LiCl-Accelerated Nickel Catalyzed Cross-Coupling of Aryl Tosylates with the Aryl Grignard Reagents

Article abstract of DOI:10.1134/S1070363219120405

A mild coupling reaction catalyzed by Ni(acac)₂-L4 has been studied. The catalyst acts efficiently in the reaction of biaryl coupling between various electrophiles and common or functionalized aryl Grignard reagents with high functional group tolerance. The study demonstrates that LiCl acts as an essential component in efficient cross-coupling by accelerating reduction of Ni(II) to Ni(0). The new catalytic system for selective couplings of aryl tosylates with aryl chlorides has been developed.

Full text of DOI:10.1134/S1070363219120405

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 12, pp. 2591–2596. © Pleiades Publishing, Ltd., 2019.
LiCl-Accelerated Nickel Catalyzed Cross-Coupling
of Aryl Tosylates with the Aryl Grignard Reagents
Xiao-Yun Hea,*, Zhi-Xun Zhanga, Chun-Jing Lia, and Yan Lia,**
a Department of Chemistry and Environmental Engineering, Hebei Chemical and Pharmaceutical College, Shijiazhuang, 050026 China
e-mail: *61027391@qq.com; **hebeihuagongyy@163.com
Received November 12, 2019; revised December 18, 2019; accepted December 19, 2019
Abstract—A mild coupling reaction catalyzed by Ni(acac)2–L4 has been studied. The catalyst acts efficiently in
the reaction of biaryl coupling between various electrophiles and common or functionalized aryl Grignard reagents
with high functional group tolerance. The study demonstrates that LiCl acts as an essential component in efficient
cross-coupling by accelerating reduction of Ni(II) to Ni(0). The new catalytic system for selective couplings of
aryl tosylates with aryl chlorides has been developed.
Keywords: aryl tosylates, C–C coupling, Ni(II)-catalyst, LiCl
DOI: 10.1134/S1070363219120405
INTRODUCTION
and the reaction of methylphenyltosylate with PhMgBr
was carried out for optimizing the reaction conditions
(Table 1). The effect of the nickel containing components
on the process was significant (Table 1). Ni(cod)2 and
Ni(acac)2 were found to be the most active ones leading
to the yields of 64% and 65% respectively without for-
mation of self-coupling products (Table 1, entries 1, 6).
Comparison of the experimental results in combination
with cost effectiveness singled out Ni(acac)2 as the most
promising system. Evaluation of the sulfonate leaving
groups, was screened with a variety of p-carbomethoxy-
phenyl sulfonates. Trifluoromethane sulfonate led to high
yield of p-toluenesulfonate (Table 1, entry 10). Benzene-
sulfonate demonstrated low leaving ability compared to
p-toluenesulfonate (Table 1, entry 11), and the low yield
was achieved for the methanesulfonate leaving group
(Table 1, entry 12).
Cross-coupling reactions catalyzed by transition met-
als currently are among the most important synthetic
methods [1, 2]. Application of inexpensive and abun-
dant nickel reagents instead of those of palladium for
the cross-coupling reactions has gained close attention
[3]. Traditionally, aryl iodides, aryl bromides, triflates
[4–6], and some more are used as organic electrophiles
in cross-coupling processes [7–12]. Application of aryl
tosylates in cross-coupling reactions became widely used
reagents due to their availability, inexpensive synthesis,
and stability towards hydrolysis [13]. Nevertheless, this
greater stability of the tosylates made those less reactive
in nickel-catalyzed processes, particularly in the course
of the first step of the catalytic cycle. For this reason
the cross-coupling reactions were carried out with the
catalysts bearing a bulky electron-rich phosphine ligand
or a bulky N-heterocyclic carbene (NHC), that could
facilitate formation of coordinatively unsaturated, highly
nucleophilic catalytic species [7]. Lately, we have re-
ported application of a variety of tertiary phosphines [14]
as excellent phosphine ligands.
A variety of phosphine ligands were also screened.
The L1 and L2 ligands did not seem to be superior to
PPh3 (Table 2, entry 1, 2), whereas L3, L4 and L5 that
contained the tert-butyl and cyclohexyl groups were
characterized by high activity, particularly L4 (Table 2,
entries 3–5). According to the data presented in Table 2
(entries 6, 7), the yield lowered down significantly upon
diminishing the equivalent of PhMgBr.
Herein, we report the study of the Grignard reagents
coupling with aryl tosylates involving the electron-rich
phosphine ligand L4, which allowed to make several
improvements in the reaction procedure.
According to the following step of the study, applica-
tion of additives, such as LiBr, LiCl or MgCl2, gave the
cross-coupling products in high yields (Table 3, entries
1–3). Surprisingly, the cross-coupling reaction yield
was significantly improved by addition of anhydrous
RESULTS AND DISCUSSION
To start with, we combined the simple ligand PPh3
with different nickel complexes in the catalytic system,
2591

2592
XIAO-YUN HE et al.
Table 1. Effect of Ni(II)-catalysts on the cross-coupling reactiona
Ni catalyst, 1%
PPh3, 2%
EtMgBr, 1.0 equiv
additives
OR +
MgBr
+
THF, 25q
C
1a
2a
3a
Time, h
4a
Yield, %b
Entry
R
Ni catalyst (1 mol %)
3a
64
18
6
4a
0
1
2
OTs
OTs
Ni(cod)2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
NiCl2
4
3
OTs
NiCO3.H2O
NiCl.6H2O
Ni(OAc)2·4H2O
Ni(acac)2
0
4
OTs
13
21
65
48
35
47
68
61
47
2
5
OTs
5
6
OTs
0
7
OTs
NiCl2(dme)
Ni(Pph3)2Cl2
NiCl2(dppp)
Ni(acac)2
25
30
18
1
8
OTs
9
OTs
10
11
12
OTf
OSO2ph
OMs
Ni(acac)2
2
Ni(acac)2
3
a
Reaction conditions: sulfonate (1.0 equiv), the Grignard reagent (1.3 equiv), Ni(cod)2 1%, L4 (2%), LiCl (1.3 equiv), THF
(3 mL). b Determined by GC using n-dodecane as an internal standard.
LiCl [15]. The solvents used were also important in the
present method. Medium yield was achieved in ether
medium (Table 3, entry 4). Application of toluene gave
almost no products (Table 3, entry 5), as well as aprotic
polar solvents, such as dioxane and 1,2-dimethoxyethane
(DME) (Table 3, entries 6, 7). Obviously, the amount of
LiCl (Table 3, entries 8, 9) influenced upon the yield of
the process, though not significantly. Higher temperature
supported formation of self-coupling products (Table 3,
entry 10). Longer process time elevated the reaction
outcome (Table 3, entry 11).
3j). The reaction of functionalized tosylates coupled with
common aryl Grignard reagents completed within 5–6 h
(3k, 3m, 3o). The functionalized Grignard reagents with
an electron-withdrawing group demonstrated low reactiv-
ity (3n, 3p–3s). On the other hand, the coupling process
of heteroaryl tosylates proceeded quite efficiently, second
only to normal aryl electrophiles (3t–3z).
The accumulated data indicated that diarylation or
polyarylation could be achieved upon catalysis by nickel
containing compounds. As outlined in Scheme 1, the
terphenyl intermediate 6 was synthesized on a multigram
scale by selective biaryl coupling. The biaryl synthesis
based on 4-ClC6H4OTs and the aryl Grignard reagent
proceeded selectively at the C–Cl bond providing com-
pound 5 (the compound had been reported in literature)
in 89% yield (Scheme 1).
A wide range of (hetero)aryl functionalized tosylates
was coupled with several representative (hetero)aryl func-
tionalized Grignard reagents under the optimized condi-
tions (Table 4). Various aryl electrophiles were tested with
different aryl Grignard reagents 3a–3h (Table 4). The
tested tosylates coupled well furnishing the correspond-
ing biaryl products in high yields. Steric hindrance of the
ortho substituted aryl Grignard reagents affected the reac-
tion progress, the coupling reaction of 2,6-dimethylphenyl
Grignard reagent proceeded with relatively low yields (3i,
EXPERIMENTAL
Most of the reagents used were purchased from
Aldrich and Alfa Aesar. Some common reagents were
available commercially elsewhere, and used without
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 12 2019

LiCl-ACCELERATED NICKEL CATALYZED CROSS-COUPLING OF ARYL TOSYLATES
Table 2. Effect of ligands on the cross-coupling reaction
2593
N(acac)2,
1%
ligand, 2%
EtMgBr, 1.0 equiv
LiCl
OTs
+
MgBr
+
THF, 25
q
C, 2 h
1a
2a
3a
4a
Yield, %b
Entry
Liganda (2 mol %)
Time, h
3a
46
52
78
82
71
75
84
4a
11
13
0
L1
L2
L3
L4
L5
L4
L4
1
2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
3
4
0
5
0
6c
7d
0
0
a The list of ligands: 1-[bis(4-methoxyphenyl)phosphanyl]naphthalene (L1); biphenyl-2-yl-bis(4-methoxyphenyl)phosphane (L2),
tert-butylcyclohexylphenylphosphane (L3), tert-butylcyclohexyl-(3,5-dimethylphenyl)phosphane (L4), tert-butylcyclohexyl-(4-
triflfluoromethylphenyl)phosphane (L5). b Determined by GC using n-dodecane as an internal standard. c 1.1 equiv of PhMgBr, 1.5 equiv of
PhMgBr. d 1.2 equiv of PhMgBr; 1.5 equiv of PhMgBr.
further purification, unless otherwise indicated. All reac-
tions were carried out under the atmosphere of Ar in dry
solvents under anhydrous conditions, unless otherwise
noted. THF was dried over alumina under the atmosphere
of N2 using a Grubbs-type solvent purification system.
All arylmagnesium bromides were prepared from the
corresponding aryl bromides and magnesium (turn-
ings). All aryl tosylates were prepared according to the
common procedures. L1–L5 were prepared according
to literature procedure [15]. The products were purified
by column chromatography on silica gel 300–400 mesh
under the atmosphere of argon. Spectroscopy data of the
known compounds matched the data reported in the cor-
responding references. Reactions were monitored by an
Agilent GC Series 6890N and a GCMS 7890A. 1H and
13C NMR spectra were measured on a Bruker 400 M
spectrometer using TMS as an internal standard and
CDCl3 as a solvent.
Synthesis of the Grignard reagents. The aryl Gri-
gnard reagents such as phenylmagnesium or 4-methyl-
Scheme 1. One-pot synthesis of asymmetric p-terphenyls.
1%
N(acac)2 ,
,
L4 2%
EtMgBr, 1.0 equiv
LiCl, 1.3 equiv
Cl
+
OTs
MgBr
Cl
q
C, 2 h
THF, 25
5
H
N
CH3
H
N
Cl
CH3
O
1%
L4 2%
N(acac)2 ,
O
,
6
EtMgBr, 1.0 equiv
q
C, 2 h
THF, 25
yield 68%
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 12 2019

2594
XIAO-YUN HE et al.
Table 3. Effect of ligands on the cross-coupling reaction
N(acac)2
, 1%
L4, 2%
EtMgBr, 1.0 equiv
additives
OTs
+
MgBr
+
Solvent, tq
, time
1a
2a
3a
4a
Yield, %a
Entry
Additives (equiv)
Solvent
Time, h
3a
4a
0
1
2
LiBr (1.3)
LiCl (1.3)
MgCl2 (1.3)
LiCl (1.3)
LiCl (1.3)
LiCl (1.3)
LiCl (1.3)
LiCl (1.1)
LiCl (1.5)
LiCl (1.3)
LiCl (1.3)
THF
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.0
89
95 (93)b
THF
0
3
THF
86
0
4
Et2O
45
0
5
Toluene
DME
5
0
6
23
0
7
1,4-Dioxane
THF
53
0
8c
9d
10e
11f
78
8
THF
96
0
THF
81
12
0
THF
96
a Determined by GC using n-dodecane as an internal standard. b Isolated yield is given in parentheses. c 1.1 equiv LiCl. d 1.5 equiv LiCl. e The
reaction mixture was refluxed. f The reaction was run over 2.0 h.
N,N-Diethyl 4-(tosyloxy)benzamide. White solid,
yield 83%. 1H NMR spectrum, δ, ppm: 1.23 (6H, CH3),
2.40 (3H, CH3), 3.31 (2H, CH2), 3.59 (2H, CH2), 7.26
(2H, CH, J = 8.0 Hz), 7.37 (2H, CH, J = 8.3 Hz), 7.45
phenyl magnesium were prepared according to the stan-
dard procedures. 2-Methoxylpyridinyl Grignard reagent
was prepared via bromine−magnesium exchange using
i-PrMgCl. The functionalized aryl Grignard reagents,
such as 2-carbomethoxyphenyl magnesium chloride,
were prepared via iodine- magnesium exchange using
i-PrMgCl.All Grignard reagents were titrated before use.
13
(2H, CH, J = 8.0 Hz), 7.51 (2H, CH, J = 8.3 Hz). C
NMR spectrum, δC, ppm: 13.3, 14.5, 21.7, 39.8, 42.6,
41.7, 128.3 (CH), 128.5 (CH), 129.1 (CH), 129.9 (CH),
131.0, 133.5, 136.6, 140.7, 168.3.
Synthesis of aryl tosylates (general procedure). To
a solution of phenol (0.941 g, 10 mmol) in anhydrous
THF (25 mL) under the atmosphere of argon, KOH
(2.24 g, 40 mmol) was added. The mixture was stirred
for 5 min at room temperature before the addition of p-
toluenesulfonyl chloride (2.29 g, 12 mmol). The reaction
mixture was warmed up to 60°C and stirred until phenol
was consumed. Upon hydrolysis by water (15 mL), the
aqueous layer was extracted with AcOEt (3×15 mL) and
the combined organic layers were washed with water
(2×15 mL) and brine (15 mL), then dried over anhydrous
MgSO4, filtered, concentrated in vacuo, and purified to
afford the corresponding product. All (hetero)aryl tosyl-
ates were prepared according to this synthetic approach
reported in literature, besides N,N-diethyl 4-(tosyloxy)
benzamide which was the new compound.
Nickel-catalyzed biaryl cross-coupling of aryl to-
sylates with the aryl Grignard reagents. General syn-
thesis of compounds 3. In a glove-box, an aryl tosylate
(1 mmol), Ni(acac)2 (1 mol %), LiCl (1.3 equiv), EtMgBr
(1.0 equiv) and L4 (2 mol %) in THF (1 mL) were loaded
in a dried two-neck round-bottom flask. The mixture was
stirred at room temperature for15 min before diluting with
THF (2 mL). The Grignard reagent (1.3 equiv) was added
slowly dropwise, then the flask was sealed, removed from
the glove-box and stirred at 25°C for 2 h. The reaction
progress was monitored by GC using n-dodecane as
the internal standard. Once completed, the reaction was
quenched with saturated NH4Cl followed by extraction
with CH2Cl2 several times. The combined organic lay-
ers were dried over anhydrous MgSO4, concentrated in
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 12 2019

LiCl-ACCELERATED NICKEL CATALYZED CROSS-COUPLING OF ARYL TOSYLATES
2595
Table 4. Ni(II)-catalyzed cross-coupling reaction of the sulfonate group with (hetero)arylmagnesium bromidea
, 1%
N(acac)2
L4, 2%
EtMgBr, 1.0 equiv
LiCl, 1.3 equiv
FG1Ar-FG2
2
FG1
Ar-OTS + FG ArMgBr
THF, 25
qC
Comp. Yield, Comp. Yield, Comp. Yield, Comp. Yield, Comp. Yield, Comp. Yield, Comp. Yield,
no
3a
3b
3c
3d
3e
%
93
81
89
95
90
no
%
78
89
91
53
51
no
3k
3l
%
83b,e
51c
78
no
3p
3q
3r
3s
3t
%
no
3u
3v
3w
3x
3y
%
83
87
83
83
81
no
3z
3β
3δ
3ε
3η
%
83
73d
48
78d
–
no
3θ
3λ
3π
3σ
%
71d
73d
76d
69d
81
35
3f
71d,f
45c,f
77d,e
3g
3h
3i
3m
3n
3o
71d
91b
3j
a The reaction was carried out on 1 mmol, the functionalized Grignard reagent was prepared by I/Mg exchange using i-prMgCl·LiCl and the
concomitant i-PrI was removed. b Ni(cod)2 2%, L4 (4%), 0°C, 5–6 h. c Ni(cod)2 2%, L4 (4%), –20°C, 3.5h. d Ni(cod)2 2%, L4 (4%), –5–0°C,
4–5 h. e 3k, 3σ. The yields were obtained with 2.3 equiv of ArMgX. f 3λ, 3π are the new compounds.
vacuo, and the crude mixture was purified by silica gel
column chromatography.
CH), 7.88 (2H, CH, J = 6.7 Hz). 13C NMR spectrum, δC,
ppm: 21.1, 26.9, 114.2 (CH), 118.9 (CH), 119.7 (CH),
120.3, 122.1 (CH), 126.3, 127.5, 128.1 (CH), 129.1 (CH),
133.5, 138.2, 143.2, 162.7. HRMS (EI): m/z: 301.1474.
Calculated for C21H19NO (301.1467).
Most of thus synthesized products had been reported
earlier, and their spectral data matched those presented
in literature. The products 3λ and 3π were the newly
synthesized compounds.
CONCLUSIONS
4'-N,N-diethylformamide-1,1'-biphenyl-4-car-
boxylic acid methyl ester (3λ). Colorless oil. 1H NMR
spectrum, δ, ppm: 1.21–1.35 (6H, CH3), 3.46 (2H, CH2),
3.53 (2H, CH2), 3.95 (3H, CH3), 7.49 (2H, CH, J =
8.1 Hz), 7.67 (4H, CH, J = 8.2, 5.5 Hz), 8.14 (2H, CH,
J = 8.3 Hz). 13C NMR spectrum, δC, ppm: 13.5, 14.6,
40.2, 42.6, 51.7, 126.3 (CH), 126.7 (CH), 127.1 (CH),
129.4 (CH),130.0, 136.8, 140.6, 144.5, 166.1, 170.7.
HRMS (EI): m/z: 311.1527. Calculated for C19H21NO3
(311.1521).
In summary, as part of our ongoing effort, we have
developed the general and practically sound method
for high-yield cross-coupling of aryl tosylates with
aryl Grignard reagents catalyzed by the Ni(acac)2–L4
system. The reaction has been supported by LiCl. Such
conditions have proven to be highly tolerable for some
sensitive functional groups including ester, cyano and
amide leading to high yields of the target products. Such
advantages of the process as high yield, mild conditions
and low cost make this protocol attractive as an alterna-
tive and complementary to nickel-catalyzed aryl–aryl
cross-coupling reactions.
4'-N,N-diethyl-4-N-methyl-Diphenylformamide
(3π). Yellow solid. 1H NMR spectrum, δ, ppm: 1.20–1.33
(6H, CH3), 3.09 (3H, CH3), 3.48 (2H, CH2), 3.57 (2H,
CH2), 6.01 (1H, NH), 7.35 (2H, CH, J = 7.8 Hz), 7.57–
7.65 (4H, CH), 8.01 (2H, CH, J = 8.0 Hz). 13C NMR
spectrum, δC, ppm: 13.3, 14.7, 26.1, 40.8, 43.9, 127.8
(CH), 128.7 (CH), 131.0 (CH), 135.8, 138.2 (CH), 141.0,
158.9, 162.1, 165.3, 168.2. HRMS (EI): m/z: 310.1687.
Calculated for C19H22N2O2 (310.1681).
FUNDING
The authors gratefully acknowledge the financial sup-
port from Hebei Chemical and Pharmaceutical College
and the key research and development project Foundation
of Hebei Province (17214416). The authors are thank-
ful to Hebei University of Science and Technology for
Agilent GC and GCMS, 1 H and 13C NMR analysis.
4''-Methyl-[1,1':4',1''-terphenyl]-N-methyl-4-car-
boxamide (6). White solid. 1H NMR spectrum, δ, ppm:
2.41(3H, CH3), 3.08 (3H, CH3), 5.81 (1H, NH), 7.29 (2H,
CH, J = 7.2 Hz), 7.33–7.50 (4H, CH), 7.61–7.70 (4H,
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
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XIAO-YUN HE et al.
https://doi.org/10.1021/ja038752r
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