry 5), and
Ni (II)-NHC(L5) with two Cl groups led to 50 % of 3aa (entry 6). Owing to both the
strong electron-donating ability and steric hindrance of a tert-butyl group, only 20% of
3aa was obtained when using Ni(II)-NHC (L6) (entry 7). When reducing the catalyst
amount from 5 to 3 mol%, the product yield was also significantly decreased (entry 8).
The reaction was further optimized by using different solvents (entries 5, 9, 10). DMF
proved to be the most favorable solvent.
Table 1. C-S cross-coupling of 4-bromotoluene with butanethiol catalyzed by Ni (II)-NHCs.a
Entry
1
Ligands
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DME
DMF
DMF
DMF
DMF
Base (equiv.)
KOtBu (1.5)
KOtBu (1.5)
KOtBu (1.5)
KOtBu (1.5)
KOtBu (1.5)
KOtBu (1.5)
KOtBu (1.5)
KOtBu (1.5)
KOtBu (1.5)
KOtBu (1.5)
NaH (1.5)
Yield (%)b
35
36
-
2
L1
L2
L3
L4
L5
L6
L4
L4
L4
L4
L4
L4
L4
3
34
4
28
5
53c (50)d
50
6
7
20
8e
9
26
36
10
11
12
13
14
trace
25
K2CO3 (1.5)
NaOtBu (1.5)
KOH (1.5)
23
39
48
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15
16
17f
DMF
DMF
DMF
KOtBu (1.0)
KOtBu (2.0)
KOtBu (1.5)
27
53
39
L4
L4
L4
a Reaction conditions: 4-bromotoluene (1.0mmol), butanethiol (1.1 mmol), NiCl2 (5 mol%), ligand
b
c
(10 mol%), and base in 3 mL solvent at 135 ºC for 3 d under N2 protection; GC yields; 13% of
d
f
1,2-dibutyldisulfanewas isolated; Isolated yield; e 3 mol% of Ni-NHC (L4) was applied. The
reaction was carried out using isolated complex Ni-NHC (L4) as the catalyst.
Further studies indicated that both the type and amount of bases affect the reaction
yields (entries 5, 11-16). Most examined bases proved to be effective, with KOtBu
leading to the highest product yield. Decreasing the KOt Bu amount, the product yield
was also decreased (entries 15). The introduction of 1.5 equiv. of KOt Bu is necessary
to complete the examined coupling reaction. Finally, the reaction using isolated
Ni-NHC(L4) showed lower activity than that of in-situ generated Ni-NHC(L4)
catalyzed process. Accordingly, the optimal reaction condition for the desired C-S
cross-coupling turned out to be 5 mol % of NiCl2, 10 mol% of NHC ligand, 1.5 eq. of
KOt Bu at 135°C in DMF under N2 protection. It should be noted that ca. 13 % of 1,
2-dibutyldisulfane could be isolated under optimal conditions (entry 5). This provided
helpful information concerning the mechanism (vide infra).
The substrate scope was further studied under the best reaction conditions found
(Table 2). In general, the catalytic cross-coupling is effective for a variety of aryl
bromides. The desired thioethers were achieved in moderate to good yields for a
variety of alkyl thiols. Aryl bromides bearing different electron-donating or
withdrawing groups were examined. Aryl bromides bearing electron-withdrawing
groups such as nitro and trifluoromethyl groups (electron poor aryl bromides) resulted
in higher than 95% of thioethers. However, the electron rich methyl or methoxyl aryl
bromides led to a lower product yield (50-70%). The weak electron-withdrawing
fluoro substituted aryl bromides also resulted in a moderate to good product yield.
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Coupling of chlorobenzene with butanethiol gave 40% of butylphenylthioether 3ak, a
lower yield than that obtained when using bromobenzene (63%).
Table 2.C-S cross-coupling of aryl halides with thiols catalyzed by Ni (II)-NHC (L4).a,b
aReaction conditions: aryl halide (1.0 mmol), thiol (1.1 mmol), NiCl2 (5 mol%), L4
b
(10 mol%), KOt Bu (1.5 eq.) in 3 mL of DMF at 135 ºC for 3 d under N2 protection;
Isolated yields.
Good thioether yields were also achieved for bromonaphthalenes and pyridine bromide
under optimal conditions. Moreover, the cross-coupling proved to be easier when aryl thiol is
used instead of alkyl thiol. It can be seen that coupling of p-methyl bromobenzene with
para-chloro or methyl substituted thiolphenol affords 80% and 85% of product yield
respectively.
Mechanistic considerations
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31-33
Based on literature precedents8-11,
and experimental observations, a possible
mechanism for the Ni (II)-NHC catalyzed C-S cross-coupling is proposed in Scheme 2. First,
a ligand exchange may occur between RS and X of the Ni (II)-NHC catalyst A, forming an
intermediate B. B undergoes reductive elimination to form a Ni (0) species, which is assumed
to be the real active species in catalysis. The observation of 13% of 1, 2-dibutyldisulfane gave
solid evidence for such an assumption (Table 1, entry 5). Subsequent oxidative addition of
ArX to C affords an intermediate D. Further ligand exchanging of D with RSH leads to the
formation of an intermediate E. E undergoes reductive elimination and transfers back to C,
forming the desired thioether product.
Scheme 2. Possible mechanism for the Ni (II)-NHC catalyzed C-S cross-coupling.
Experimental Section
General procedure for the coupling reaction. In a typical procedure, NiCl2 (6.5 mg, 0.05
mmol), NHC ligand precursor L4 (35 mg, 0.1 mmol), KOtBu (168 mg, 1.5 mmol) were added
to a Schlenk tube under an atmosphere of nitrogen, DMF (3 mL) was then injected and stirred.
After 30 minutes, aryl halide (1.0 mmol) and thiol (1.1 mmol) were injected, and the mixture
was immediately heated to 135°C under vigorous stirring. After the reaction, the mixture was
cooled to room temperature and quenched by addition of distilled water. The aqueous phase
was extracted with ethyl acetate for three times. The combined organic layers were dried with
MgSO4, and the sample was used for GC analysis. The sample solution was further
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evaporated under vacuum to remove the solvent. The obtained crude product was purified by
column chromatography (eluent, petroleum) on silica gel to afford the desired thioethers.
Conclusions
In conclusion, C-S cross-coupling of aryl halides with alkyl thiols catalyzed by in-situ
generated Ni (II)-NHCs is described. The examined Ni (II)-NHC complexes are efficient
catalysts for the coupling of various aryl halides. Both electronic and steric effects of
functional groups on the aromatic ring of the NHC ligands affect the catalytic performance of
Ni (II)-NHCs significantly. In the coupling reaction, a reductive elimination of Ni (II)-NHC
complex may initially occur, forming an Ni (0) species, which is assumed to be the real active
species. Similar to other nickel or palladium catalyzed coupling reactions, the active Ni (0)
species may further undergo oxidative addition with ArX, the ligand exchanges of Ar-Ni-X
with RSH, and finally reductive elimination of Ar-Ni-SR to form the desired Ar-SR coupling
product.
Acknowledgements
M.D.Z thanks the National Science Foundation of China (21101085), Natural Science
Foundation of Liaoning Province (2015020196), Fushun Science & Technology Program
(FSKJHT 201423), Liaoning Excellent Talents Program in University (LJQ2012031), and
Talent Scientific Research Fund of LSHU (No. 2016XJJ-006) for the financial supports.
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Nickel (II) N-heterocyclic carbene complex has been applied as efficient catalyst for the C-S
cross-coupling of aryl halides with alkyl thiols, affording various alkylphenyl thioethers as the
coupling products.
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Highlights
C-S cross-coupling catalyzed by in situ generated Ni (II)-NHCs

 The C-S coupling showed good catalytic activity towards various aryl halides
 The formation of Ni (II)-NHCs were proven by X-ray single crystal structures
12