A nickel precatalyst for efficient cross-coupling reactions of aryl tosylates with arylboronic acids: Vital role of dppf

Article abstract of DOI:10.1016/j.tet.2014.04.059

An air-stable and easy-to-handle nickel precatalyst, (9-phenanthrenyl) Ni(II)(PPh₃)₂Cl, was examined for the cross-coupling reactions of aryl tosylates with arylboronic acids. Under the optimized reaction conditions, the catalytic system tolerates a wide range of activated, neutral and deactivated substrates. The selectivity of this cross-coupling reaction towards aryl tosylates and arylboronic acids has been investigated. It is proposed that ligand 1,1′-bis(diphenylphosphino)ferrocene (dppf) plays a key role in the coupling by enforcing a cis geometry in key intermediates and the active Ni(0) species.

Full text of DOI:10.1016/j.tet.2014.04.059

Tetrahedron 70 (2014) 3854e3858
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Tetrahedron
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A nickel precatalyst for efficient cross-coupling reactions of aryl
tosylates with arylboronic acids: vital role of dppf
*
Feng Hu, Xiangyang Lei
Department of Chemistry & Biochemistry, Lamar University, P.O. Box 10022, Beaumont, TX 77710, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An air-stable and easy-to-handle nickel precatalyst, (9-phenanthrenyl)Ni(II)(PPh3)2Cl, was examined for
the cross-coupling reactions of aryl tosylates with arylboronic acids. Under the optimized reaction
conditions, the catalytic system tolerates a wide range of activated, neutral and deactivated substrates.
The selectivity of this cross-coupling reaction towards aryl tosylates and arylboronic acids has been
investigated. It is proposed that ligand 1,10-bis(diphenylphosphino)ferrocene (dppf) plays a key role in
the coupling by enforcing a cis geometry in key intermediates and the active Ni(0) species.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 19 February 2014
Received in revised form 20 April 2014
Accepted 21 April 2014
Available online 30 April 2014
Keywords:
Nickel precatalyst
Cross-coupling reaction
Aryl tosylates
Arylboronic acids
1. Introduction
chosen as a model reaction to optimize the reaction conditions.
According to the reported Ni-catalyzed Suzuki reactions, the ad-
Transition metal-catalyzed SuzukieMiyaura cross-coupling is
one of the most commonly used reactions in the construction of
CeC bonds, in which the formation of biaryl/polyaryl motifs is
particularly valuable due to its significance in biologically active
molecules and chemical materials.1e4 Pd catalysts have been well
studied in this field.5,6 In the recent decades, however, Ni-based
catalytic systems have attracted considerable attention due to
their lower cost, high reactivity and lower toxicity.7e13 In this
context, the electrophilic substrates involve aryl halides, tosylates,
mesylates as well as less common carboxylates, carbamates and
sulfamates.7,14e18 Among them, aryl tosylates have been regarded
as excellent substrates due to their high reactivity and wide avail-
dition of excess phosphine ligand is essential to stabilize the in situ
generated Ni(0) catalyst and the intermediate aryl nickel species
during the entire catalytic cycle.27 Therefore, as a regular pro-
cedure, some common commercially available ligands were
screened. As shown in Table 1, ligand 1,10-bis(diphenylphosphino)
ferrocene (dppf) was the most efficient one with the order of li-
gand efficiency of dppf>PPh3>PCy3>1,3-bis(diphenylphosphino)
propane (dppp) when other reaction conditions were the same
(entries 1e4). Bases K2CO3 and CsF were more efficient than
K3PO4, Cs2CO3 and Na2CO3 when the coupling reaction was carried
out in toluene with dppf as ligand (entries 4e8). Although K2CO3
and CsF showed the same efficiency, K2CO3 was chosen for further
study due to its availability and relatively low price. Among tolu-
ene, THF, DMF, EtOH, MeCN and 1,4-dioxane, toluene was the best
choice for solvent (entries 4 and 9e13). A short reaction time of
20 h resulted in a yield of 78%, much lower than 95% when the
reaction lasted for 30 h (entries 4 and 14). Moreover, the yield
decreased from 95% to 43% when the catalyst load was reduced
from 5.0 mol % to 2.5 mol % (entries 4 and 15), which indicated that
a load of 5.0 mol % of precatalyst 1 was needed to maintain its
efficiency. In all cases 2e3% of biphenyl formed by homo-coupling
of phenylboronic acid was observed. It should be pointed out that
due to the consumption of arylboronic acid in its homo-coupling
and in the precatalyst activation process,25 a slight excess of
arylboronic acid over aryl tosylate was required in the cross-
coupling reaction. Finally, the optimal reaction conditions were
set as entry 4 in Table 1.
ability from phenols.19e22 Recently, Ni(II)
s-aryl complexes, which
are air-stable and easy-to-handle, have shown high efficiency as
precatalysts in various cross-coupling reactions.16,20,23e25 Herein,
we report the application of (9-phenanthrenyl)Ni(II)(PPh3)2Cl (1) as
a precatalyst in the cross-coupling reactions of aryl tosylates with
arylboronic acids.
2. Results and discussion
Precatalyst 1 was easily prepared according to the reported
procedure.26 In the preliminary studies, as shown in Table 1, the
coupling reaction of tosylate 2a with phenylboronic acid (3a) was
* Corresponding author. E-mail address: xlei@lamar.edu (X. Lei).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.04.059

F. Hu, X. Lei / Tetrahedron 70 (2014) 3854e3858
3855
Table 1
Optimization of reaction conditionsa
Entry
Ligand
Base
Solvent
Time (h)
Yieldb (%)
c
1
2
3
4
5
6
7
8
PPh3
PCy3
K2CO3
K2CO3
K2CO3
K2CO3
CsF
K3PO4
Cs2CO3
Na2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
DMF
EtOH
MeCN
1,4-Dioxane
Toluene
Toluene
30
30
30
30
30
30
30
30
30
30
30
30
30
20
30
72
40
27
95
95
90
89
15
58
8
13
41
7
78
43
c
dppp
dppf
dppf
dppf
dppf
dppf
dppf
dppf
dppf
dppf
dppf
dppf
dppf
9d
10d
11d
12d
13d
14
15e
a
Reaction conditions: 2a (1.0 mmol), 3a (1.2 mmol), 1 (0.05 mmol), ligand (0.05 mmol), base (3.0 mmol), solvent (3 mL), 110 ꢀC.
Determined by GC using hexadecane as the internal standard.
0.10 mmol.
100 ꢀC.
b
c
d
e
1 (0.025 mmol) and dppf (0.025 mmol).
With the optimized catalytic system in hand, we explored the
Table 2
Scope of aryl tosylatesa
scope of aryl tosylates by examining the coupling reactions of
phenylboronic acid with aryl tosylates with various electronic and
steric properties. During this study the reactions were monitored
by thin-layer chromatography. When the reaction was judged
complete by the disappearance of aryl tosylate from the reaction
mixture, it was stopped. As shown in Table 2, aryl tosylates bearing
electron-donating groups, such as methoxy, methyl and acetyla-
mino groups can efficiently couple with phenylboronic acid to yield
the corresponding biaryls in good to excellent yields (68e95%,
entries 1e6). Aryl tosylates with electron-withdrawing groups also
gave the corresponding biaryls in good to excellent yields (70e97%,
entries 7e15) except for the nitro-substituted aryl tosylate (entry
16), which didn’t yield any detectable cross-coupling product at all.
This is because that the catalyst may form a stable (nitroso)nick-
el(II) species and lose its activity.28,29 The successful coupling of 4-
formylphenyl tosylate with phenylboronic acid (entry 11) indicates
that our catalytic system is more compatible than that of a similar
Entry
1
Ar-OTs
Time (h)
30
Product
Yieldb (%)
93
2
3
24
24
95
92
4
5
24
18
90
84
catalytic system using a Ni(II)
s
-aryl complex as precatalyst.23 In
addition, pyridyl and quinolyl tosylates, respectively, were coupled
with phenylboronic acid in good to excellent yields (86% and 97%,
entries 17 and 18). This catalytic protocol was also efficient for the
formation of polyaryls as indicated by the successful coupling of
ditosylates with phenylboronic acid (entries 19 and 20). The cata-
lytic system is not very sensitive to the steric hindrance of aryl
tosylates with relatively small substituents, such as methyl and
acetyl groups, as their ortho-, meta- and para-substituted isomers
gave similar yields (entries 2e4 and 13e15). More obvious steric
effects were observed under more bulky situations (entries 6, 9 and
19).
Next, the cross-coupling reactions of 4-methoxyphenyl tosylate
(2a) with various arylboronic acids were examined to determine
the scope of arylboronic acids, and the results are summarized in
Table 3. Phenylboronic acids bearing electron-donating groups and
naphthylboronic acids were successfully coupled with 4-
methoxyphenyl tosylate to give the cross-coupling products in
good to excellent yields (83e92%, entries 1e6). Arylboronic acids
bearing weak electron-withdrawing groups, such as the fluoro and
6
30
68
7
8
12
30
92
78
9
30
70
(continued on next page)

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F. Hu, X. Lei / Tetrahedron 70 (2014) 3854e3858
Table 2 (continued )
Table 3
Scope of arylboronic acidsa
Entry
Ar-OTs
Time (h)
20
Product
Yieldb (%)
87
10
Entry
1
ArB(OH)2
Product
Yieldb (%)
90
11
12
13
20
15
30
95
97
90
2
3
87
83
4
5
88
92
14
15
18
24
95
90
6
92
81
16
17
30
12
0
7
8
86
88
42c
28d
18
18
98
80
9
78
12c
41d
19c
18
18
10
11
0
0
20c
90
a
Reaction conditions:
2
(1.0 mmol), 3a (1.2 mmol),
1
(0.05 mmol), dppf
(0.05 mmol), K2CO3 (3.0 mmol), toluene (3 mL), 110 ꢀC .
12
0
b
Isolated yields.
3a (2.4 mmol) was used.
c
a
Reaction conditions: 2a (1.0 mmol),
3
(1.2 mmol),
1
(0.05 mmol), dppf
(0.05 mmol), K2CO3 (3.0 mmol), toluene (3 mL), 110 ꢀC, 30 h.
b
Isolated yields.
PPh3 (0.10 mmol) .
dppp (0.05 mmol).
methoxycarbonyl groups also produced the corresponding diaryls
in good yields under the optimal reaction conditions (78e88%,
entries 7e9), though strong electron-withdrawing groups, such as
the formyl and cyano groups significantly deactivated the corre-
sponding arylboronic acids and no cross-coupling product was
obtained (entries 10 and 11). Likewise, the coupling of electron-
deficient pyridin-4-ylboronic acid with 4-methoxyphenyl tosylate
did not yield any detectable cross-coupling product (entry 12).
However, it is likely that biaryls 4d0ef0 can be synthesized by the
cross-coupling reactions of electron-deficient 4-formylphenyl
tosylate, 4-cyanophenyl tosylate and 4-pyridyl tosylate with
electron-rich 4-methoxyphenylboronic acid, respectively, under
the optimal reaction conditions. Steric effects were observed as the
yields followed the sequence of p-tolylboronic acid>m-tolylboronic
acid>o-tolylboronic acid (entries 1e3). It should be pointed out
that dppf proved again to be the optimal ligand as it gave much
higher yields than PPh3 and dppp in the same reactions under
otherwise same reaction conditions (entries 8 and 9).
c
d
In order to determine the selectivity of this cross-coupling re-
action towards aryl tosylates, an equimolar mixture of tosylates 2a
and 2l was treated with an excess of phenylboronic acid (3a) under
the optimal reaction conditions. As shown in Scheme 1, cross-
coupling products 4a and 4l were obtained in 44% and 42%
yields, respectively, using tosylates 2a and 2l. Meanwhile, the in-
termolecular competition between arylboronic acids 3a and 3j to
couple with tosylate 2a, as shown in Scheme 2, yielded solely biaryl
4a in an 84% yield with no detectable biaryl 4c0, though arylboronic
acid 3j can smoothly couple with tosylate 2a on its own (entry 9 in
Table 3). These results indicate that the efficiency of the cross-
coupling reaction depends on electronic factors in the arylboronic
acids and not the aryl tosylates. This is probably because that
arylboronic acids participate in both the precatalyst activation

F. Hu, X. Lei / Tetrahedron 70 (2014) 3854e3858
3857
Scheme 1. Intermolecular competition between aryl tosylates.
Scheme 2. Intermolecular competition between arylboronic acids.
process and the rate-determining transmetalation step in the main
catalytic cycle,25 and electron-withdrawing groups on arylboronic
acids may retard these two steps.
arylboronic acids. The catalytic system is compatible with various
aryl tosylates bearing electron-donating or electron-withdrawing
groups. Coupling with arylboronic acids with weak electron-
withdrawing groups under the optimal reaction conditions also
gave the corresponding diaryls in good yields, though strong
electron-withdrawing groups significantly deactivated the corre-
sponding arylboronic acids and no cross-coupling product was
obtained. This coupling reaction is highly selective towards aryl-
boronic acids, but not selective towards aryl tosylates. It is proposed
that ligand dppf plays a key role in the coupling by enforcing a cis
geometry in key intermediates and the active Ni(0) species. All
isolated cross-coupled biaryl products have been characterized by
1H and 13C NMR, and their spectral data are consistent with those
reported.
Similar to other cross-coupling reactions using Ni(II)
s-aryl
complexes as precatalysts,16,25 the catalytic mechanism is believed
to start with the activation of precatalyst 1 to form the active Ni(0)
species, and the subsequent main catalytic cycle involves oxidative
addition, transmetalation and reductive elimination. Complex 5,
shown in Fig. 1, is believed to be the active Ni(0) species. It is pro-
posed that precatalyst 1 has ligand exchange with dppf to form
complex 6, which undergoes transmetalation with activated aryl-
boronic acid to give complex 7. The reductive elimination of com-
plex 7 yields active Ni(0) species 5 as well as side product 9-
arylphenanthrene (8), which has been isolated and character-
ized.25 The argument of complex 5 as the active Ni(0) species is
supported by the results of Hartwig that the reaction of dppf-
ligated cinnamylnickel(II) chloride with 2-thienyl boronic acid
with K3PO4 as a base in THF in the presence of 1 equiv of dppf
generated (dppf)2Ni(0) quantitatively in 10 min at room tempera-
ture.30 It is further supported by the recent results reported by
Buchwald that complex (Ph3P)2Ni(o-tolyl)Cl can easily exchange its
two triphenylphosphine ligands with dppf in THF at room tem-
perature to form (dppf)Ni(o-tolyl)Cl in an 83% yield, and the latter is
an efficient precatalyst for the amination of a variety of aryl and
heteroaryl electrophiles.15 This argument is also supported by our
experimental results that dppf is a more efficient ligand than PPh3,
PCy3 and dppp under otherwise the same reaction conditions
(entries 1e4 in Table 1, entries 8 and 9 in Table 3). It is believed that
ligand dppf plays a key role in the precatalyst activation process by
enforcing a cis geometry of the 9-phenanthrenyl and chloro or aryl
groups in complexes 6 and 7, respectively, and facilitating the re-
ductive elimination step. The cis geometry of complex 5 is benefi-
cial to the subsequent main catalytic cycle in the same way.
4. Experimental section
4.1. General
Precatalyst 1 was prepared according to a literature method.26
Aryl tosylates were prepared according to our unpublished pro-
cedures.31 Bases (Na2CO3, K2CO3, Cs2CO3 and K3PO4) were ground
into powder and dried under vacuum at 125 ꢀC for 4 h prior to use.
Toluene and THF were refluxed over Na/benzophenone and dis-
tilled under nitrogen, respectively. All other reagents and solvents
were purchased from commercial suppliers and used as received.
NMR spectra were recorded on a Bruker Avance 400 MHz spec-
trometer in CDCl3 and referenced to the residual solvent signals
(1H: 7.26 ppm; 13C: 77.16 ppm). Peaks were characterized as singlet
(s), doublet (d), triplet (t), quartet (q), doublet of doublet (dd),
triplet of triplet (tt) and multiplet (m). An Agilent 6890N Network
Gas Chromatograph, equipped with a capillary column (HP-5) and
a TCD detector, was used to assay the reaction yields for the opti-
Fig. 1. Proposed mechanism for the formation of the active Ni(0) species (Phen¼9-phenanthrenyl).
3. Conclusions
mization of reaction conditions. All glasswares were dried in an
oven at 120 ꢀC for 8 h and cooled under nitrogen atmosphere in
a desiccator before use. Column chromatography was performed
with 300e400 mesh silica gel.
We have demonstrated that complex 1 is an efficient precatalyst
for the SuzukieMiyaura cross-coupling of aryl tosylates with

3858
F. Hu, X. Lei / Tetrahedron 70 (2014) 3854e3858
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4.2. General procedure for the Suzuki cross-coupling
reactions
Aryl tosylate (1.0 mmol), arylboronic acid (1.2 mmol), pre-
catalyst 1 (0.05 mmol), ligand (0.05 mmol) and base (3.0 mmol)
were added to a Schlenk tube equipped with a magnetic stirring
bar, a septum and a reflux condenser. After the tube was evacuated
and refilled with nitrogen gas three times, degassed solvent (3 mL)
was added via a syringe. The reaction mixture was heated to the
described temperature for the required time. After the reaction
cooled to room temperature, water (10 mL) was added to the re-
action mixture. The resulting mixture was extracted with CH2Cl2
(3ꢁ10 mL). The combined organic layers were dried over anhydrous
Na2SO4, filtered and concentrated to dryness. The remaining resi-
due was analyzed by GC (Table 1) or purified by flash chromatog-
raphy on silica gel with ethyl acetateehexanes (0e20% ethyl acetate
in hexanes) of as eluents (Tables 2 and 3).
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We thank the Robert A. Welch Foundation (Grant No. V-1815)
for financial support of this research.
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31. Note: we have discovered a convenient and environmentally friendly method
to synthesize aryl tosylates. The manuscript based on this research is in prep-
aration for publication.
Supplementary data
Experimental procedures, spectra data and NMR spectra. Sup-
plementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.04.059.
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